Evidence-Based Oncology
October 2015
Volume 21
Issue SP14

FDA Updates in Oncology

Updates on FDA approvals and extended indications for oncology drugs.

FDA Grants Priority Review for Alectinib in Advanced NSCLC Resistant to Crizotinib

Roche has announced1 that an oral anaplastic lymphoma kinase (ALK) inhibitor developed by the company has been granted priority review by the US regulatory authority. The company filed a New Drug Application (NDA) for alectinib (Alecensa) within 2 years of being granted a Breakthrough Therapy designation for the treatment of patients with ALK-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed or are intolerant to crizotinib.

Alectinib was approved in Japan last year for the treatment of patients with ALK-positive NSCLC based on the results of a phase 1/2 study that included individuals whose tumors had advanced, were recurrent, or were unresectable. The 90% response rate in the Japanese population may have led to the drug’s approval based on early phase results.2

The NDA filed with the FDA provides results of two phase 2 studies. One was a single-arm, open-label, multicenter trial (NP28761) evaluating the safety and efficacy of alectinib in 87 individuals with ALK-positive NSCLC whose disease progressed on crizotinib. Nearly 50% of trial participants saw their tumors shrink. Those with metastases to the brain or other regions of the central nervous system (CNS) also saw their cancer respond to alectinib, indicating that the drug crosses the blood—brain barrier, a lipid-rich region which is usually difficult to penetrate. The duration of primary tumor response was sustained for a median period of 7.5 months. Most common grade 3 or greater adverse events in the trial were dyspnea and increased levels of muscle and liver enzymes.

A second trial (NP28673) evaluated the safety and efficacy of alectinib in 138 individuals with a similar profile compared with NP28761. Using RECIST criteria, a 50% response rate was observed with respect to tumor shrinkage in this population. Although the median duration of response was longer in this group (11.2 months), a CNS response in those with brain and other CNS metastases was observed. Dyspnea was the most common grade 3 or higher adverse event observed in NP28673.

Sales discussions around the drug began immediately following approval in Japan, with experts predicting a blockbuster status for alectinib. Analysts at Cowen and Company project the drug could bring in annual sales of $1 billion by 2020.3


The decision date for alectinib for US approval is set for March 4, 2016.


  1. FDA grants Roche's alectinib Priority Review for specific type of ALK-positive lung cancer. Published and accessed September 9, 2015.
  2. Japan becomes first country to approve Roche’s alectinib for people with a specific form of advanced lung cancer [press release]. Basel, Switzerland: Roche; July 4, 2014. Accessed September 9, 2015.
  3. Roche lung cancer drug sees first approval. Pharmafile website. Published March 7, 2014. Accessed September 9, 2015.

Opdivo-Yervoy Combination Approved for Metastatic Melanoma Harboring Wild-Type BRAF

In a press release1 published on October 1, 2015, Bristol-Myers Squibb (BMS) announced the approval of its combination regimen of 2 immuno-oncology agents, nivolumab (Opdivo) and ipilimumab (Yervoy), for patients with BRAF V600 wild-type metastatic melanoma.

This approval marks the first-ever approval of 2 immuno-oncology agents in cancer treatment. According to the FDA,2 the approval was based on objective response rate, prolonged duration of response, and improvement in progression free survival—outcomes from the CheckMate-069 trial in 142 treatment-naïve patients with unresectable or metastatic melanoma. The trial showed a statistically significant increase in confirmed objective response rate in 95 patients with melanoma expressing wild-type BRAF treated with the combination (60%; 95% confidence interval (CI), 48-71; P<.001), compared with ipilimumab and placebo (47 patients) (11%; 95% CI, 3-25). Nearly 17% of patients treated with the combination had a complete response, while 43% had a partial response.

A 60% reduction in the risk of progression was observed with the combination treatment compared with ipilimumab alone (Hazard ratio = 0.40; 95% CI: 0.22-0.71; P<.002). Median survival improved by more than 4 months with the combination, 8.9 months compared with 4.7 months seen with the ipilimumab-treated cohort.

The combination was, however, responsible for more serious adverse events (62% vs 39%), adverse reactions leading to permanent discontinuation (43% vs 11%) or dose delay (47% vs 2%), and grade 3 or 4 adverse reactions (69% vs 43%). The most frequent serious adverse reactions in patients receiving the combination were colitis (17%), diarrhea (9%), pyrexia (6%), and pneumonitis (5%). Additional clinically significant immune-mediated adverse reactions included pneumonitis, hepatitis, endocrinopathies, nephritis/renal dysfunction, and rash.


