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Expanded Approval for ZYTIGA® for the Treatment of Castration-sensitive Prostate Cancer

On February 7th, the FDA expanded the approval of abiraterone acetate (ZYTIGA®) treatment to patients with high-risk castration sensitive prostate cancer [1]. Abiraterone acetate (AA), marketed by Janssen Biotech Inc., was previously approved in 2011 in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel-containing chemotherapy, which was expanded to any patient with mCRPC in 2014. Prostate cancer is the most common malignancy in men in western countries and accounts for about 28,000 deaths per year in the United States [2]. Androgen deprivation therapy (ADT), or medical castration, is the most common treatment for prostate cancer; however, this technique only limits androgens synthesized in the testes while the pituitary and prostate cancer tissue continues to produce androgens. AA is a small molecule inhibitor of cytochrome P450 17α-hydroxylase (CYP17), an enzyme that plays a key role in the synthesis of endogenous androgens, thus reducing circulating androgen levels in the body and preventing activation of androgen-dependent cancer cells [3].

The extended approval was based on positive results from a randomized phase 3 study that assessed the safety and efficacy of AA and prednisone plus standard ADT vs. ADT alone in the treatment of newly diagnosed castration-sensitive prostate cancer (NCT01715285) [4]. Patients in the AA arm experienced a significantly longer mean overall survival (not reached vs. 34.7 months) and progression free survival (33 vs. 14.8 months) compared to those in the ADT arm [5]. Other benefits experienced in the AA arm included a longer time to chemotherapy and pain progression over patients in the ADT arm [5]. Grade 3 hyperkalemia and hypertension events occurred at a higher rate than standard ADT; however, AA plus prednisone was found to be a well-tolerated regimen with a favorable safety profile. These results confirm the safety and efficacy of AA for the treatment of castration-sensitive prostate cancer and offers a survival advantage to patients with newly diagnosed prostate cancer.

–Zachary Moore

  1. ZYTIGA™ (abiraterone acetate) Tablets 2018. Drugs@FDA: FDA Approved Drug Products 02/07/2018 [cited 2018 April 10]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202379s024lbl.pdf.
  2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 5-29.
  3. Rehman, Y. and J.E. Rosenberg, Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer. Drug Des Devel Ther, 2012. 6: p. 13-8.
  4. A Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Participants With High-Risk, Metastatic Hormone-Naive Prostate Cancer (mHNPC). ClinicalTrials.gov  [cited 2018 April 10]; Available from: https://clinicaltrials.gov/ct2/show/NCT01715285.
  5. Fizazi, K., et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med, 2017. 377(4): p. 352-360.

Tisagenlecleucel for Patients with Relapsed or Refractory Large B-cell Lymphoma

On May 1, 2018, the FDA granted approval to Novartis Pharmaceuticals Corp. to market KYMRIAH® (tisagenlecleucel) for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma, who have already received two or more prior lines of systemic therapy [1]. Tisagenlecleucel is a CD-19-targeted autologous chimeric antigen receptor (CAR) T-cell therapy designed for the treatment of patients with B-cell malignancies (CD-19 expressing cells). It has already been approved in 2017 for the treatment of patients, up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, after a phase 1-2a study concluded with impressive efficacy results [1].

The approval for R/R LBCL was based on the results of a single-arm, open-label, multi-center, phase 2 trial, JULIET, examining the safety and efficacy of tisagenlecleucel therapy for the treatment of adults with R/R LBCL (NCT02445248) [2]. Out of 68  evaluable patients, the overall response rate was 50% and the complete response rate was 32% [1]. The median duration of response experienced was longer in the patients who achieved a complete response than those who achieved only a partial response, not reached vs. 3.4 months, respectively. Despite the impressive efficacy results, safety  concerns were raised as cytokine release syndrome was experienced by 74% of patients on study, three of whom died [1]. Tisagenlecleucel was the first CAR T-cell therapy approved by the FDA and has provided proof-of-concept for future CAR T-cell therapy development.

–Zachary Moore

  1. KYMRIAH™ (tisagenlecleucel) suspension for intravenous infusion. Vaccines, Blood & Biologics May 1, 2018 [cited 2018 May 9]; Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf.
  2. Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET). ClinicalTrials.gov April 17, 2018 [cited 2018 May 9]; Available from: https://clinicaltrials.gov/ct2/show/NCT02445248.

Rucaparib for Maintenance Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

On April 6, 2018, the FDA approved RUBRACA® (rucaparib), marketed by Clovis Oncology Inc., as a maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy [1]. There are about 22,000 incidences of ovarian cancer per year in the United States (US) and ovarian cancer is the fifth leading cause of cancer-related deaths amongst US women [2]. Standard frontline treatment for ovarian cancer is platinum-based chemotherapy; however, most patients who respond to treatment eventually relapse. Thus, there is a need for effective maintenance therapies that can prevent or prolong post-platinum relapse. Rucaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that works by preventing DNA repair in cells with homologous recombination deficiency (HRD) [3]. It was previously approved in December of 2016 for the third-line treatment of patients with deleterious BRCA1 or BRCA2 mutation-positive ovarian cancer [4]. BRCA1/2 proteins function as tumor suppressors by supporting homologous recombination, and therefore cells with dysfunctional BRCA1/2 proteins are sensitive to PARP inhibition [5].

The recent approval was based on the results of a randomized phase 3 trial, ARIEL3, assessing rucaparib as a maintenance therapy for patients with platinum-sensitive high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, who had received at least two prior platinum-based chemotherapy regimens (NCT01968213) [6]. Patients were randomized 2:1 to receive rucaparib or placebo and were stratified based on BRCA1/2 mutation and HRD status. Median progression-free survival (mPFS) in the intent-to-treat population was doubled in patients receiving rucaparib over placebo, 10.8 vs. 5.4 months, respectively [3]. Additional benefit was experienced by patients with BRCA1/2 mutant-positive or HRD-positive disease with a mPFS of 16.6 months and 13.6 months, respectively [3]. The safety profile of rucaparib therapy was found to be tolerable with the most common grade 3 or 4 adverse events being anemia (19%) and increased liver enzymes (10%).

–Zachary Moore

  1. RUBRACA® (rucaparib) tablets, for oral use. Drugs@FDA: FDA Approved Drug Products 04/06/2018 [cited 2018 May 3]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf.
  2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.
  3. Coleman, R.L., et al., Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017. 390(10106): p. 1949-1961.
  4. RUBRACA™ (rucaparib) tablets, for oral use Initial U.S. Approval: 2016 Drugs@FDA: FDA Approved Drug Products  [cited 2018 May 3]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209115s000lbl.pdf.
  5. Lee, J.M., J.A. Ledermann, and E.C. Kohn, PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol, 2014. 25(1): p. 32-40.
  6. A Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer (ARIEL3). ClinicalTrials.gov  [cited 2018 May 3]; Available from: https://clinicaltrials.gov/ct2/show/NCT01968213.

Osimertinib for the Frontline Treatment of EGFR-mutant NSCLC

On April 18, 2018, the FDA expanded approval to AstraZeneca Pharmaceuticals Inc. to market TAGRISSO® (osimertinib) for the treatment of frontline epidermal growth factor receptor (EGFR)-mutant-positive non-small cell lung cancer (NSCLC) [1]. EGFR is a tyrosine kinase receptor that can activate cellular growth and survival pathways and activating mutations in the EGFR gene have been identified in approximately 15-50% of NSCLC adenocarcinoma samples [2]. The most common EGFR alterations found in NSCLC samples include deletions in exon 19 and a single base substitution in exon 21, L858R, which are both sensitive to first- and second-generation tyrosine kinase inhibitors (TKIs) erlotinib (TARCEVA®), gefitinib (IRESSA®), and afatinib (GIOTRIF®) [3]. Unfortunately, almost all patients develop resistance to these therapies within two years, and thus there is a need for therapies that provide durable remissions in patients with EGFR-mutant-positive NSCLC [3]. Osimertinib is a third generation TKI that inhibits common EGFR mutants such as exon 19 deletions and L858R, as well as the TKI-resistant mutant T790M [4]. It was initially approved in 2015 for the treatment of patients with EGFR T790M mutation-positive NSCLC [5].

The expanded approval was based on the results of a randomized phase 3 trial, FLAURA, assessing the safety and efficacy of osimertinib vs. gefitinib or erlotinib in the frontline treatment of EGFR-mutant (exon 19 or L858R) NSCLC (NCT02296125) [6]. Patients in the osimertinib arm experienced a longer progression-free survival than those in the gefitinib/erlotinib arm, 18.9 months vs. 10.2 months, respectively [4]. Additionally, the median duration of response experienced by patients receiving osimertinib was longer at 17.2 months vs. patients receiving standard TKIs, 8.5 months [4]. These results suggest that osimertinib can produce durable responses for frontline patients with EGFR-mutant NSCLC.

–Zachary Moore

  1. TAGRISSO® (osimertinib) tablets, for oral use ClinicalTrials.gov 04/18/2018 [cited 2018 May 4]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf.
  2. Zhang, Y.L., et al., The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget, 2016. 7(48): p. 78985-78993.
  3. Heydt, C., et al., Novel approaches against epidermal growth factor receptor tyrosine kinase inhibitor resistance. Oncotarget, 2018. 9(20): p. 15418-15434.
  4. Soria, J.C., et al., Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2018. 378(2): p. 113-125.
  5. TAGRISSO™ (osimertinib) tablet, for oral use. Initial U.S. Approval: 2015. Drugs@FDA: FDA Approved Drug Products  [cited 2018 May 4 ]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf.
  6. AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA). ClinicalTrials.gov  [cited 2018 May 4]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf.

