FDA Actions & Updates
The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.
Friday, October 09, 2015
The U.S. Food and Drug Administration has approved Opdivo (nivolumab) for the treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC) that has progressed during or after platinum-based chemotherapy. Opdivo, made by Bristol-Myers Squibb, works by inhibiting the PD-1 pathway, which blocks the body's immune system from attacking cancer cells.
Opdivo is being approved for this indication after receiving priority review designation and breakthrough therapy status just last month—with approval coming three months ahead of the prescription drug fee goal date of January 2 (OT 10/10/15 issue). Opdivo was also approved earlier this year for the treatment of patients with metastatic squamous NSCLC that has progressed on or after platinum-based chemotherapy (OT 4/10/15 issue).
“There is still a lot to learn about the PD-1/PD-L1 pathway and its effects in lung cancer, as well as other tumor types,” Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release. “While Opdivo showed an overall survival benefit in certain non-small cell lung cancer patients, it appears that higher expression of PD-L1 in a patient’s tumor predicts those most likely to benefit.”
Opdivo has also previously received accelerated approval to treat patients with unresectable or metastatic melanoma who no longer respond to other drugs (OT 1/25/15 issue); and it previously received breakthrough therapy status for the treatment of patients with metastatic renal cell carcinoma (OT 10/10/15). And just last week Opdivo was approved for use in combination with Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma, which was the first approval of a combination regimen of two immuno-oncology agents for the treatment of cancer.
Safety and Effectiveness
Opdivo’s approval for this new indication were based on data from an international, open-label CheckMate-057 trial of 582 patients with advanced NSCLC that had progressed during or after treatment with platinum-based chemotherapy and appropriate biologic therapy. Patients were included regardless of PD-L1 status. Patients were randomized to receive Opdivo or docetaxel; and the data showed median overall survival for patients who received Opdivo was 12.2 months compared with 9.4 months for the patients who received docetaxel. Of the patients who received Opdivo, 19 percent had their tumors completely or partially shrink (for 17 months on average), compared with 12 percent of patients who received docetaxel having their tumors completely or partially shrink (for six months on average).
The safety profile for Opdivo for patients in the CheckMate-057 trial was consistent with prior studies. The most frequent serious adverse reactions (occurring in at least two percent of patients) were pneumonia, pulmonary embolism, dyspnea, pleural effusions, and respiratory failure. The most common adverse reactions were fatigue, musculoskeletal pain, cough, decreased appetite, and constipation.
PD-L1 Biomarker Test also Approved
While patients who received Opdivo lived longer than those who received docetaxel across the study, an evaluation of samples from a subgroup of patients’ tumors suggests that the level of PD-L1 expression in NSCLC tumors may help identify patients who are more likely to live longer due to treatment with Opdivo. Therefore, the FDA also approved the PD-L1 IHC 28-8 pharmDx test to detect PD-L1 protein expression levels and help physicians determine which patients may benefit most from treatment with Opdivo. Biomarker testing, though, is not required for treatment with Opdivo.
The test is marketed by Dako, an Agilent Technologies.
Thursday, October 08, 2015
The U.S. Food and Drug Administration has granted breakthrough therapy designation to abemaciclib for the treatment of patients with refractory hormone-receptor-positive advanced or metastatic breast cancer. Abemaciclib is a cyclin-dependent kinase 4 and 6 inhibitor.
The breakthrough therapy designation, enacted as part of the FDA’s 2012 Safety and Innovation Act, was created to expedite the development and review time of a potential new drug for serious or life-threatening disease where early clinical evidence suggests the drug may demonstrate substantial improvement compared with existing therapies.
This designation for abemaciclib is based on data from the breast cancer cohort expansion of the Phase I JPBA trial, which studied the efficacy and safety of the drug in women with advanced or metastatic breast cancer. The patients in this trial cohort had received a median of seven prior systemic therapies. The data were presented at the San Antonio Breast Cancer Symposium in 2014.
Abemaciclib is also being evaluated in the ongoing Phase II MONARCH 1 trial for women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. And the drug is also being assessed in two Phase III clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant in postmenopausal patients with patients with hormone-receptor-positive, HER2-negative advanced or metastatic breast cancer; and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in patients with hormone-receptor-positive, HER2-negative locoregionally recurrent or metastatic breast cancer.
The drug is being marketed by Lilly Oncology.
Tuesday, October 06, 2015
The U.S. Food and Drug Administration has approved an expanded indication for the Optune device for the treatment of patients with newly-diagnosed glioblastoma multiforme (GBM), to be given in combination with the chemotherapy drug temozolomide (TMZ) following standard treatments that include surgery, chemotherapy, and radiation therapy. Optune (also known as Tumor Treating Fields or TTFields) is a therapy delivered by a portable, non-invasive medical device designed for continuous use by patients that creates low-intensity, alternating electric fields within a tumor that exert physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cancer cell death.
“Patients newly diagnosed with this challenging and aggressive form of brain cancer now have another treatment option available,” William Maisel, MD, MPH, Acting Director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health, said in a news release. “While the treatment is not a cure, it can increase survival by several months.”
Optune was initially approved in 2011 (then called the NovoTTF-100A System or NovoTTF) to treat patients with GBM that recurred or progressed after chemotherapy (OT 5/10/11 issue). With this expanded indication, Optune can be used as part of a standard treatment for GBM before the disease progresses. Optune had received priority review designation for this indication earlier this year (OT 6/25/15 issue).
Approximately 23,000 individuals in the U.S. will be diagnosed with brain or other nervous system cancers in 2015, with GBM accounting for approximately 15 percent of them, according to data from the National Cancer Institute.