“Today’s approval of the Opdivo + Yervoy Regimen marks another first for our research in Immuno-Oncology and represents our unwavering commitment to continually redefine cancer care, and offer patients new treatment options with the goal of improved outcomes,” said Giovanni Caforio, CEO of BMS.


  1. Bristol-Myers Squibb Receives Approval from the U.S. Food and Drug Administration for the Opdivo (nivolumab) + Yervoy (ipilimumab) Regimen in BRAF V600 Wild-Type Unresectable or Metastatic Melanoma [press release]. Princeton, NJ: Bristol-Myers Squibb; October 1, 2015.
  2. Nivolumab in combination with ipilimumab. FDA website. Published and accessed October 1, 2015.

Elotuzumab Accepted for Priority Review by FDA for Previously Treated Patients With Multiple Myeloma

The FDA has accepted elotuzumab, being developed as Empliciti, for priority review.1 A monoclonal antibody that stimulates the signaling lymphocyte activation molecule F7 (SLAMF7) cell-surface receptor, the biologics license application for elotuzumab was submitted jointly by Bristol-Myers Squibb and AbbVie for the treatment of multiple myeloma in patients who have received one or more prior therapies.

The submission primarily includes results from the ongoing ELOQUENT-2 trial, a phase-3, open-label, multicenter global study that included 646 patients at 168 sites who were randomized to receive elotuzumab in combination with lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group) in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. Primary end points of the trial, results of which were published in the New England Journal of Medicine,2 were progression-free survival (PFS) and overall response rate (ORR). Secondary end points were overall survival (OS) and severity of pain or interference with daily life.

At a median follow-up of 24.5 months, 35% of patients in the elotuzumab group and 20% in the control group were receiving study treatment. PFS at 1 year was 68% (95% confidence interval [CI], 0.63-0.73) in the elotuzumab group and 57% (95% CI, 0.51-0.62) in the control group. Median PFS in the elotuzumab group was 19.4 months (95% CI, 0.16-0.22) compared with 14.9 months (95% CI, 0.12-0.17) in the control group, with a hazard ratio of 0.70 (95% CI, 0.57-0.85; P <.001).

The authors concluded that in patients with relapsed or refractory multiple myeloma, the addition of elotuzumab to lenalidomide and dexamethasone, compared with lenalidomide and dexamethasone as control therapy, improved PFS and ORR, showing that direct activation and engagement of the innate immune system to selectively kill myeloma cells can provide clinically meaningful and statistically significant improvements in treatment outcomes. The elotuzumab group presented a 30% reduction in disease progression or death compared with the control group. OS studies are ongoing.

Results from a phase 2 open-label study, which were presented3 at the annual meeting of the American Society of Clinical Oncology in May this year, were also a part of the submission to the FDA. The study evaluated the advantage of adding elotuzumab to a treatment regimen of bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma. Results presented showed that the study met its primary end point of PFS: elotuzumab significantly improved PFS when combined with bortezomib and dexamethasone, and elotuzumab-treated patients had a 28% reduction in their risk of disease progression. Elotuzumab is simultaneously undergoing accelerated assessment in Europe.


“Bristol-Myers Squibb is delighted by the approach both agencies have taken to review the Empliciti applications as it underscores the unmet medical need in the treatment of multiple myeloma and the role immuno-oncology may play,” said Michael Giordano, MD, senior vice president, head of oncology development, Bristol-Myers Squibb, in a press release.1 “The acceptance of our applications by the FDA and EMA [European Medicines Agency] brings Bristol-Myers Squibb’s immuno-oncology science a step closer to helping patients with hematologic malignancies.”


  1. U.S. Food and Drug Administration accepts for priority review the biologics license application for Empliciti (elotuzumab) for the treatment of multiple myeloma in patients who have received one or more prior therapies [press release]. Princeton, NJ: Bristol-Myers Squibb. September 1, 2015. September 2, 2015.
  2. Lonial S, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621-631.
  3. Dangi-Garimella S. Novel options in melanoma and multiple myeloma. AJMC website. Published July 16, 2015. Accessed September 1, 2015.
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