Olaparib, the First PARP Inhibitor to Gain FDA Approval to Treat BRCA-mutant Breast Cancer

On January 12, 2018, the FDA granted regular approval to LYNPARZA® (olaparib) for the treatment of patients with a deleterious, or suspected deleterious, germline BRCA 1 or BRCA 2 mutation (gBRCAm), who have human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) and have received prior chemotherapy in the neoadjuvant, adjuvant or metastatic setting [1]. Wild type BRCA1 and BRCA 2 proteins function as tumor suppressors by supporting DNA repair pathways in cells, thus preventing an accumulation of mutations that may lead to cancer [2]. gBRCAms can result in dysfunctional BRCA1 or BRCA2 proteins and have been implicated in several cancer types including ovarian, breast, prostate, and pancreatic [3]. Tumor cells that lack functional BRCA1 or BRCA2 protein are acutely dependent on other DNA repair molecules such as poly ADP-ribose polymerase (PARP) for proliferation and survival, and are therefore uniquely sensitive to PARP inhibition, a phenomenon known as synthetic lethality [4].

Olaparib (marketed by AstraZeneca), as well as other PARP-specific small molecule inhibitors, have already been approved for the treatment of various types of ovarian cancer, but this approval marks the first of its kind for breast cancer patients. The approval was based on results from a randomized, open-label phase 3 trial, OlympiAD, that compared olaparib monotherapy to standard chemotherapy for patients with gBRCAm-positive, HER2-negative, relapsed or refractory breast cancer (NCT02000622O) [5]. Those who received olaparib demonstrated a progression free survival (7 months vs. 4.2 months, respectively) and response rate (59.9% vs. 28.8%) benefit over patients who received standard single agent chemotherapy [6]. Additionally, the safety profile of olaparib was found to be superior to standard chemotherapy in this study with 36.6% and 50.5% of patients experiencing grade 3 or higher adverse events, respectively. This approval provides hope for patients who typically have few therapeutic options available to them and paves the way for similar agents in this space.

–Zachary Moore

  1. LYNPARZA (olaparib) tablets. Drugs@FDA: FDA Approved Drug Products 01/12/2018 [cited 2018 April 6]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf.
  2. Chen, J., et al., Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell, 1998. 2(3): p. 317-28.
  3. Paul, A. and S. Paul, The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci (Landmark Ed), 2014. 19: p. 605-18.
  4. Ceccaldi, R., et al., Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature, 2015. 518(7538): p. 258-62.
  5. Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations. (OlympiAD). ClinicalTrials.gov February 26, 2018 [cited 2018 April 9]; Available from: https://clinicaltrials.gov/ct2/show/NCT02000622.
  6. Robson, M., et al., Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med, 2017. 377(6): p. 523-533.

Combination of Nivolumab Plus Ipilimumab for Frontline Treatment of Renal Cell Carcinoma

On April 16, 2018, the FDA granted approval to treat frontline, intermediate or poor risk advanced renal cell carcinoma (RCC) with the combination of nivolumab (OPDIVO®) and ipilimumab (YERVOY®) [1]. There are about 65,000 new cases of RCC in the United States (US) each year, and RCC accounts for about 15,000 deaths per year in the US [2]. Standard frontline treatment for RCC includes anti-angiogenic treatment with sunitinib, a tyrosine kinase inhibitor (TKI) that targets several angiogenesis-promoting kinases [2]. Unfortunately, most patients with advanced RCC eventually progress on therapy, thus there is an unmet need for treatments that can provide a durable response. Both nivolumab and ipilimumab are immune checkpoint inhibitors that can stimulate or enhance autonomous anti-tumor immune responses and have been found to produce durable responses in many tumor types. These agents work on different, but parallel, immune checkpoint pathways, and therefore may further enhance immune responses when used in combination [3].  

The combination was approved to treat frontline, intermediate or poor risk advanced RCC based on the results of a randomized, open-label phase 3 trial, CheckMate 214, that compared the combination to standard sunitinib therapy (NCT02231749) [4]. Patients were randomized 1:1 to receive nivolumab plus ipilimumab intravenously every 3 weeks for a total of four doses, followed by nivolumab every 2 weeks, or daily oral sunitinib for four weeks out of 6-week cycles. Patients receiving the nivolumab-ipilimumab combination experienced an improved overall survival rate at 18-months compared to those receiving sunitinib treatment, 75% vs 60%, respectively [3]. Additionally, the overall response rate was improved in the nivolumab-ipilimumab arm, 42% vs. 27% as well [3]. Remarkably, grade 3 or 4 adverse events occurred at a lower rate in the combination arm than the sunitinib arm with 46% vs. 65% of patients experiencing a grade 3 or 4 event, respectively [3]. This approval provides another therapeutic option for patients with advanced RCC.

–Zachary Moore

  1. OPDIVO (nivolumab) injection, for intravenous use Drugs@FDA: FDA Approved Drug Products  [cited 2018 May 4]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf.
  2. Board, P.D.Q.A.T.E., Renal Cell Cancer Treatment (PDQ(R)): Health Professional Version, in PDQ Cancer Information Summaries. 2002, National Cancer Institute (US): Bethesda (MD).
  3. Motzer, R.J., et al., Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med, 2018. 378(14): p. 1277-1290.
  4. Nivolumab Combined With Ipilimumab Versus Sunitinib in Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214). ClinicalTrials.gov  [cited 2028 May 4]; Available from: https://clinicaltrials.gov/ct2/show/NCT02231749.

 

Nilotinib Receives FDA-approval to Treat Pediatric Patients with Chronic Phase CML

On March 22, 2018, the FDA granted Novartis approval to market TASIGNA® (nilotinib) for the treatment of pediatric patients with frontline or resistant Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) [1]. CML is a disease characterized by hyper-proliferative white blood cells that harbor a chromosomal translocation resulting in a constitutively active fusion kinase, BCR-ABL1 (Ph) [2]. The pathogenesis of CML is directly driven by the BCR-ABL1 kinase, thus targeting its activity has proved to be an effective therapeutic strategy for the treatment of CML. Several tyrosine kinase inhibitors (TKIs) have been developed that inhibit the activity of BCR-ABL1 and provide clinical efficacy in both adults and children with CML. Currently, there are five TKIs that have been approved by the FDA to treat CML: imatinib (GLEEVEC®), dasatinib (SPRYCEL®), nilotinib, bosutinib (BOSULIF®), and ponatinib (ICLUSIG®); the prior three are approved for frontline treatment of CML in adults and children [1, 3-6]. Nilotinib was initially approved in 2007 for the treatment of adults with Ph+ CML who were resistant or intolerant to imatinib-based therapies and was then expanded to frontline treatment of adults with CML in 2010 [1].

Nilotinib received approval to treat pediatric patients with Ph+ CML-CP based on results of two open-label, multicenter studies investigating the safety and efficacy of nilotinib in pediatric patients older than one year of age with Ph+ CML-CP that is resistant or intolerant to imatinib or dasatinib (n=44), or who have newly diagnosed Ph+ CML-CP (n=25) (NCT01077544) (NCT01844765) [7, 8]. The major molecular response rate at 12 months was 40.9% in patients with resistant or intolerant Ph+ CML-CP and 60% in patients with newly diagnosed Ph+ CML-CP [1]. Additionally, the safety profile was found to be similar to what is observed in adults. This approval adds another agent to the pediatric CML armamentarium.

–Zachary Moore

  1. TASIGNA® (nilotinib) capsules, for oral use. Drugs@FDA: FDA Approved Drug Products March 22, 2018 [cited 2018 May 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022068s027lbl.pdf.
  2. Chereda, B. and J.V. Melo, Natural course and biology of CML. Ann Hematol, 2015. 94 Suppl 2: p. S107-21.
  3. Gleevec™(imatinib mesylate)Tablets. Drugs@FDA: FDA Approved Drug Products May 20, 2003 [cited 2018 May 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021588s001lbl.pdf.
  4. SPRYCEL (dasatinib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products November 9, 2017 [cited 2018 May 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf.
  5. BOSULIF® (bosutinib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products December 19, 2017 [cited 2018 May 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf.
  6. ICLUSIG® (ponatinib) tablets for oral use. Drugs@FDA: FDA Approved Drug Products November 28, 2016 [cited 2018 May 1]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203469s022lbl.pdf.
  7. Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients. ClinicalTrials.gov  [cited 2018 May 1]; Available from: https://clinicaltrials.gov/ct2/show/NCT01844765.
  8. A Pharmacokinetic (PK) Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphoblastic Leukemia (ALL). ClinicallTrials.gov  [cited 2018 May 1]; Available from: https://clinicaltrials.gov/ct2/show/NCT01077544.

Lutathera®, a New Treatment Option for Patients with Neuroendocrine Tumors

On January 26th, the FDA approved a novel radioactive treatment, lutetium-177 dotatate (Lutathera), for patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [1]. GEP-NETs are rare tumors that develop from neuroendocrine cells that typically secrete large amounts of hormones and express high levels of somatostatin receptors, typically type II [2]. Lutathera, developed and marketed by Advanced Accelerator Applications, is a somatostatin analog, dotatate, bound to a radioisotope, lutetium-177, that can bind to the somatostatin receptor with high affinity, delivering β-emitting radiation directly to GEP-NET cells within the body [3]. Radiolabeled somatostatin analogs were first utilized to image GEP-NETs in vivo, and were then used in repeated, high doses to treat somatostatin receptor-positive tumors [4]. Lutetium-177 dotatate was identified as an alternative to early radiolabeled somatostatin analogs that did not require repeated large doses for efficacy against GEP-NETs [5].

The approval was based on the results of a pivotal, randomized, open-label, international phase 3 clinical trial (NETTER-1) that compared Lutetium-177 dotatate plus standard therapy, octreotide LAR (somatostatin analog that blocks hormonal secretion) versus octreotide LAR alone in patients with midgut neuroendocrine tumor (NCT01578239) [6]. The combination demonstrated an enhanced 20-month progression free survival rate over octreotide LAR monotherapy with 62.5% vs. 10.8%, respectively, and an improved response rate of 18% vs. 3%, respectively [7]. Additionally, the combination was found to be well tolerated with an acceptable safety profile. This approval brings new therapeutic alternatives to patients with limited options and may provide a significant survival advantage over standard treatments.