How It Works
When using Optune, a health care professional places electrodes on the surface of the patient’s scalp to deliver low-intensity, alternating electrical fields called “tumor treatment fields” (TTFields). The unique shape and special characteristics of rapidly dividing tumor cells make them susceptible to damage when exposed to TTFields, which could halt tumor growth.
The device is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home or work, allowing them to continue their normal daily activities.
Safety and Efficacy
Approval for the Optune device was based on data from a randomized, Phase III clinical trial of 695 patients with newly diagnosed GBM who either used the Optune device and received TMZ or received TMZ alone. Patients receiving TMZ and using the Optune device had a median overall survival of 20.5 months, while patients receiving TMZ alone had a median overall survival of 15.6 months.
The most common side effect reported by patients using the Optune device was skin irritation. And patients on the clinical trial who used the Optune device also experienced a slightly higher incidence of neurological side effects, including convulsions and headaches, compared to subjects receiving TMZ alone.
The Optune device is made by Novocure Inc.
Friday, October 02, 2015
The U.S. Food and Drug Administration has granted accelerated approval for Keytruda (pembrolizumab) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and express the PD-L1 protein. Keytruda is being approved with a companion diagnostic, PD-L1 IHC 22C3 pharmDx, which detects PD-L1 expression in NSCLC tumors. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
“Our growing understanding of underlying molecular pathways and how our immune system interacts with cancer is leading to important advances in medicine,” Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release. “Today’s approval of Keytruda gives physicians the ability to target specific patients who may be most likely to benefit from this drug.”
Keytruda is being approved for this indication under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.
Keytruda has previously received priority review designation for this NSCLC indication (OT 6/25/15 issue), as well as breakthrough therapy designation (OT 11/25/14).
Keytruda has also previously received priority review designation for the first-line treatment of patients with unresectable or metastatic melanoma (OT 9/10/15 issue); and the drug has also previously been approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab and, if BRAF V600-mutation positive, a BRAF inhibitor (OT 10/10/14 issue).
Keytruda's approval for this new indication is based on data from the multicenter, open-label KEYNOTE-001 trial, early data from which were reported in April at the American Association for Cancer Research Annual Meeting (OT 6/10/15 issue). The trial included a subgroup of 61 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and who had a PD-L1 tumor proportion score of at least 50 percent, as determined by a clinical trial immunohistochemistry assay who received Keytruda monotherapy every two or three weeks until unacceptable toxicity or disease progression. Twenty-five of the patients (41%) responded to treatment with Keytruda; all responses were partial. Twenty-one of the patients who responded (21/25; 84%) had ongoing responses, including 11 patients with ongoing responses of six months or longer. The overall response rate and duration of response were similar for both dosing schedules.
The most frequent serious adverse reactions (reported in at least 2% of patients) were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of the study’s patients) were fatigue, cough, decreased appetite, and dyspnea.
Multiple Phase III trials for Keytruda are being conducted by the drug’s marketer, Merck, according to a news release.
The FDA has also given Pre-Market Approval to the first predictive companion diagnostic for use in detecting PD-L1, the PD-L1 IHC 22C3 pharmDx kit. The diagnostic is made by Dako North America, Inc., and will be available commercially to laboratories in the U.S. through Dako. Testing using the assay will be available at U.S. reference laboratories including Laboratory Corporation of America Holdings (LabCorp), Quest Diagnostics, and GE Healthcare Clarient Diagnostic Services.
Thursday, October 01, 2015
The U.S. Food and Drug Administration has approved Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. Opdivo is a PD-1 checkpoint inhibitor and Yervoy is a CTLA-4 checkpoint inhibitor. This approval is the first approval of a combination regimen of two immuno-oncology agents for the treatment of cancer.
“Historically, metastatic melanoma has been a difficult disease to treat. Now, a new treatment option based on the combination of two valued immuno-oncology agents demonstrates significant efficacy versus ipilimumab (Yervoy) in metastatic melanoma,” Jedd D. Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service in the Department of Medicine and at the Ludwig Center at Memorial Sloan Kettering Cancer Center, said in a news release. “Today’s approval represents a step forward for the melanoma community, providing hope for patients with metastatic melanoma.”
The Opdivo-Yervoy combination is being approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.
Safety and Efficacy
Safety and efficacy for the Opdivo-Yervoy combination were established in the Phase II, double-blind CheckMate-069 trial of 142 patients with previously untreated unresectable or metastatic melanoma who were randomized to receive Opdivo with Yervoy or Yervoy alone (OT 6/10/15 issue). Median progression free survival for the patients with BRAF wild-type melanoma was 8.9 months for patients receiving the combination compared with 4.7 months for patients receiving Yervoy alone.
Serious adverse reactions were more common in the patients receiving the combination regimen than for patients receiving Yervoy alone. The most common serious adverse reactions associated with the combination regimen were colitis, diarrhea, pyrexia, and pneumonitis. Other common adverse reactions for patients receiving the combination therapy were: rash, pruritus, headache, vomiting, and colitis.
Responses from the Oncology Community
The approval was applauded by the Melanoma Research Foundation in a statement from Tim Turnham, the organization’s Executive Director: “Today’s approval marks a turning point in melanoma treatment. For the first time patients will have access to a regimen that utilizes two critical findings—that the patient’s own immune system can be engaged in the fight against cancer, and that the right combination of two or more drugs can have a synergistic effect.”
And the decision was also praised by the Society for Immunotherapy of Cancer. In a statement, SITC President Howard L. Kaufman, MD, FACS, of Rutgers Cancer Institute of New Jersey, said: “Today marks a milestone in the field of cancer immunotherapy. … Not only does this combination immunotherapy demonstrate an impressive, durable response in patients with metastatic melanoma, but today’s approval also illustrates the potential advantage of combining immunotherapy agents offering previously unavailable options to cancer patients.”
Both drugs are marketed by Bristol-Myers Squibb.