FDA Updates: Oncology

Published on: 
Evidence-Based Oncology, December 2015, Volume 21, Issue SP16

Several new FDA approvals and research advances in oncology have the potential for improved outcomes among cancer patients.

Tagrisso Approved, but Can Patients With EGFR-Mutant NSCLC Afford It?

AstraZeneca’s epidermal growth factor receptor (EGFR) inhibitor, osimertinib (Tagrisso), was recently approved in patients harboring T790M-mutated non-small cell lung cancer (NSCLC) who have regressed following treatment with other EGFR inhibitors.1 The approval comes within 3 years of the company having launched drug trials for osimertinib, which showed an objective response rate of 59%, and a sustained response of over a year.

Having specifically developed the drug for a subset of NSCLC patients, Astra- Zeneca collaborated with Roche Diagnostics to develop a companion diagnostic, the cobas EGFR Mutation Test v2, which detects EGFR mutations in NSCLC tissue samples.

While oncologists, including Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, have hailed osimertinib to have the potential to be the standard of care in EGFRm T790M NSCLC, the question now is how much will it cost the patient and the healthcare system overall, and, will this cost add value?

According to a company spokeswoman, a 1-month supply of this oral medication is estimated to cost nearly $13,0002—quite comparable with Pfizer’s Xalkori (prices at $11,500 a month) and Zykadia by Novartis ($13,200), both approved for treating Alk-mutated lung cancer. And, we have not yet started talking about the cost of the companion diagnostic test that will determine patient eligibility for osimertinib.

While previous estimates from AstraZeneca projected a $3 billion annual market for the drug, the news of Clovis Oncology’s competitor product hitting a snag in their FDA review could further open up the market for AstraZeneca. CO-1686 or rociletinib, which has shown promising results in EGFR-mutated (T790M) NSCLC patients, now needs additional data for FDA review.

Meanwhile, Diplomat Pharmacy, the largest independent specialty pharmacy in the country, has announced plans to offer osimertinib to a few select patients. “Diplomat is proud to support patient adherence and compliance with therapy through enhanced clinical outreach programs, with customized messaging, developed in collaboration with AstraZeneca, to patients through various stages of treatment,” said Gary Kadlec, president of the company, when making the announcement.3


1. TAGRISSO (AZD9291) approved by the US FDA for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer [press release]. Wilmington, DE: AstraZeneca; November 13, 2015. media-centre/press-releases/2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-patients-with-EGFR-T790M-mutation- positive-metastatic-non-small-cell-lung-cancer-13112015.html.

2. AstraZeneca’s Tagrisso to cost $12,750 for a month’s supply. Reuter’s website. article/2015/11/17/us-astrazeneca-cancer-tagrisso-idINKCN0T61J420151117?feedType=RSS&feed- Name=health&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+reuters%2FINhealth+%28News- +%2F+IN+%2F+Health%29. Published and accessed November 17, 2015.

3. Diplomat to dispense AstraZeneca Drug TAGRISS (osimertinib) [press release]. Flint, MI: Diplomat Pharmacy, Inc; November 16, 2015. 300179523.html.

Daratumumab Approval Yields the First Monoclonal Antibody, and Another Option, in Multiple Myeloma

The FDA has approved daratumumab for patients with multiple myeloma who have previously been treated with at least 3 regimens.1 Daratumumab, which received breakthrough status 2 years ago, is the first monoclonal antibody approved for multiple myeloma.

The approval follows review of 2 open-label studies that included 106 and 42 participants. The first study (phase 2 MMY2002) saw 29% of patients with a complete or partial reduction in tumor burden that was sustained for at least 7.4 months. These patients had received a median of 5 lines of prior therapy. The second study (phase 1/2 GEN501) saw a complete or partial reduction in tumor burden of 36% of patients. These patients had received a median of 4 lines of prior therapy. Today’s approval is the first for a CD38 antibody and comes just 2 months after the drug was submitted for priority review.


Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, hailed daratumumab as another option for patients to turn to when their disease has developed resistance to all other existing therapies.

Some of the side-effects associated with the drug include infusion-related reactions, fatigue, nausea, back pain, fever, and cough. Daratumumab may also result in low counts of infection-fighting white blood cells (lymphopenia, neutropenia, and leukopenia) or red blood cells (anemia), and low levels of blood platelets (thrombocytopenia).

Daratumumab, approved under the FDA’s accelerated approval program, had an orphan drug designation.


1. FDA approves Darzalex for patients with previously treated multiple myeloma [press release]. Silver Spring, MD: FDA; November 16, 2015.

A Cancer Prevention Trial Identifies Predictive Biomarker in Oral Cancer Development

Oral premalignant lesions (OPL) can be risk factors for oral cancer, and chemoprevention strategies can be developed to stop or reverse the cancer.

A trial designed to test one such strategy—the Erlotinib Prevention of Oral Cancer (EPOC)—evaluated whether inhibiting the epidermal growth factor receptor (EGFR) could reduce oral cancer development in patients with high-risk OPLs. While the EGFR inhibitor being evaluated, erlotinib, did not improve cancer-free survival (CFS), the trial validated loss of heterozygosity (LOH) as a marker of oral cancer risk and was associated with increased copy number of the EGFR gene.

