FDA News – October 2015

October 2015, Vol 6, No 9 - FDA Approvals, News & Updates


In This Article




A Turning Point in Cancer Therapy: First Combination of 2 Immunotherapies Approved for Advanced Melanoma

The FDA approved the use of the first combination regimen of 2 immunotherapies for the treatment of patients with wild-type BRAF V600 unresectable or metastatic melanoma (October 1, 2015). The new combination includes 2 therapies that are currently approved as monotherapies for patients with melanoma—nivolumab (Opdivo), a PD-1 checkpoint inhibitor, and ipi­limumab (Yervoy), a CTLA-4 checkpoint inhibitor; both drugs are manufactured by Bristol-Myers Squibb.

The FDA used its accelerated review process to approve this new regimen based on the results from the pivotal CheckMate-69 clinical trial, a phase 2, double-blind, randomized study of 140 patients with treatment-naïve unresectable or metastatic melanoma; of these, 109 patients had BRAF wild-type melanoma. The primary end point was objective response rate (ORR).

The study results showed a significant increase in ORR in the 109 patients without the BRAF mutation (ie, BRAF wild-type melanoma) who received the combination regimen of nivolumab plus ipilimumab (60%; 95% confidence interval [CI], 48-71; P <.001) compared with patients who received ipilimumab alone (11%; 95% CI, 3-25). Furthermore, 17% of patients had complete responses. Partial responses were reported in 43% of the patients who received the combination regimen versus 11% of the patients receiving ipilimumab monotherapy.

In addition, the combination regimen resulted in a 60% reduction in the risk for disease progression compared with ipilim­umab alone (hazard ratio, 0.40; 95% CI, 0.22-0.71; P <.002). The median progression-free survival was 8.9 months with the combination regimen versus 4.7 months with ipilimumab monotherapy (95% CI, 7.0-NA vs 2.8-5.3).

In total, 79% of patients had ongoing responses lasting at least 6 months at the time of data analysis, with 20 patients showing response duration of at least 9 months. The side effects were similar to those seen with each monotherapy.

Melanoma experts responded to the FDA news with excitement.

“Historically, metastatic melanoma has been a difficult disease to treat,” said Jedd D. Wolchok, MD, PhD, Chief, Melanoma and Immunotherapeutics Service, Department of Medicine and Ludwig Center at Memorial Sloan Kettering Cancer Center. “Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”

Tim Turnham, Executive Director, Melanoma Research Foundation, said, “We are currently witnessing a turning point in cancer history, based on the significant impact Immuno-Oncology is making in the lives of patients with metastatic melanoma. Today’s approval…is an exciting moment for our community.”

The Society for Immunotherapy of Cancer (SITC) issued a press release applauding the approval and its implications. “The approval of this combination therapy is a major turning point, offering patients a new treatment option, and opens the door for many other synergistic therapies to emerge.”

SITC President, Howard L. Kaufman, MD, FACS, Rutgers Cancer Institute of New Jersey, added, “Today marks a milestone in the field of cancer immunotherapy….Today’s approval also illustrates the potential advantage of combining immunotherapy agents offering previously unavailable options to cancer patients.” Specifically, Dr Kaufman said, “This approval will establish the combination as a new standard of care for patients with metastatic melanoma.”

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Another Immunotherapy, Keytruda, Approved for Metastatic Lung Cancer Together with a Companion Diagnostic

The FDA granted accelerated approval and a priority review for pembrolizumab (Keytruda; Merck & Co) for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) that has progressed after other treatments and with tumors that express the PD-1 ligand 1 (PD-L1) protein (October 2, 2015). Pembrolizumab initially received a breakthrough therapy designation for this indication after preliminary clinical evidence showed that this drug may offer a substantial improvement over available therapies.

Pembrolizumab was approved for this indication with an immunohistochemistry (IHC) companion diagnostic test called PD-L1 IHC 22C3 pharmDx (Dako North America Inc), the first test designed to detect PD-L1 expression in NSCLC tumors.

“Our growing understanding of underlying molecular pathways and how our immune system interacts with cancer is leading to important advances in medicine,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “Today’s approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.”

Pembrolizumab targets the PD-1/PD-L1 proteins found on the body’s immune cells and on cancer cells. Blocking the overexpression of these proteins helps the patient’s immune system fight the cancer cells.

In 2014, pembrolizumab was approved by the FDA for the treatment of patients with advanced melanoma after receiving treatment with ipilimumab. Pembrolizumab is the second PD-1/PD-L1 approved for NSCLC. Earlier in 2015, nivolumab, which also targets the PD-1/PD-L1 pathway, was approved for the treatment of squamous NSCLC.

The efficacy of pembrolizumab in NSCLC was studied in a subgroup of 61 patients who participated in a large, multicenter, open-label, clinical trial. The 61 patients had advanced NSCLC that progressed after platinum-based chemotherapy or after targeted therapy in those with the ALK or EGFR mutation. The patients in this subgroup had PD-L1 overexpression that was determined with the PD-L1 IHC 22C3 pharmDx diagnostic test. The major outcome measure was overall response rate (ORR). The ORR was 41% in patients who received pembrolizumab, which lasted between 2.1 and 9.1 months.

