On February 7th, the FDA expanded the approval of abiraterone acetate (ZYTIGA®) treatment to patients with high-risk castration sensitive prostate cancer . 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 . 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 .
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) . 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 . Other benefits experienced in the AA arm included a longer time to chemotherapy and pain progression over patients in the ADT arm . 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.
- 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.
- Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 5-29.
- 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.
- 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.
- Fizazi, K., et al., Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med, 2017. 377(4): p. 352-360.
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 . 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 .
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) . Out of 68 evaluable patients, the overall response rate was 50% and the complete response rate was 32% . 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 . 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.
- 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.
- 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.
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 . 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 . 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) . It was previously approved in December of 2016 for the third-line treatment of patients with deleterious BRCA1 or BRCA2 mutation-positive ovarian cancer . BRCA1/2 proteins function as tumor suppressors by supporting homologous recombination, and therefore cells with dysfunctional BRCA1/2 proteins are sensitive to PARP inhibition .
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) . 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 . 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 . 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%).
- 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.
- Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.
- 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.
- 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.
- 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.
- 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.
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) . 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 . 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®) . 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 . 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 . It was initially approved in 2015 for the treatment of patients with EGFR T790M mutation-positive NSCLC .
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) . 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 . 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 . These results suggest that osimertinib can produce durable responses for frontline patients with EGFR-mutant NSCLC.
- 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.
- 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.
- Heydt, C., et al., Novel approaches against epidermal growth factor receptor tyrosine kinase inhibitor resistance. Oncotarget, 2018. 9(20): p. 15418-15434.
- 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.
- 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.
- 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.
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 . 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 . gBRCAms can result in dysfunctional BRCA1 or BRCA2 proteins and have been implicated in several cancer types including ovarian, breast, prostate, and pancreatic . 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 .
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) . 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 . 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.
- 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.
- 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.
- 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.
- Ceccaldi, R., et al., Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature, 2015. 518(7538): p. 258-62.
- 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.
- 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.
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®) . 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 . Standard frontline treatment for RCC includes anti-angiogenic treatment with sunitinib, a tyrosine kinase inhibitor (TKI) that targets several angiogenesis-promoting kinases . 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 .
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) . 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 . Additionally, the overall response rate was improved in the nivolumab-ipilimumab arm, 42% vs. 27% as well . 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 . This approval provides another therapeutic option for patients with advanced RCC.
- 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.
- 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).
- 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.
- 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.
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) . 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) . 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 .
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 . 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.
- 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.
- Chereda, B. and J.V. Melo, Natural course and biology of CML. Ann Hematol, 2015. 94 Suppl 2: p. S107-21.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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) . 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 . 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 . 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 . 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 .
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) . 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 . 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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 . 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 . 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 . 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) . 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 . 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 . 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.
- 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.
- 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.
- 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.
- 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.
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 . ATC is a rare and deadly malignancy composed of highly undifferentiated thyroid cells . 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 . 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 .
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) . The overall response rate in patients with ATC, was 61% (N=23) with 64% of responses lasting longer than 6 months . 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.
- 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.
- Tiedje, V., et al., Anaplastic thyroid carcinoma: review of treatment protocols. Endocr Relat Cancer, 2018. 25(3): p. R153-r161.
- Tiedje, V., et al., NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma. Oncotarget, 2017. 8(26): p. 42613-42620.
- 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.
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 . 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 . 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 .
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) . The estimated 3-year rate of relapse-free survival was enhanced in the arm receiving the combination at 58% vs. 39% respectively . 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.
- 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.
- Long, G.V., et al., Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol, 2011. 29(10): p. 1239-46.
- 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.
- Robert, C., et al., Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med, 2015. 372(1): p. 30-9.
- 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.
- 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.
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) . 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 . 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 . Blinatumomab was originally approved in 2014 for the treatment of relapsed or refractory Philadelphia chromosome-negative ALL .
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) . 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 . Blinatumomab was well tolerated with the most common grade 3 or 4 adverse events being neurological events (13%) and cytokine release syndrome grade (2%) . 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.
- 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.
- 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.
- 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.
- 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.
- 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.
On February 14th, the FDA approved apalutamide (Erleada™) tablets for the treatment of nonmetastatic castration resistant prostate cancer . Prostate cancer is the most common malignancy and second most common cause of cancer-related death in men in the United States . 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 . Apalutamide is a small molecule that directly binds to and inhibits AR molecules, thus bypassing various castration resistance mechanisms .
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 . 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 . 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%) . 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.
- 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.
- Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 5-29.
- Dai, C., H. Heemers, and N. Sharifi, Androgen Signaling in Prostate Cancer. Cold Spring Harb Perspect Med, 2017. 7(9).
- Clegg, N.J., et al., ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res, 2012. 72(6): p. 1494-503.
- 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.
- Smith, M.R., et al., Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med, 2018.
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 . 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 . 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 . 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 . 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 . 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 . 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.
- 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.
- 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.
- 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.
- 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.
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) . 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 . 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 . 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 .
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) . 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 . 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.
- 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.
- 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.
- 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.
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) . It was originally approved in September of 2017 for patients with
HR-positive, HER2-negative advanced BC who had previously received endocrine therapy .
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 . CDK4 and CDK6
overactivity has been implicated in several malignancies including non–small cell lung cancer
(NSCLC), melanoma, glioblastoma, mantle cell lymphoma, and BC .
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) .
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% . 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].
- VERZENIO™ (abemaciclib) tablets, for oral use. Drugs@FDA: FDA Approved Drug Products
February 26, 2018 [cited 2018 April 13]; Available from:
- VERZENIO™ (abemaciclib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products
09/28/2017 [cited 2018 April 13]; Available from:
- 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.
- KISQALI® (ribociclib) tablets, for oral use Drugs@FDA: FDA Approved Drug Products 03/13/2017
[cited 2018 April 13]; Available from:
- IBRANCE® (palbociclib) capsules, for oral use Drugs@FDA: FDA Approved Drug Products
02/06/2018 [cited 2018 April 13]; Available from:
- 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.
- Goetz, M.P., et al., MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J
Clin Oncol, 2017. 35(32): p. 3638-3646.
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:
- Staffing Turnover
- Deliverable Quality
- 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.
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.
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