–Zachary Moore

  1. LUTATHERA. Drugs@FDA: FDA Approved Drug Products January 26, 2018 [cited 2018 April 9]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf.
  2. Krenning, E.P., et al., Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med, 1993. 20(8): p. 716-31.
  3. Severi, S., et al., Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life. Onco Targets Ther, 2017. 10: p. 551-557.
  4. Krenning, E.P., et al., Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy. Ann Oncol, 1999. 10 Suppl 2: p. S23-9.
  5. Kwekkeboom, D.J., et al., Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol, 2008. 26(13): p. 2124-30.
  6. A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours (NETTER-1). ClinicalTrials.gov  [cited 2018 April 9]; Available from: https://clinicaltrials.gov/ct2/show/NCT01578239.
  7. Strosberg, J., et al., Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med, 2017. 376(2): p. 125-135.

Durvalumab receives FDA-approval as a consolidation treatment for Stage III NSCLC

On February 16, 2018 the FDA approved Imfinzi® (durvalumab) as a consolidation treatment for patients with stage III non-small cell lung cancer (NSCLC) who disease has not progressed after chemoradiation therapy [1]. Durvalumab is an anti-programmed death-ligand 1 (PD-L1) antibody that belongs to a class of drugs known as immune checkpoint inhibitors (ICIs) which work by releasing the breaks on the immune system, enabling anti-tumor immune responses. Durvalumab was initially approved by the FDA in 2017 for the treatment of patients with metastatic urothelial carcinoma who had progressed on platinum-based chemotherapy [2]. Concurrent platinum-based chemotherapy and radiation is standard of care therapy for patients with stage III NSCLC; however, most patients eventually develop disease progression after therapy, thus consolidation is an important treatment step to improve patient outcomes.

The approval of durvalumab for NSCLC came after results of a randomized phase 3 trial showed a significant improvement in median progression free survival for patients receiving durvalumab consolidation therapy over placebo, 16.8 months versus 5.6 months, respectively [3]. The study, PACIFIC, was conducted in 709 patients with stage III NSCLC who did not experience disease progression after two or more cycles of platinum-based chemoradiotherapy (NCT02125461) [4]. The patients were randomized 2:1 to receive durvalumab or placebo consolidation treatment for up to 12 months. The overall response rate for patients receiving durvalumab was 28.4% and 16% for patients receiving placebo. Additionally, durvalumab improved the median time to death or distant metastasis from 14.6 months in the placebo arm to 23.2 months [3]. The rate at which grade 3 or 4 adverse events occurred were similar between arms with 29.9% for patients who received durvalumab and 26.1% for those who received placebo [3]. These results suggest that durvalumab can provide a significant clinical benefit as a consolidation treatment for patients with stage III NSCLC and has favorable safety profile in this patient population.

–Zachary Moore

  1. IMFINZI® (durvalumab) injection, for intravenous use. Drugs@FDA: FDA Approved Drug Products February 16, 2018 [cited 2018 April 26]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf.
  2. IMFINZI™ (durvalumab) injection, for intravenous use Initial U.S. Approval: 2017 Drugs@FDA: FDA Approved Drug Products May 1, 2017 [cited 2018 April 26]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf.
  3. Antonia, S.J., et al., Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med, 2017. 377(20): p. 1919-1929.
  4. A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC). Clinicaltrials.gov January 16, 2018 [cited 2018 April 26]; Available from: https://clinicaltrials.gov/ct2/show/NCT02125461.

Dabrafenib and Trametinib for the Treatment of BRAF V600E-positive Anaplastic Thyroid Cancer

On May 4, 2018, the FDA approved the combination of TAFINLAR® (dabrafenib) and MEKINIST® (trametinib) for the treatment of patients with anaplastic thyroid cancer (ATC) whose tumors harbor a BRAF V600E mutation [1]. ATC is a rare and deadly malignancy composed of highly undifferentiated thyroid cells [2]. BRAF mutations have been identified in about 11% of ATC samples and additional mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway are found in about 20% of ATC samples [3]. Constitutively active MAPK pathway signaling supports tumor cell proliferation and survival, thus, some patients with ATC may benefit from MAPK pathway blockade via tyrosine kinase inhibitors (TKIs) dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Combination therapy of dabrafenib and trametinib has already been approved by the FDA for the treatment of unresectable or metastatic BRAF V600E/K-positive melanoma, adjuvant treatment for completely resected stage III BRAF V600E/K melanoma, and metastatic BRAF V600E-positive non-small cell lung cancer [1].

The approval to treat patients with BRAF V600E-positive ACT was based on results from a nine-cohort, non-randomized, open-label trial investigating the anti-tumor efficacy of the combination in patients with rare cancers with the a BRAF V600E mutation, including locally advanced, unresectable, or metastatic ATC (NCT02034110) [4]. The overall response rate in patients with ATC, was 61% (N=23) with 64% of responses lasting longer than 6 months [1]. Adverse events reported in patients with ATC were similar to those reported in other indications. This approval of dabrafenib and trametinib therapy provides a durable therapeutic option to patients with limited therapeutic options available.

–Zachary Moore

  1. MEKINIST® (trametinib) tablets, for oral use. Drugs@FDA: FDA Approved Drug Products

05/04/2018 [cited 2018 May 9]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204114Orig1s009lbl.pdf.

  1. Tiedje, V., et al., Anaplastic thyroid carcinoma: review of treatment protocols. Endocr Relat Cancer, 2018. 25(3): p. R153-r161.
  2. Tiedje, V., et al., NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma. Oncotarget, 2017. 8(26): p. 42613-42620.
  3. Efficacy and Safety of the Combination Therapy of Dabrafenib and Trametinib in Subjects With BRAF V600E- Mutated Rare Cancers. ClinicalTrials.gov March 30, 2018 [cited 2018 May 9]; Available from: https://clinicaltrials.gov/ct2/show/NCT02034110.

Dabrafenib and Trametinib for Adjuvant Treatment of BRAF V600E/K-Positive Melanoma

On April 30, 2018 the FDA approved the combination of TAFINLAR® (dabrafenib) and MEKINIST® (trametinib) for the adjuvant treatment of patients with completely resected stage III melanoma whose tumors harbor a BRAF V600E or V600K mutation [1]. Both dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, are tyrosine kinase inhibitors (TKIs) that block the cellular proliferation- and survival-supporting, mitogen-activated protein kinase (MAPK) pathway. Activating BRAF mutations are found in about 50% of melanoma samples, resulting in constitutive activation of the MAPK pathway; thus, BRAF and MEK inhibitors have been developed to treat BRAF-mutant-positive cancers [2]. BRAF V600E and V600K are the most common BRAF mutations found in melanoma, and the combination of dabrafenib and trametinib has exhibited anti-tumor efficacy in patients with BRAF V600E/K-positive unresectable or metastatic melanoma [3, 4]. The combination has already been approved by the FDA for the treatment of unresectable or metastatic BRAF V600E/K-positive melanoma and metastatic BRAF V600E-positive non-small cell lung cancer [1].

The FDA approved the combination as an adjuvant treatment based on the results of a randomized phase 3 study investigating dabrafenib and trametinib vs. placebo as an adjuvant treatment for patients with completely resected, stage III BRAF V600E/K-positive melanoma (NCT01682083) [5]. The estimated 3-year rate of relapse-free survival was enhanced in the arm receiving the combination at 58% vs. 39% respectively [6]. The 3-year overall survival rate was also improved by the combination therapy with 86% survival and 77% survival, respectively.  No new safety concerns were identified with the combination therapy in this patient population. This approval provides a therapeutic option for patients undergoing stage III melanoma resection whose tumors harbor BRAF V600E/K mutations.

–Zachary Moore

  1. TAFINLAR® (dabrafenib) capsules, for oral use Drugs@FDA: FDA Approved Drug Products 04/30/2018 [cited 2018 May 7]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202806s008lbl.pdf.
  2. Long, G.V., et al., Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol, 2011. 29(10): p. 1239-46.
  3. Long, G.V., et al., Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med, 2014. 371(20): p. 1877-88.
  4. Robert, C., et al., Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med, 2015. 372(1): p. 30-9.
  5. A Study of the BRAF Inhibitor Dabrafenib in Combination With the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection. (COMBI-AD). ClinicalTrials.gov May 8, 2018 [cited 2018 May 8]; Available from: https://clinicaltrials.gov/ct2/show/NCT01682083.
  6. Long, G.V., et al., Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med, 2017. 377(19): p. 1813-1823.

Blinatumomab for Patients with MRD-positive B-cell Precursor ALL

On March 29, 2018 the FDA granted Amgen Inc. approval to market BLINCYTO® (blinatumomab) for the treatment of adult and pediatric patients with minimal residual disease (MRD)-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission (CR) [1]. MRD detection in patients with ALL who have achieved a CR is an indicator of chemotherapy resistance and a risk factor for hematologic relapse, thus achieving MRD-negativity after chemotherapy is an important treatment goal [2]. Blinatumomab is a bispecific antibody, known as a CD3 T-cell engager, that binds to T-cells and directs them to CD19-positive cells (most B-cell precursors), which can then stimulate and/or enhance T-cell immune responses against CD19-expressing cells [3]. Blinatumomab was originally approved in 2014 for the treatment of relapsed or refractory Philadelphia chromosome-negative ALL [4].

The approval to treat MRD-positive ALL was based on a single-arm, multicenter phase 2 study investigating the safety and efficacy of blinatumomab in patients with MRD-positive B-cell precursor ALL who had received at least three cycles of standard chemotherapy (NCT01207388) [5]. A total of 116 patients received blinatumomab daily for up to four cycles. Of those who were evaluable (n=113), 78% achieved a complete MRD-negative response which was associated with a longer relapse-free survival (23.6 vs 5.7 months) and overall survival (38.9 vs 12.5 months) compared to those who did not achieve MRD-negativity on study [3]. Blinatumomab was well tolerated with the most common grade 3 or 4 adverse events being neurological events (13%) and cytokine release syndrome grade (2%) [3]. This is a groundbreaking study assessing MRD-negativity as a primary endpoint, provides support for the need to achieve MRD-negativity and the use of blinatumomab to help achieve that goal.