The safety of pembrolizumab was evaluated in 550 patients with advanced NSCLC. The most common side effects included fatigue, decreased appetite, dyspnea, and cough. In addition, severe immune-mediated side effects were reported, involving the lungs, colon, and hormone-producing glands. Other uncommon immune-mediated side effects were rash and inflammation vasculitis.

However, an improvement in survival has not yet been demonstrated with this drug; the FDA may request additional data to confirm the clinical benefits of this drug for this indication.

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015, according to the National Cancer Institute.

Quest Diagnostics announced it will provide laboratory testing using the PD-L1 IHC 22C3 pharmDx companion diagnostic test. Frank Clyburn, President of Merck Oncology, commented, “We believe that testing for the PD-L1 biomarker can provide important information that will help guide treatment decisions for patients with metastatic non–small-cell lung cancer. We are pleased that Quest Diagnostics is making PD-L1 testing available to physicians and patients across the country given their experience and capabilities in oncology diagnostics.”

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Lonsurf, a New Oral Combination, Approved for Patients with Metastatic Colorectal Cancer

The FDA approved the oral combination of tipiracil plus trifluridine (Lonsurf; Taiho Oncology Inc) for the treatment of patients with metastatic colorectal cancer who are no longer responding to other therapies (September 22, 2015).

“The past decade has brought a new understanding around colorectal cancer, in how we can both detect and treat this often devastating disease,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “But there are many patients who still need additional options, and today’s approval is a testament to the FDA’s commitment to work with companies to develop new drugs in disease areas where unmet needs remain.”

The tipiracil plus trifluridine oral combination therapy is indicated for the treatment of patients with metastatic colorectal cancer who have previously received chemotherapy and biologic therapy.

The efficacy and safety of the new combination drug were evaluated in an international, randomized, double-blind study that included 800 patients with metastatic disease who had received previous therapy.

The patients received the oral combination plus best supportive care, or placebo plus best supportive care, until their disease progression or until the side effects became intolerable. The primary end point was overall survival (OS); the secondary end point was progression-free survival. The OS was 7.1 months among patients who received the oral combination of tipiracil plus trifluridine compared with an OS of 5.3 months in patients who received placebo.

The average time to disease progression was 2 months with the combination therapy versus 1.7 months with placebo.

The most common side effects of tipiracil plus trifluridine were anemia, neutropenia, thrombocytopenia, physical weakness, fatigue, nausea, decreased appetite, diarrhea, vomiting, abdominal pain, and fever. The patient’s complete blood count should be evaluated before prescribing this oral combination, because this new therapy may cause myelosuppression.

Colorectal cancer is the third most common nonskin cancer in men and women in the United States, according to the National Cancer Institute. Although still the second leading cause of cancer-related death in the United States, the number of colorectal cancer cases and related deaths have decreased, in part because of screenings.

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Emend Receives Expanded Indication for CINV Prevention in Pediatric Patients

The FDA approved a new indication for the NK1 receptor antagonist aprepitant capsules (Emend; Merck & Co) in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with chemotherapy in young patients aged 12 to 17 years, and for children and adolescents aged <12 years who weigh ?30 kg and are receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy (August 28, 2015).

This expanded indication to young patients was based on the results of a phase 3 clinical trial that investigated the use of aprepitant plus ondansetron (Zofran) versus ondansetron plus placebo. The study included 302 young patients aged 6 months to 17 years. Among patients aged 12 to 17 years or those aged <12 years (N = 132), 34.9% of those receiving the combination of aprepitant plus ondansetron achieved complete response, defined as no nausea or vomiting or retching, versus 13% of those receiving ondansetron plus placebo.

Overall, 49.2% of patients receiving the aprepitant plus ondansetron combination achieved complete response in the delay phase, defined as 25 to 120 hours after the initiation of chemotherapy, compared with 18.8% of those receiving ondansetron monotherapy. In the acute phase (first 24 hours after chemotherapy), 55.6% of patients receiving the combination had a complete response compared with 37.7% receiving ondansetron alone.

“Historically, significant improvements in pediatric medicine have been slow due to many challenges such as clinical trial size. However, at Merck, these obstacles have invigorated our efforts to bring forward a new option for these patients,” said Stuart Green, MD, Vice President, Clinical Research, Merck Research Laboratories.

All-grade adverse events were reported in 79% of patients receiving the combination therapy versus 77% with ondansetron alone. The most common grade 3 or 4 adverse events with aprepitant plus ondansetron versus ondansetron alone were febrile neutropenia (15% vs 14%, respectively), anemia (9% vs 17%, respectively), and reduced neutrophils (7% vs 11%, respectively). Febrile neutropenia was the most common serious adverse event (15% of patients in each group).

Currently, there is no appropriate dose of aprepitant available for patients aged <12 years who weigh <30 kg. An application for an investigational powder for suspension formulation for pediatric patients is pending.

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