The EPOC study, conducted between November 2006 and July 2012, recruited 395 participants with OPL in 5 academic institutions in the United States. Following LOH profiling, 379 patients were classified as high-risk (LOH-positive) or low-risk (LOH-negative). Treated with 150 mg/day erlotinib or placebo for 12 months, the trial followed patients for 35 months. One hundred and fifty of the 254 LOH-positive patients were randomized—75 received erlotinib and 75 were on placebo. The 3-year CFS rate was 70% and 74%, respectively, when comparing these 2-patient cohorts. However, 3-year CFS of LOH-negative patients was much better than that of LOH-positive patients—87% versus 74%, respectively. Further, the authors deduced a correlation between EGFR gene copy number and LOHpositive status, as well as EGFR gene copy number and lower CFS. A serendipitous finding of the trial was that patients who developed a skin rash, a side-effect of erlotinib, had better CFS.1

According to study author William N. William Jr, MD, associate professor at MD Anderson, “One of the greatest challenges in developing chemopreventive agents is to identify the population at highest cancer risk. Not all patients with an oral premalignant lesion will develop cancer. By developing a molecular test that can identify those at highest risk, we hope to focus future preventive efforts on these specific individuals.”2

The authors write that, while their results support using LOH testing as a prognostic tool in routine clinical practice, they do not support erlotinib use in this setting. Another feather in the cap of personalized medicine in the preventive setting.


1. William WN Jr, Papadimitrakopoulou V, Lee JJ, et al. Erlotinib and the risk of oral cancer: the Erlotinib Prevention of Oral Cancer (EPOC) randomized clinical trial [published online November 5, 2015]. JAMA Oncol. doi: 10.1001/jamaoncol. 2015.4364.

2. First precision medicine trial in cancer prevention identifies molecular-based chemoprevention strategy. EurelAlert! website. Published November 9, 2015. Accessed November 10, 2015.

Exceptional Response in Brain Tumor Patient Instills Confidence in Personalized Medicine

Ayoung man, less than 40 years old, with recurrent craniopharyngioma (pituitary tumor) harboring a BRAF V600E mutation, showed a dramatic response when treated with BRAF V600E inhibitors—85% reduction in tumor volume. This case has the “potential of completely changing the management of papillary craniopharyngiomas,” according to study author Priscilla Brastianos, MD, of the Massachusetts General Hospital (MGH) Cancer Center.1

The study, published in the Journal of the National Cancer Institute,2 reports on the case study of a patient who came to the emergency department at MGH, 7 months after having undergone surgery to excise a brain tumor. A CT scan of the patient, who complained of confusion, impaired vision, severe headaches, and vomiting, revealed a 4-cm cystic tumor. Six weeks following partial removal of the tumor, the patient was brought back and underwent additional surgery. At this point, the tumor was confirmed to carry a mutant BRAF. Another unsuccessful surgery and a recurrence in 2 weeks prompted the providers handling the case to treat the patient with the BRAF-V600E inhibitor dabrafenib, currently approved for the treatment of patients with unresectable or metastatic melanoma harboring the BRAF-V600E mutation.

A dramatic response was seen within 4 days of treatment, with a 25% tumor shrinkage, the authors report. Following a 50% shrinkage in tumor by day 17, the authors added a MEK inhibitor, trametinib, which has been approved for use in patients expressing a mutant BRAF (V600E or V600K).3 When the tumor reduced to 80% its original size, another surgery removed any accessible tumor at day 38 and drug treatment was stopped a week later, followed by radiation. The patient has been reported to be symptom—free for a year. Another extremely important outcome of the study was the ability to detect circulating tumor cells, which carried the BRAF mutation, using a blood-based assay. For patients with a brain tumor, a noninvasive test can be a tremendous advantage and can significantly reduce patient morbidity.

“It is quite remarkable how quickly we have been able to go from identifying the genetic driver of papillary craniopharyngiomas to testing the idea in a patient that needed help. It was only last year that, along with Dr Brastianos and colleagues, we first described in Nature Genetics that nearly all papillary cranionpharyngiomas have mutations in BRAF,” said co-senior author Sandro Santagata, MD, PhD, of Brigham and Women’s Hospital’s Pathology Department.


1. Targeted treatment produces rapid shrinkage of recurrent, BRAF-mutant brain tumor. ScienceDaily website. www. Published November 6, 2015. Accessed November 9, 2015.

2. Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst. 2015;108(2):pii:djv310. 3. Trametinib. FDA website. Accessed November 9, 2015.

Another First for Nivolumab: Approved as Frontline for BRaf Wild Type Melanoma

The new class of immuno-oncology molecules are definitely keeping up with their promised potential. Nivolumab was approved as first line for treatment-naïve melanoma patients whose tumors express a wild type (WT) BRaf V600.1 The approval follows 5 months after Bristol-Myers Squibb submitted phase 3 results of the Checkmate-066 trial for FDA review.