–Zachary Moore

  1. BLINCYTO® (blinatumomab) for injection, for intravenous use. Drugs@FDA: FDA Approved Drug Products 03/29/2018 [cited 2018 May 4]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125557s013lbl.pdf.
  2. Berry, D.A., et al., Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis. JAMA Oncol, 2017. 3(7): p. e170580.
  3. Gokbuget, N., et al., Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood, 2018. 131(14): p. 1522-1531.
  4. BLINCYTO (blinatumomab) for injection, for intravenous use. Initial U.S. Approval: 2014 Drugs@FDA: FDA Approved Drug Products 12/03/2014 [cited 2018 May 3]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125557lbl.pdf.
  5. Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL) (BLAST). ClinicalTrials.gov May 1, 2017 [cited 2018 May 3]; Available from: https://clinicaltrials.gov/ct2/show/NCT01207388.

Apalutamide, a New Treatment for Nonmetastatic Castration Resistant Prostate Cancer

On February 14th, the FDA approved apalutamide (Erleada™) tablets for the treatment of nonmetastatic castration resistant prostate cancer [1]. Prostate cancer is the most common malignancy and second most common cause of cancer-related death in men in the United States [2]. Prostate cancer cells are typically dependent on androgen receptor (AR) signaling for proliferation and survival, thus androgen deprivation therapy (ADT), or medical castration, is a standard treatment for patients with prostate cancer. Unfortunately, most prostate cancers develop resistance to ADT by evolving androgen independent AR signaling, resulting in disease progression and life-threatening metastases [3]. Apalutamide is a small molecule that directly binds to and inhibits AR molecules, thus bypassing various castration resistance mechanisms [4].

The approval was based on impressive efficacy results from a large, randomized phase 3 study, SPARTAN, that compared apalutamide treatment plus standard ADT to ADT alone for the treatment of men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis [5]. The study found that the addition of apalutamide to ADT reduced the risk of metastasis or death by 70% compared to ADT alone with a median metastasis-free survival of 40.5 months vs. 16.2 months, respectively [6]. Apalutamide was found to be well tolerated; however, it was associated with a higher incidence of rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%) [6]. Apalutamide has the potential to fill an unmet medical need by preventing metastasis in men with nonmetastatic castration resistant prostate cancer and paves the way for other molecules with similar mechanisms of action to be explored.

–Zachary Moore

  1. ERLEADA (apalutamide) tablets. Drugs@FDA: FDA Approved Drug Products 02/14/2018 [cited 2018 April 11]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf.
  2. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 5-29.
  3. Dai, C., H. Heemers, and N. Sharifi, Androgen Signaling in Prostate Cancer. Cold Spring Harb Perspect Med, 2017. 7(9).
  4. Clegg, N.J., et al., ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res, 2012. 72(6): p. 1494-503.
  5. A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN). ClinicalTrials.gov February 8, 2018 [cited 2018 April 11]; Available from: https://clinicaltrials.gov/ct2/show/NCT01946204.
  6. Smith, M.R., et al., Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med, 2018.

Afatinib receives extended approval for frontline treatment of Patients with Non-resistant EGFR Mutation-positive NSCLC

On January 12, 2018 the FDA expanded approval to Boehringer Ingelheim Pharmaceutical, Inc. to market Gilotrif® (afatinib) for the frontline treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors harbor a non-resistant epidermal growth factor receptor (EGFR) mutation [1]. Afatinib, an EGFR tyrosine kinase inhibitor (TKI), was originally approved in 2013 to treat patients with NSCLC whose tumors harbored an EGFR exon 19 deletion or an exon 21 (L858R) substitution [2]. Activated EGFR stimulates cellular growth and survival and has been implicated in the progression and maintenance of several malignancies. About 14-38% of NSCLC tumors harbor activating mutations in the EGFR gene with exon 19 deletions and L858R substitutions being the most common alterations detected [3]. Rare, activating EGFR mutations, which make up about 10% of detected EGFR mutations in NSCLC, include other exons 18-21 point mutations or duplications, exon 20 insertions, and de-novo T790M mutations [4]. The latter mutation is a known resistance mechanism to first- and second-generation EGFR TKIs such as afatinib.

The expanded approval was based on a retrospective subset analysis of patients with rare EGFR mutations in three previously conducted trials: LUX-Lung 2, LUX-lung 3, and LUX-lung 6. Patients with other exons 18-21 point mutations or duplications experienced a 71% objective response rate (ORR), while patients with de-novo T790M mutations and exon 20 insertions experienced only a 14.3% and 8.7% ORR, respectively [4]. Median progression free survival and overall survival were also superior in the group of patients with other exons 18-21 point mutations or duplications compared to the other groups [4]. These data suggest that afatinib is clinically active against certain types of rare EGFR mutations and can help guide treatment decisions based on the specific EGFR mutation detected in a NSCLC sample.

–Zachary Moore

  1. GILOTRIF® (afatinib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products 2018 January 12, 2018 [cited 2018 April 24]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf.
  2. GILOTRIF™ (afatinib) tablets, for oral use, Initial U.S. Approval: 2013 Drugs@FDA: FDA Approved Drug Products July 12, 2013 [cited 2018 April 24]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf.
  3. Zhang, Y.L., et al., The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget, 2016. 7(48): p. 78985-78993.
  4. Yang, J.C., et al., Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol, 2015. 16(7): p. 830-8.

 

Adcetris is Approved for the Frontline Treatment of stage III or IV Classical Hodgkin Lymphoma in Combination with Chemotherapy

On March 20, 2018, the FDA granted Seattle Genetics, Inc. approval to market Adcetris® (Brentuximab Vedotin), in combination with chemotherapy, for the frontline treatment of patients with classical Hodgkin lymphoma (cHL) [1]. The standard frontline regimen for patients with cHL is a four-drug chemotherapy regimen, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine); however, up to 30% of patients are refractory to treatment or relapse after treatment [2]. Brentuximab vedotin (BV) is a CD30-targeted antibody-drug conjugate that selectively delivers a cytotoxic agent to cHL cells, thus reducing systemic toxicity and enhancing anti-neoplastic activity [2]. Brentuximab vedotin was previously approved as a salvage treatment and post-transplantation consolidation therapy for patients with cHL as well as for the second-line treatment of systemic and primary anaplastic large cell lymphoma and CD30­expressing mycosis fungoides [1].

The most recent approval was based on the results of an open-label, multicenter, randomized phase 3 trial, ECHELON-1, comparing brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) to standard ABVD therapy for the frontline treatment of patients with stage III or IV cHL (NCT01712490) [3]. A total of 664 patients received A+AVD while 670 patients received ABVD. Efficacy was based on a 2-year modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) rate which was 82.1% for A+AVD group and 77.2% for the ABVD group [3]. Overall, patients receiving A+AVD experienced a 23% reduction in the risk of failure of the primary chemotherapy treatment. Additionally, treatment with A+AVD reduced the incidence of pulmonary toxicity supporting its use in this indication.

–Zachary Moore

  1. ADCETRIS® (brentuximab vedotin) for injection, for intravenous use Drugs@FDA: FDA Approved Drug Products March 20, 2018 [cited 2018 April 26]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125388s097lbl.pdf.
  2. Connors, J.M., et al., Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med, 2018. 378(4): p. 331-344.
  3. Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma. ClinicalTrials.gov August 1, 2017 [cited 2018 April 27]; Available from: https://clinicaltrials.gov/ct2/show/NCT01712490.

Abemaciclib, Another Option for Frontline Treatment of HR-positive Breast Cancer

On February 26 th , the FDA expanded approval of abemaciclib (VERZENIO™), manufactured by
Eli Lilly Inc., for the frontline treatment of hormone receptor (HR)-positive, human epidermal
growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) in combination with an
aromatase inhibitor (AI) [1]. It was originally approved in September of 2017 for patients with
HR-positive, HER2-negative advanced BC who had previously received endocrine therapy [2].
Abemaciclib is a small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6 which are
involved in cell cycle progression and the prevention of cellular senescence [3]. CDK4 and CDK6
overactivity has been implicated in several malignancies including non–small cell lung cancer
(NSCLC), melanoma, glioblastoma, mantle cell lymphoma, and BC [3].

The expanded approval was based on the results of a randomized phase 3 study, MONARCH 3,
which assessed the safety and efficacy of abemaciclib in combination with an AI versus an AI
alone for the treatment of HR-positive, HER2-negative advanced BC (NCT02246621) [6].
Patients in the abemaciclib arm experienced a prolonged median progression free survival, not
reached vs. 14.7 months and a higher objective response rate in patients with measurable
disease, 59% vs. 44% [7]. In general, the combination was found to be well tolerated with the
most common adverse event reported being diarrhea which was experienced in 81.3% of
patients (44.6% grade 1). Two other CDK4/6 inhibitors, ribociclib (Kisqali®) and palbociclib
(Ibrance®), have previously been approved for the frontline treatment of patients with HR-
positive, HER2-negative advanced BC, thus it may be difficult for oncologists to determine
which CDK4/6 inhibitor is appropriate for their patients [4, 5].

–Zachary Moore

  1.  VERZENIO™ (abemaciclib) tablets, for oral use. Drugs@FDA: FDA Approved Drug Products
    February 26, 2018 [cited 2018 April 13]; Available from:
    https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208855s000lbl.pdf.
  2.  VERZENIO™ (abemaciclib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products
    09/28/2017 [cited 2018 April 13]; Available from:
    https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716Orig1s000lbl.pdf.
  3. Gelbert, L.M., et al., Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell
    cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.
    Invest New Drugs, 2014. 32(5): p. 825-37.
  4. KISQALI® (ribociclib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products 03/13/2017
    [cited 2018 April 13]; Available from:
    https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf.
  5. IBRANCE® (palbociclib) capsules, for oral use Drugs@FDA: FDA Approved Drug Products
    02/06/2018 [cited 2018 April 13]; Available from:
    https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207103s007lbl.pdf.
  6. A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal
    Women With Breast Cancer (MONARCH 3). ClinicalTrials.gov March 23, 2018 [cited 2018 April
    13]; Available from: https://clinicaltrials.gov/ct2/show/NCT02246621.
  7.  Goetz, M.P., et al., MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J
    Clin Oncol, 2017. 35(32): p. 3638-3646.

Take a Look Into Our Market Access Work

Have you wondered what our Market Access work is like? Take a peek below at some recent projects.

If you have similar needs in your organization for our assistance, we’d be happy to hear what your needs are and discuss how we would approach addressing them.  Email Greg Hall at ghall@cadenceresearch.com to find out more.

  1. Biosimilar coding scenario testing. Worked with a biosimilar company to determine the impact that various coding scenarios could have on product uptake at the time of launch and beyond.  Conducted a qualitative market research study with 20 oncology practice managers as well as a quantitative study with another 50 practice managers and developed a financial impact model.  Completed all aspects of the project (from proposal to reporting results) in less than 4 weeks!!
  2. Reimbursement hotline and patient assistance program service vendor contract review and input. Assisted two separate clients by reviewing their vendor contracts and provided input for improvements in terms of service level metrics, contract terms, performance evaluations of their vendor, etc.  One client garnered 10% annual savings moving forward with improved contractual terms based on our input and direction.
  3. Perceptions of marketed product. We conducted an in-depth market research study with pharmacists and clinicians regarding a product used in the hospital inpatient and outpatient setting.  We probed on clinical, cost and payment issues impacting product uptake.  Significant findings included how this class of products is evaluated both from a therapeutic and economic stand point and what are the key differentiators among this class of products given similar safety and efficacy profiles.

Are you getting the most out of the Specialty Pharmacies (SPs) in your network / HUB?

Specialty drugs have been a major growth area for pharmaceuticals and are expected to grow even more in the next several years.  Specialty drugs have one or more of the following characteristics:

  1. High cost – generally this is greater than $600 per month as set forth in the Medicare Part D regulations.
  2. Indicated for the treatment of a chronic, rare illness.
  3. Products are usually injectable or infused, although some products (such as oral oncolytics) may be oral or have some other type of administration.
  4. Complex manufacturing process in association with the production of the product (not usually small molecules).
  5. Special storage and handling (such as refrigeration) requirements might be needed.
  6. Complex monitoring for patient compliance, persistency and side effects may be required.
  7. May be covered under the medical benefit, pharmacy benefit, or, in some cases, both.

The FDA is expected to approve a record 25 specialty drugs this year!  Spending in the U.S. on specialty drugs – to treat chronic, complex diseases such as cancer, multiple sclerosis and rheumatoid arthritis – is projected to increase 67% by the end of this year.

Screenshot_2_27_15__10_52_AM

Source:  Express Scripts

There are a number of models that a pharma company can utilize with the launch (and beyond) of their specialty drug product and companies to date vary in their approach to specialty pharmacy (SP):

  • Some use one specific SP to handle distribution and other aspects;
  • Some use a small group (3-5) SPS to handle distribution and other services;
  • Some have an open network utilizing as many as 10-15 SPs;
  • Some direct all patients and providers through a centralized hub that determines the services and distribution options for the patient and directs them accordingly.

Whether you use one or more SPs in your network / HUB, you might not know what your end-user customers (physicians, nurses, billing staff, patients, etc.) think about those specialty pharmacies.  In many cases, pharma companies set up a network / HUB and just assume it is meeting the needs of their end-user customers.  These pharmacies (and the services they provide – or don’t) reflect on your product, so you need to be absolutely sure that they are meeting the needs of your end-user customers.

It is entirely possible that you launched your product with no research done to determine the effectiveness of the various SPs that are being utilized and how end-user customers perceive their value.

Cadence Research & Consulting can help you to determine customer feedback about each SP in order to understand (among other things):

  1. Do your customers value the SPs in your network?  If so, are there certain aspects they are lacking?
  2. Should you consider eliminating an SP from your network / HUB?  Are there other SPs that you are considering?
  3. What are the services provided by each SP in your network / HUB (benchmarking)?
  4. What services could you add to improve the functioning of your network / HUB?

If we can be of service to you in this area, please contact Greg Hall at ghall@cadenceresearch.com. We would welcome the opportunity to work with you.

Act NOW!

Sometimes I ask my clients ‘what will it take for you to act on your idea or vision right now?’ Very often they will respond, ‘Gee, I would love to but…’ and finish with one of a litany of reasons why they need to wait.  I have heard everything (and said some of these myself):  ‘I need to finish my plan’, ‘I don’t have enough money’, ‘I am too busy’, ‘I am scared’ (the most honest of all the answers), and the catch-all ‘I don’t know what I want to do.’  All of these excuses (yes, they are excuses) seem highly justified at the time but they are, in reality, simply ways of avoiding our own fears.

When we take action toward our dreams we intuitively know that our life will change, and this generates fear.  We are familiar with our life as it is today, and although we may not like it, we at least are comfortable with this reality.  Taking action puts at risk all that we have become accustomed to, and so we avoid doing even those things we know will make us happy and successful.

The only way to move past this fear is to confront it.  Look around you right now.  What have you been avoiding that you KNOW would help you move forward?  What small action can you take in that direction?  What could you do RIGHT NOW to start this process?  It may be sending an email or calling someone, or perhaps just writing one sentence of that book.  Or maybe sketching a list of things that you know you want out of your life.  My point is that there are many small things you can do right now to jar you out of your stasis.

If you want to achieve and move toward anything, there is a first step, then a second, and a third.  All you need to do is choose to act RIGHT NOW toward your dreams.  Then in every moment simply ask yourself again, what can I do NOW?  And NOW?  And NOW? Your small steps begin to add up until voila, you find yourself at your destination.  Success is not an event…it is a process.  Like drops of water wearing away a stone, so can you achieve anything if you take simple, moment by moment steps.  Try this!  Start NOW on something you desire…and watch what happens!

KC Hildreth

Tips on Cultivating Vision in your Organization

Leadership is a term that can mean a wide range of things to people.  What does it mean to you?  Who have been powerful leaders is your world? Who has created powerful vision for the organizations you’ve been a part of?  Who has inspired the individuals within that organization to implement and move that vision into action?

Leadership encompasses a wide range of skills, but envisioning a powerful and inspiring path to focus an organization is a key component.  But why is this not enough?

Establishing a vision, like all goals or great intentions, needs follow up and nurturing.  This is where it gets a little trickier.  It takes the engagement of the whole organization or at least a substantial part of it to bring it into fruition.  What can a leader do to create the climate for this to happen?

  1. Beat the visionary drum.  Repeating the vision, communicating it over and over in ways that truly inspire and engage people is necessary.  A single pronouncement or publishing of that vision isn’t enough.  It’s the repeat conversations about what it means on a daily basis that begin to create integration.  Challenging the vision, practicing it, tweaking it and discussing it as experience is gained can enhance any brilliant idea.
  2. Allow it to morph.  Vision is only as fresh and perfect as in the moment it is created, no matter how inspired it feels.  Allowing the vision to have integrity, but change as circumstances evolve can give it longer life and allow for it to have true impact on an organization.
  3. Engage the next level of leadership to embody it, and inspire their teams to do the same.  It is the ‘walking the talk’ at numerous levels of a business that create a real change.  Hold yourself and your teams accountable for continuing to move towards the vision, while allowing them to make mistakes and get back on track.  It’s an organizational skill to learn from mistakes in a healthy way and move on to do things better the next time.
  4. Revisit the organization’s progress, celebrate the wins and feed the beast.  All things require sustained focus to be fully developed and vision is no different.  Evaluate progress in part by watching for success.   The attention to success and where things are going right aids the process and gives you opportunity to acknowledge and celebrate them.

While leading vision for an organization is not the only task of a leader, it is a powerful place worthy of attention and nurturance.  Outlining a path for success requires cultivating focus on that vision for the long haul while inspiring a team to engage and implement it.

Laura Smith

Reflections on the Legacy of Dick Fordyce

For the last eight years I have had the honor of presenting the R.R. Fordyce award at the Pharmaceutical Marketing Research Group (PMRG) Institute held each fall.  As Dick Fordyce’s daughter, it is a highly emotional evening for me.

Established in 1999, the R.R. Fordyce award is PMRG’s most prestigious award.  It is given to the person who, like my father, exemplifies the principles of excellence, innovation, and integrity in pharmaceutical market research.  Recipients have demonstrated an exemplary level of character, ethics, and leadership in their professional and personal lives.  They have made an outstanding contribution to healthcare market research in their leadership, decision-making, and mentoring activities.

On the evening of the awards dinner each year, many of the people in attendance seek me out in order to share their stories about my father.  I listen with a mix of joy and sadness.  I knew him as a loving, family-focused father who I miss every day even sixteen years after his passing.  But it also warms my heart to hear about the impact he had in the industry that he loved so much.

I have heard stories about how he had a direct impact on people’s choice of market research as a career; how he made C-suite associates see the importance and value of market research; how he mentored others not just by what he said but how he acted; and how so many looked to him for leadership especially during difficult situations.  It is humbling to know that seventeen years after he retired, his legacy lives on.  He made a difference in the industry and in the people he touched during his career.

My father has undoubtedly influenced my inevitably career choice.  After spending ten years in other areas within healthcare, I started my own career in market research after his passing.  I have find similar joy in the industry working with others to make a significant contribution.  He continues to inspire me to learn new things, grow in the profession, and bring integrity to everything that I do.