With overall survival (OS) as the primary endpoint, Checkmate-066 evaluated nivolumab as a single agent in treatment-naïve patients with unresectable or metastatic BRaf WT melanoma. Patients received either nivolumab (n = 210; 3 mg/kg intravenously, once every 2 weeks) or dacarbazine (n = 208; 1000 mg/m2, once every 3 weeks). Progression-free survival (PFS) and objective response rate (ORR) were the secondary endpoints. Interim trial analysis showed a superior OS with nivolumab compared with dacarbazine. Median OS was not reached for nivolumab at the time of analysis; for dacarbazine, it was 10.8 months (95% CI, 9.3-12.1). Nivolumab significantly improved PFS: 5.1 months (95% CI, 3.5-10.8) compared with 2.2 months (95% CI, 2.1-2.4) for patients treated with dacarbazine (Hazard ratio [HR], 0.43; 95% CI, 0.34- 0.56; P <.0001), and ORR was 34% (4% complete response rate [CRR], 30% partial response rate [95% CI, 28-41]) compared with 9% with dacarbazine (1% CRR, 8% partial response rate [95% CI, 5-13]). Nearly 88% of patients had ongoing responses at the time of analysis, about 68% of whom had at least a 6-month response.

Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center who has been actively involved with Checkmate-066, said, “Advanced melanoma continues to be one of the deadliest and most challenging cancers to treat, and ongoing research in immunooncology from clinical trials like CheckMate -066 shows the potential to provide improved overall survival for newly diagnosed patients with BRAF wild-type metastatic melanoma. This important news means that we now have another new option to offer patients with BRAF wild-type metastatic melanoma.”

Grade 3 and 4 adverse events (AE) were observed in 43% of patients treated with nivolumab, the most common being gamma-glutamyltransferase increase and diarrhea. AE resulted in permanent discontinuation of nivolumab treatment in 7% of patients and dose interruption in 26% of patients. Other documented AE included fatigue, musculoskeletal pain, rash, and pruritis.


1. Bristol-Myers Squibb announces US Food and Drug Administration approval for Opdivo (nivolumab) as a single agent for the treatment of patients with previously untreated BRAF wild-type advanced melanoma [press release]. Princeton, NJ: Bristol- Myers Squibb; November 24, 2015. administration-approval-opdivo-nivolum.

Nivolumab Approved for Third Indication: Advanced Renal Cell Carcinoma

Two months after being granted a Breakthrough Therapy designation by the FDA for metastatic renal cell carcinoma (mRCC), nivolumab was today approved by regulators for treating mRCC patients who have failed a certain type of prior therapy.

The approval1 was based on the results of a phase 3 trial published earlier this month in the New England Journal of Medicine, which compared nivolumab with everolimus in 821 patients with advanced clear-cell renal-cell carcinoma who had received prior treatment with 1 or 2 antiangiogenic agents. The randomized trial assigned patients to receive either an intravenous infusion of nivolumab (3mg/ kg) every 2 weeks or oral everolimus (10 mg tablet, once daily). The secondary endpoints were objective response rate and safety, and the primary trial endpoint was overall survival. The study design allowed dose modification for everolimus but not for nivolumab.

This international study, dubbed Checkmate-025, recruited patients at 146 sites across 24 countries in 5 continents (North and South America, Australia, Asia, and Europe). Only 803 of the 821 patients were treated, with 406 in the nivolumab group and 397 in the everolimus group. By data cutoff in June 2015, 17% (67) of patients in the nivolumab group and 7% (28) in the everolimus group continued to receive treatment. Minimum follow-up period was 14 months and disease progression as the primary reason for discontinuation of treatment (observed in 70% of nivolumab-treated patients and 69% of everolimus-treated patients).

Patients in the nivolumab group had significantly better overall survival (25 months; 95% confidence interval (CI), 21.8 to not estimable) compared with those treated with everolimus (19.6 months; 95% CI, 17.6 to 23.1). Nearly 45% of patients (183 of 410) in the nivolumab cohort died, as opposed to 52% (215 of 411) in the everolimus group. The hazard ratio for all-cause death was 0.73 (98.5% CI, 0.57 to 0.93; P = .002) for nivolumab versus everolimus.


In the press release announcing the drug’s approval, Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “Opdivo [nivolumab] provides an important therapy option for patients with renal cell carcinoma. It is one of few therapies that have demonstrated the ability to extend patients’ survival in treating this disease. Additionally, Opdivo’s extended indication, from melanoma and nonsmall cell lung cancer to renal cell cancer, demonstrates how immune therapies can benefit patients across a wide range of tumors.”


1. FDA approves Opdivo to treat advanced form of kidney cancer [press release]. Silver Spring, MD: FDA; November 23, 2015. medium=email&utm_source=govdelivery.

2. Motzer RJ, Escudier B, McDermott, DF; CheckMate 025 Investigators. Nivolumab versus everolimus in advanced renalcell carcinoma. N Engl J Med. 2015;373(19):1803-1813.