Looking at the changing healthcare landscape, I can only hope others (and myself included) can continue to follow his example within healthcare market research.

Katie Fordyce

Starbucks, Pumpkin Spice Latte and Why Medical Myths Persist in the Age of Information

September is almost upon us and with it, the sights and smells of autumn: kids in school, college football, leaves on the ground and for some, most importantly, the return of Starbucks’ Pumpkin Spice Latte (PSL). With its own Twitter account, Facebook page and an army of avid lovers, this seasonal drink is a rock star among lesser beverages. Recently, a friend of mine reposted a dire warning from a popular food blogger about PSL. The photo showed a close up view of the drink and listed nine different reasons not to drink it: everything from pesticide residue to potentially hazardous ingredients. Most ominously, Carmel Color Level IV leads the list with the claim that it is considered to be a carcinogen.

Almost two decades of being a market researcher has made me skeptical of any claim of medical benefit or harm. It’s too easy to be misled or to misunderstand data, especially any that involve provocatively scientific conclusions. In the PSL, the issue is the formation of 4-methylimidazole (4-MI) in the manufacturing process of the caramel coloring. The claim cited a 2008 toxicity and carcinogenicity study by Chan, Hills, Kissling and Nyska (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366200/) as scientific proof of the chemical’s harmful effects and the company’s intentional disregard for the safety of its consumers. A little digging and a few keystrokes led me to a snopes.com article that debunked the claims (http://www.snopes.com/food/ingredient/pumpkinspicelatte.asp). I also found that the US Food and Drug Administration and the European Food Safety Authority have both concluded that consumers should not be concerned about 4-MI.

If the truth about this claim was so easy to find, why do this and other medical myths persist? The answer involves the way humans make decisions when confronted with overwhelming and conflicting information. Specifically, the shortcuts we use and assumptions we make in evaluating the credibility of data. In this case, I looked for data from information sources I trusted (e.g., snopes.com and government sites). In evaluating the credibility of the data, I made three specific assumptions: 1) snopes.com has the ability to correctly evaluate the claim, 2) information published on government websites are accurate, and 3) I have the ability to understand clinical trial information published in a journal article. Implicit in each of these assumptions, of course, are many more assumptions. When combined, they form a heuristic structure that helps to interpret the information I receive and decide what to do next. My friends’ assumptions were fundamentally different from mine, which led her to a very different conclusion. In identifying the assumptions, we quickly understood how two intelligent people could come to vastly different conclusions.

This same pitfall applies to marketers as they wade through a sea of potentially conflicting data about their markets, consumers and competitors. It’s not only the data itself, but also the lens through which that data is evaluated that can make all the difference between a successful and failed campaign. It is for this reason Cadence staffs projects with people from varied backgrounds: brand planning, sales, market research, regulatory, etc. It helps us to identify and (if needed) challenge the assumptions we work with as we design, execute and interpret research. For everyone from brand managers to consumers, a little skepticism and a willingness to identify hidden assumptions is the key.

As for me, I can sleep tight, knowing that my favorite Starbucks drink isn’t going to kill me anytime soon.

 —Sugata Biswas

The Cadence Concierge Experience

I often get asked why I joined Cadence and what sets us apart from other Medical Communications companies. For me, it’s a very obvious answer: we provide a concierge-level quality of customer service.

All agencies care about the outcome of each project. Each team stands a hundred percent behind what they do and are committed to each task at hand, no matter how big or small. But our clients have told us that we consistently go above and beyond that level. A few weeks ago, a client told me that he had just watched the film, “The Grand Budapest Hotel,” and she couldn’t help thinking of how we made her experience feel like she was being looked after by Ralph Fiennes’ character. She said, “You know, you should call it the ‘Cadence Concierge Experience.’”

I knew exactly what she meant. Many hotels have someone that you can ask for advice as to what activities you could do, or where you should go and eat, and you will usually talk to someone who will pull out a city map start drawing circles. However, the very best properties have professional concierge who is genuinely thrilled to guide the guests’ itineraries and usher them through an exquisite experience. At Cadence, we only hire these concierge-level people, screening for individuals with good attitudes and who demonstrate the ability to truly care about our clients. This cannot be simply taught, nor can it be simply bought.

There are a number of unique situations we’ve found ourselves in over the years, and each time our team has gone above and beyond the letter of the contract. We pride ourselves of being one of the best medical communication companies in the industry, and all our team members are highly qualified with many years of experience in the field. As such, we know the extent to which careful attention to what others might consider to be minor or small details can make a major difference to our clients.

In one situation, our team was managing a European meeting and our client was looking forward to exploring the city once the meeting was completed. However, he was a bit intimidated by the public transport system, and mentioned that he was nervous about taking the local train. Our team researched the train lines, accompanied him to the station, and outlined how he could get to his destination and back to the hotel again. He arrived back that evening, full of stories and enthusiastically grateful for our assistance and the boost of confidence it gave him.

On another occasion, the meeting we had organized happened to coincide with a major storm that had moved into the area at the same time advisors were scheduled to arrive. Our client was extremely concerned about the participants getting to the meeting safely and timely, given the cancelled and delayed flights that resulted. To allay their fears, we posted team members in the hotel lobby until very late at night to personally greet each advisor upon arrival, to show them how grateful our client was that they still made the trip despite the delays and less than convenient travel experience. The next day, several of the advisors commented that this small gesture was greatly appreciated, and our client told us that we had made them feel taken care of at the end of a long and frustrating travel day.

One other situation occurred at one of the major European Medical Conferences, where in addition to supervising several projects for large clients, the Cadence team was also assisting in a smaller project for a start-up company. When the Cadence team landed on the tarmac, they found several urgent voicemails from the start-up client disclosing that there had been a terrible mix-up in the printed materials their internal team had prepared for another project, and they didn’t have the ability to fix the problem on their own. Our team jumped to action immediately and found a local printer who was able to recreate the materials. The Cadence team went to the printer, proofed them for accuracy, and then personally delivered them to the hotel where our client told us, “You really saved my bacon!”

Of course, small situations like this don’t make or break any event; however, it has definitely been our experience that if clients and meeting participants feel that all the details of the meeting are being handled professionally and that the organizing team truly demonstrates that it cares, it frees the client to focus on the big picture. Ultimately, our mission is to help our clients reach their short-term and long-term goals, and I think we have found that small acts of kindness go a long way.

Susanne Blassingille

The Forward March of Regress

The Annual Meeting of the American Society of Clinical Oncology (ASCO) is one of the largest (if not the largest) cancer meetings in the world, and certainly within the United States. Practicing oncologists, nurses, physician scientists, research scientists, and thousands of pharmaceutical and biotechnology professionals, to say nothing of the myriad of patient support and advocacy experts, descend each year on Chicago the first weekend in June to network, recruit partners and allies, and of course to present the results of clinical trials both large and small.

The expectation within the American media, as well as within the culture it serves, is that ASCO should herald the announcement of some Grand New Development in cancer therapeutics, some kind of breakthrough treatment taking advantage of the bleeding edge of scientific and translational research to completely change the paradigm of care for some (or all) cancer patients. And while this does happen from time to time (such as with Herceptin or Gleevec), the advance of cancer care usually doesn’t follow this pattern. More often, new investigational agents are shown to make only incremental gains against the standard of care, subtly shifting the balance of the therapeutic index for patients. And sometimes new research shows that impressive new advances can be made with old drugs.

Take for example, the report on the Eastern Cooperative Group (ECOG) trial E3805 (aka “CHAARTED”), which compared androgen deprivation therapy (ADT) with or without the drug Taxotere in men with metastatic hormone-sensitive prostate cancer.[1] In this trial, Dr. Christopher Sweeney explained that Taxotere, which had been approved in 2004 for use in metastatic prostate cancer (but only in men whose disease was no longer responsive to hormone therapy) had been shown to confer a two-month increase in overall survival. The hypothesis of this trial, however, was that Taxotere would be more effective at prolonging overall survival if administered before the metastatic disease became refractory to hormone therapy. It turned out that their hypothesis was right, as the addition of Taxotere to ADT resulted in an increase of nearly 14 months to median overall survival for the entire patient population, and an increase of 17 months for patients with high volume disease. Thus, a substantial gain in survival was achieved not by developing either new drugs for new targets, or even new drugs for old targets, but simply by using old drugs for old targets in a new way.

And sometimes new advances can’t be made with new drugs either. The first report of the Phase 3 collaboration between the Breast International Group and the Alliance for Clinical Trials in Oncology (previously known as the North Central Cancer Treatment Group), BIG-2-06/N063D (also known as “ALTTO”), was also reported at this year’s ASCO meeting.[2] Dr. Martine Piccart-Gebhart discussed how she (along with co-PI Dr. Edith Perez) and many in the breast cancer community had been impressed by the improved survival outcomes associated with Herceptin use in the adjuvant setting for patients with early-stage HER2+ breast cancer, and designed the trial to determine if dual blockade of the HER2 receptor (using both Herceptin as well as the HER2-targeted tyrosine kinase inhibitor Tykerb) would provide any additional clinical advantage. The ALTTO trial was a massive undertaking, with over 8000 patients registered to four different treatment arms; I was present at the initial investigator’s meeting which kicked off the trial in 2007, and even then it seemed like a mind-boggling feat to accomplish. But accomplish they did, though it turned out to be a negative trial. In her presentation, Dr. Piccart-Gebhart explained that excluding the Tykerb monotherapy arm (which had been shut down in 2011 due to evidence it would not show non-inferiority to the Herceptin monotherapy arm), the three remaining arms were virtually indistinguishable in terms of disease-free survival and overall survival, and the Tykerb-containing arms demonstrated significantly higher incidence of adverse events, particularly with regard to diarrhea and rash.

The ALTTO results were a blow, not just to the study investigators and sponsors, but also to those who work in the field of breast oncology. In his commentary immediately following the ALTTO results, Dr. George Sledge (one of my favorite oncologists ever[3]) expressed his frustration with the failure of the trial, not just because of its immediate ramifications, but because it signals a failure of the field of breast oncology to understand a key aspect of the disease, as well as to be able to extrapolate success in the neoadjuvant or metastatic settings to the adjuvant setting. It had been hoped that showing a benefit to pathologic complete response (pCR) in the neoadjuvant setting (which had been shown for the combination of Tykerb and Herceptin in the NeoALTTO trial) could serve as a reliable indicator of overall survival benefit in the adjuvant setting. Unfortunately, the experience with Herceptin in this regard now appears to be the exception, not the rule. Indeed, Dr. Sledge pointed out that the role of biologics as adjuvant therapy for multiple tumor types now appears to be largely futile.

But I don’t lose hope. Negative trial data may be disappointing, and they may be a psychological roadblock for research, but scientifically they are just as informative as positive data.[4] Indeed, with the public presentation of ALTTO now all but completed (there will be some future updates that are unlikely to change the outcome), researchers can now move away from its answered question and explore other options. More molecular targets are ripe for investigation, such as PI3K, MET, and Hsp90. Researchers and pharmaceutical companies are hard at work on the bleeding edge of the oncological pipeline, and future ASCO meetings will display the fruits of their labor.

Meeting Planning Processes 101’s

Planning 101’s

No matter where you are in the planning process for your upcoming program, we thought you could use some ideas of what to discuss with your vendor of choice. Here are some of our top 10 tools & priceless pieces of advice.

Six or more weeks prior to the meeting

#1        Pick a date that works best for your speakers and team members. Make sure to review the calendar to ensure that the date doesn’t fall over any holidays.

#2        Determine the start and end times of the meeting, and if you will require a separate room for meals and or breakouts. This is important to know when venue sourcing.

#3        Work on an invitation that will get people’s attention by using your companies branding for added visuals. Cadence can also assist you with specific meeting graphics based on the content of your program. Just ask us how we can help!

#4        We suggest using email as your first line of communication. Most physicians don’t have time to read through their physical mail, and faxes tend to get ignored.

#5        Ensure confirmations go out as soon as possible so the attendee has all the information they need to block out their calendar and book any travel arrangements necessary.

#6        Submit your rooming list, menu, AV requirements and final meeting details to the hotel. Make sure to include a final head count.

One week prior to the meeting

#7        Ensure all attendees receive a final confirmation with all the meeting/travel details including: ground transportation, hotel parking, flight arrival & departure details, hotel confirmation numbers and contact information for them to be able to reach someone in the event they are having a travel issue.

#8        Finalize Meeting Agenda.

#9        Print all meeting handouts ahead of time when possible.

#10       Partner with a great vendor like Cadence Research, to ensure that your next meeting is a great success!

Hotel Do’s & Don’ts

☐         Make sure that the hotel cannot move the meeting room location without your prior written consent. One way to ensure this is by having the hotel list the names of the meeting rooms on the contract.

☐         Ensure that your sleeping room rate is effective three days prior and post meeting. In the event you have a guest that wants to stay over or come in early.

☐         Confirm there is a “Force Majeure” clause in your contract to protect you against acts of God, war or terrorism.

☐         A “No Walk Clause” – is also a necessity when signing a contract. You want to make sure the hotel cannot walk any of your guests to another hotel.

We hope you found this to be helpful, these are just a few key items to remember when planning a meeting. Cadence Research & Consulting has more thorough checklists for each and every program, and we would appreciate the opportunity to plan your next program. Please let us know how we can help YOU to ensure that your next meeting is an amazing success!

Can you create Competitive Immunity through the Challenger Sales Model?

With the global healthcare market becoming more and more complex, and the number of decision makers involved in patients’ care decisions growing exponentially, those competing in today’s integrated delivery networks (IDN) need to re-think their current sales approaches.

Sales organizations that depend on a transactional based sales approach, where the focus is on presenting as much information about your products or services as possible, or the relationship approach, where it’s all about making friends, need to seriously consider what Mathew Dixon & Brent Adamson have coined as, “The Challenger Approach to sales.” Here the focus is providing solutions tailored to your customers’ business challenges and challenging your customers to take action.

A Challenger Representative is defined by:

  1. The unique ability to teach for differentiation during a sales call
  2. Delivering a tailored message based on their understanding of their customer’s unique economic drivers
  3. Taking control of the sales process by comfortably challenging customers.

So what makes the Challenger Selling Model a perfect fit for organizations selling in the IDN setting? It enables you to build the competitive immunity that comes from becoming an invaluable business partner. By offering your customer tailored business solutions that allow them to be successful, you take the focus from selling based on just price and shift to a more powerful value proposition.

The good news is that selling is a science, a teachable skill, and a process that anyone can learn, but you must provide your sales organization with the tools and training needed to deliver effective selling messages.

How do you do this?

  1. Build content through your respective marketing teams to ensure tight collaboration.
  2. Create messages that are scalable and repeatable.
  3. Be clear that your marketers bear the responsibility of identifying the message that will be of most value to each respective client stakeholder.
  4. Bring the two teams together that must work closely to make your organization’s transition to the Challenger Selling Model successful – Marketing and Sales Training.

There is no question that transitioning to the Challenger Model approach with your complex clients will be key to the future success of your organization, but the close alignment of your sales training and marketing teams will assure that this transition goes smoothly!

What Does it Mean for a Vendor to be of Service?

Service, like so many words in the business lexicon, seems to have lost it’s meaning as it has become a ubiquitous marketing term.   At Cadence, service speaks to not only what we do but also how we do it.  Service means consistently providing outstanding work AND a providing a great client experience.  Client experience is the foundation of everything we do.  Having walked in our client’s shoes, we understand the dynamic nature of their work environment and the daily demands that are placed upon them that go beyond a single project.   As such, our aim is to be a collaborative partner that our clients can rely on to consistently deliver high quality service.   Our biggest compliment is when our clients tell us that they don’t have to worry about any project that we are involved with.  Giving our clients this peace of mind is what we strive for in every single project.

Sugata Biswas

Leveraging Innovation Centers to Re-prime the Development Pump!

Innovation!

Innovation is a hot word right now in pharmaceutical strategy.  It is futuristic, creative, cutting-edge, energizing, and entrepreneurial.  Innovation is not hype, though.  It is the solution to the reality that internal R&D labs are losing productivity, drug approvals are down, and venture capital for start-ups is drying up.  Innovation has just a little do with a brilliant idea, though, and everything to do with executing it with discipline.

How is this exciting?  This sounds dull.

There is a vibrant community of biotechs, academics, incubators, and accelerators teeming with cutting-edge science.  To forge the deals that will re-prime its development pump, pharma must take its careful processes, performance criteria, gates, and thresholds and apply them to this wild and exciting space.  Innovation is a methodical, stepwise process of diligence, negotiation, contracting, planning, and collaborating.

Inside Out

Innovation is about creating value.  Innovation centers are cropping up in scientific hot spots – outside of traditional pharma campuses – all over the globe.  Pharma’s goal is to embed its best and brightest in the scientific community to partner with entrepreneurs and academicians.  Innovation has, quite simply, turned the pharma model inside out. Done well, innovation can result in on-boarding new products and business models at a sustainable steady state over time.  By looking outside, innovation creates value inside.

— Sherry Danese

What are the biggest concerns manufacturers have about the Sunshine Act?

With regard to the Sunshine Act, the pharmaceutical, biotechnology, and medical device industry are presently concerned with a number of issues:

1)  How will the Sunshine Act weigh on reporting indirect payments to physicians?

The CMS allows manufacturers to send payments to physicians through third-party agents if and only if they remain unaware of the identities of said physicians. Otherwise, the CMS is concerned that manufacturers might adjust their financial relationships to take advantage of an indirect model for sending payments. In addition, CMS will require third-party agents to track payment information on behalf of manufacturers, which can then be reported by either the third-party or the manufacturer, but not both.

2)  How will companies develop and execute aggregate spend plans?

Manufacturers will need to be highly confident in the quality and accuracy of their master databases, including verifying the accuracy of their physician information (including license numbers), removing duplicate records, and improving the usability of their database systems. In addition, manufacturers will need to designate someone within their organization to validate and communicate these payments to physicians, as well as to handle reporting disputes.

3)  How will the Sunshine Act affect physician learning and research?

Dr. Henry Black, a clinical professor in the Department of Medicine at NYU Langone Medical Center, views the Sunshine Act as an “abomination.” Of most concern is that the Sunshine Act requires documentation of gifts and dinners alongside grants that sponsor new research, and may have a chilling effect on the state of clinical research in America. Thus, the Act may prompt a decrease of medical innovation in the United States, shifting the tremendously expensive burden of novel drug and device development to an already overburdened public health system.

4)  How educated and prepared are physicians on the new guidelines?

The American Medical Association has developed an online resource for physicians to help educate themselves on the reporting process outlined by the Sunshine Act. This resource will include, as it becomes publicly available, a physician portal through CMS that will allow physicians to access reporting information, as well as an informational chart that characterizes the differences between federal and state Sunshine Laws.

5)  How can companies maintain relationships with physicians?

The relationships between manufacturers and physicians are essential for both scientific innovation and clinical research. However, relationships between the two are subject to more scrutiny now than ever before, from the CMS and state oversight laws, as well as hospitals and academic institutions. At present, the onus is on physicians to understand the reporting and transparency rules, but manufacturers can help by creating systems that are as simple and painless as possible.

Zachary Moore

Will the Sunshine Act eliminate bias from the US healthcare system?

Whether or not the Sunshine Act will improve or diminish the practice of medicine in the United States remains to be seen. But it will not eliminate the role of bias in the medical field or the pharmaceutical industry. Earlier this year, the Department of Health and Human Services ruled that the so-called “Physician Payments Sunshine Act” (Section 6002 of The Patient Protection and Affordable Care Act), will go into effect. The goal of this Sunshine Act is to introduce more transparency into the financial relationships between drug, device, and biologic manufacturers and the physicians who advise, consult, and work with them. Any payment or gift greater in value than $10 given to any physician must be submitted to the Secretary of Health and Human Services, and be posted on a publicly-available website, or prompt a fine of as much as $10,000 per gift, which will be the responsibility of the company. Data will be collected by the Centers for Medicare and Medicaid Services (CMS) beginning August 1, and all 2013 data is due by March 31, 2014. The CMS will begin making these data public by September 30, 2014.

Ostensibly, this Sunshine Act has been created to limit the amount of physician bias in the modern healthcare system, something with which Dan Ariely is intimately acquainted. As a burn patient, he was at the mercy of forces beyond his control, and as he found, often beyond rationality itself. Now, as a noted behavioral economist and psychologist, he’s published widely on the irrationality of human behavior. In his blog, Ariely comments frequently on his research into irrationality and the effects of cognitive bias in the world around us.

In this video from TED, Ariely speaks about how physicians (and other researchers) can be motivated by their own biases to persuade their patients to follow a specific course of treatment.

For companies like Cadence Research and Consulting, the impact of the Act depends on the specifics of the project through which physicians are engaged. Guidance from CMS indicates that market research is exempted from reporting requirements due to the fact that a manufacturer is not paying physicians directly, and that the identity of the manufacturer is necessarily kept hidden from the physician. However, money spent on physician travel, food, and lodging for “promotional” activities like advisory board meetings or investigator meetings should already be recorded. For these items, Cadence proactively maintains a master list of these expenses for each physician that can be tailored to each individual client’s needs. In many cases, clients already provide us with individual reporting spreadsheets that can be completed and submitted with meeting deliverables and close-out files.

Of course, whether or not the Sunshine Act will improve or diminish the practice of medicine in the United States remains to be seen. But it will not eliminate the role of bias in the medical field or the pharmaceutical industry. As Dan Ariely notes, “It’s just a fact of human life: we are compelled to reciprocate favors, and an ingrained inability to disregard what’s in our financial interest.”

Zachary Moore

Mixology…Blending Methodologies for Today’s Challenges

Mixed methodologies research offers the best of both worlds: the in-depth, contextualized, and natural but more time-consuming insights of qualitative research coupled with the more-efficient but less rich or compelling predictive power of quantitative research.

Mixologists practice mixology and bartenders tend bar.   Mixologists evolve the field of bartending, creating innovative cocktails the world has never seen.  A bartender serves the drinks that customers order.

It is time for the mixologists in all of us to shake up market research. Questions rarely come in a box and rarely are contained to a single department.  Now is the time to mix up the methodological approach to help all the stakeholders answer their questions.

Mixed Methods.  What are they?  For some, it means blending primary and secondary research techniques.  Others leverage epidemiology to inform subsequent phases of research.  And others apply social media analytics to augment their data collection beyond traditional channels.

We don’t think the definition really matters.  At Cadence, we like mixing methods to take the best advantage of research techniques across marketing, clinical development, business analytics and forecasting.  There’s no question that traditional concept testing using in-depth personal interviews provides deep qualitative input that is invaluable to answering key questions.   After all, sometimes all you really need from the bartender is a martini.

But, let’s say our client really wants to know if the concept’s underlying technology meets an unmet need in a highly specialized facet of the oncology market.  And, if so, what is the market size and how would the technology be positioned?  And what would the forecast look like at various price points for a product used in this position?   It turns out our client didn’t really want a simple drink, but never imagined the perfection of a Melograno made with orange infused vodka, orange liqueur, fresh pomegranate and fresh pineapple.   To truly be of service to this client, we need to find our inner mixologist and bring a fresh, sophisticated approach.

On March 27, 2013, the Wall Street Journal reported that ASCO announced a new clinical tool in development called CancerLinQ.  This is a database that essentially converts all cancer patients in the U.S. to clinical study participants.  The system collects data that doctors record in a patient’s files, such as age, gender, medications and other illnesses, along with the patient’s diagnosis, treatment and, eventually, date of death.   Doctors tap the database for help in developing treatments for other patients.

Our methodology for this client can borrow analytic techniques from epidemiologist and use this new data set to mix it up:

  1. Quantify the market:  Connect to the CancerLinQ database to query real patient data
  2. Assess the technology on-line:  Specialists are too far-flung for in-person research and are too busy for telephone interviews.  Undertake a technology assessment using a longitudinal on-line focus group that allows users to log in and out for short periods of time over several days.  You actually get broader and deeper data at a lower cost.
  3. Leverage social media analytics to determine what is being said in the millions of conversations happening in patient groups, physician networks, Twitter YouTube, Facebook; the possibilities are endless.  Algorithms being employed to look at back-of-mind sentiment and attitudinal behavior are as powerful and complex as those employed by the FBI.
  4. Build a model:  Feed the market size and adoption data into a forecasting model using scenarios for various price points. You can use a choice model if you are after a dynamic assessment or start with a univariate test if you have discrete price points and a fixed product profile.

So, in the end, we mixed a database query, a technology assessment using an on-line longitudinal format, and a dynamic forecast to answer what started out as a “concept assessment” question.  Dig a little deeper, mix up the methods, and deliver truly impactful research.

— Sherry Danese

Founder’s Blog: Why You Should Give a Damn about Your Vendor’s Culture

We think we have something pretty special at Cadence that you may never see directly.  It is technically invisible and a little hard to describe, but we think it’s tangibly felt by all our clients.  What is it?  It’s simply our internal culture.   Perhaps you are thinking, “Sure, but why should I care about it?”

I’ll give you 3 good reasons that impact you and the work you do every day with a vendor:

  1. Staffing Turnover
  2. Deliverable Quality
  3. Partnership Skills

It’s undeniable that when you work with a vendor, you’d prefer to have a consistently knowledgeable team, quality output and a great service over and over again.

1. Turnover (or the lack thereof)

A company’s internal culture has a big impact on whether you will see the same staff at the next engagement. If internal culture is poor, it results in high turnover leaving you exposed. You may face new team members who need to come up the learning curve on your project once again. The Harvard Business Review recounts a surgeon that achieved 2.5 times more surgeries than his peers with better outcomes by building teams that worked well together for long periods of time.  (HBR Dec 2013).   At Cadence we focus on staffing our projects from start to finish with the same experienced team, and building a great place to work that leads to high staff retention. For you, this means longer-term support with real continuity.

2. Quality

It’s somewhat simple.  The quality of the work is a function of not just the intelligence of the team working on it, but their ability to focus and deliver valuable insights.  Ultimately, a team of people deliver the work. The environment that they operate in has a huge impact on their focus and effectiveness.  Are team members in a culture that helps them resolve conflicts? Is it a place that supports creative thinking and honest conversation? Does the culture empower them to contribute their best?  If not, you aren’t getting the best output on your project.

3. Partnership

In my view, the best partners are a bit like a good friend.  They can tell you the straight story even if it is hard to hear, they show up for you, and your interactions are genuine and beneficial.  These relationships feel authentic to you for good reason.  You have mutual trust, they have your best interest at heart and you succeed together.  What does culture have to do with this?  Well, if we can’t build strong relationships inside our organization, how are we going to foster them outside of it?   Teams are more successful in providing services when they have these partnership qualities – authenticity, a proactive work ethic, team orientation, strong communication skills, etc.   We look for these qualities in bringing staff in the door, and work with them to consistently deliver a great partnership – inside and outside Cadence.

Do these factors seem obviously simple?   Maybe so, but we bet you’ll find they deliver a powerful experience.

Laura Smith

What will be the impact of the ACA on cancer treatment?

The Patient Protection and Affordable Care Act of 2010 (ACA), commonly called “Obamacare,” is currently approaching full implementation. As of January 1, the Health Insurance Marketplace will provide coverage to those who do not have it provided by their employers. Two years ago the American Society of Clinical Oncology (ASCO) assembled a team to assess the implications of the ACA and craft an official policy statement for the organization. Led by Dr. Beverly Moy, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital, the statement notes several challenges within the ACA specifically with regard to cancer care. The expansion of Medicaid in particular was pointed out as having limited applicability to cancer patients, creating potentially poorer standards-of-care for those who participate in the system, and resulting in suboptimal reimbursement across the board. In addition, ASCO statement noted that the ACA preferentially benefits community health centers while disadvantaging the specialty treatment centers which have now become standard for cancer therapy. In addition, the ASCO statement suggests that Medicaid patients may not be able to participate in clinical trials.

Opinions vary regarding the overall positivity or negativity of the ACA with regard to cancer care. Forbes contributor Scott Gottlieb suggested that the ACA will restrict patients’ access to specialist physicians, including oncologists. He predicted that insurance providers may mitigate costs from cancer patients by limiting their access to in-network providers, effectively forcing them to pay out-of-pocket for the bulk of their care. However, the President of the ASCO, Dr. Clifford Hudis, recently noted in an interview with Reuters that he felt the implementation of the ACA would be a net benefit for his patients, and would especially improve the situation for cancer patients who have had difficulties securing coverage for long-term treatment of their disease.

Dr. Robert Figlin, of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, has expressed a more skeptical view of the ACA with regard to cancer care. In a discussion with CadenceTalk, he noted that the ACA will likely improve treatment of common diseases like hypertension, diabetes, and pneumonia. However, he agreed with Gottlieb that access to oncology specialists would be limited. In addition, he noted that since much of the clinical research in cancer is driven by expert physicians, patients covered by ACA plans are not likely to have access to the latest experimental treatment options, and thus will not have access to the optimal care for their disease. Furthermore, Dr. Figlin observed that the number of available oncologists for patients with insurance coverage prior to the activation of the ACA was already too low, and adding more patients into the coverage pool will likely strain available resources for the whole country.

It will yet remain to be seen whether the increased availability of cancer care will offset any potential limitations in the quality of care, though oncologists all over the country are keenly anticipating the outcome as ACA coverage begins next year.

Zachary Moore