FDA News - December 2015

December 2015, Vol 6, No 11

In This Article

Darzalex First Monoclonal Antibody Approved by the FDA for Multiple Myeloma

November 2015 may be remembered as the "multiple myeloma month" in the annals of the FDA. On November 16, 2015, the FDA approved daratumumab (Darzalex; Janssen Biotech) injection for the treatment of patients with multiple myeloma who have received ≥3 previous treatments for this condition. Daratumumab is the first monoclonal antibody approved by the FDA for multiple myeloma. Daratumumab was approved under the FDA's priority review and was granted an orphan drug status.

"Targeting proteins that are found on the surface of cancer cells has led to the development of important oncology treatments," said Richard Pazdur, MD, Director of the FDA's Office of Hematology and Oncology Products. "Darzalex provides another treatment option for patients with multiple myeloma who have become resistant to other therapies."

The safety and efficacy of daratumumab were based on 2 open-label studies. Of the 106 patients who received daratumumab in one of these studies, 29% had a complete or partial reduction in their tumor lasting 7.4 months on average. Among the 42 patients in the second study who received daratumumab, the objective response rate was 36%.

The most common side effects associated with daratumumab were infusion-related reactions, fatigue, nausea, back pain, fever, and cough. Daratum­umab may also lead to lymphopenia, neutropenia, and leukopenia; anemia; and thrombocytopenia. Furthermore, this drug may interfere with certain tests that are done by blood banks (such as antibody screening). Women who are pregnant should not use Darzalex, and women planning to become pregnant should use effective contraceptives during treatment and for at least 3 months after treatment.

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Ninlaro First Oral Proteasome Inhibitor Approved for Multiple Myeloma

On November 20, 2015, the FDA approved ixazomib (Ninlaro; Takeda Pharmaceuticals), an oral proteasome inhibitor, for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received ≥1 previous therapies. The FDA approved ixazomib under its priority review process and granted it an orphan drug designation.

"As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease," said Dr Pazdur. "Today's approval is the third drug for multiple myeloma approved this year and provides patients with a new oral treatment that slows disease progression when other therapy has failed." The other 2 drugs approved earlier in 2015 for multiple myeloma were panobinostat (Farydak; in February) and daratumumab (Darzalex) earlier in November.

Ixazomib is the first oral proteasome inhibitor to be approved by the FDA for this indication. The approval was based on an international, randomized, double-blind clinical trial involving 722 patients with multiple myeloma who had received previous treatment. In this study, patients received ixazomib in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. The average progression-free survival was 26 months with the active combination versus 14.7 months with the placebo regimen.

The most common side effects associated with ixazomib were diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, and back pain.

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Empliciti Second Monoclonal Antibody Approved by the FDA for Multiple Myeloma

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received from 1 to 3 previous therapies. Elotuzumab received a breakthrough therapy designation and was approved under the FDA's priority review process. This drug, too, has an orphan drug status.

"We are continuing to learn about the ways the immune system interacts with different types of cancer, including multiple myeloma," said Dr Pazdur. "Today's approval is the second monoclonal antibody approved to treat patients with multiple myeloma and works with another approved therapy to provide additional benefit." Earlier in the month, daratumumab (Darzalex) became the first monoclonal antibody to be approved by the FDA for the treatment of patients with multiple myeloma

Elotuzumab activates the body's immune system to kill multiple myeloma cells. Like ixazomib, elotuzumab is approved for use in combination with lenalidomide and dexamethasone.

The FDA approval of elotuzumab was based on a randomized, open-label clinical study of 646 patients with recurrent or resistant multiple myeloma. Progression-free survival was 19.4 months in patients taking elotuzumab plus lenalidomide and dexamethasone compared with 14.9 months in patients taking lenalidomide and dexamethasone without elotuzumab. In addition, the patients using the 3-drug regimen had an objective response rate of 78.5% compared with 65.5% among patients using the 2-drug regimen.

The most common side effects associated with elotuzumab are fatigue, diarrhea, fever, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia.

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Cotellic Approved for Patients with Advanced Melanoma

On November 10, 2015, the FDA approved cobimetinib (Cotellic; Genentech), a MEK inhibitor, for use in combination with vemurafenib (Zelboraf), a BRAF mutation inhibitor, for the treatment of patients with metastatic melanoma or with melanoma that cannot be surgically removed, plus the BRAF V600E or V600K mutation. Cobimetinib was approved under the FDA's priority review and received an orphan drug status.

"As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge," said Dr Pazdur. "Today's approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma."

The safety and efficacy of the combination of cobimetinib and vemurafenib were demonstrated in a randomized clinical trial of 495 patients with previously untreated BRAF V600 mutation–positive melanoma that has metastasized or cannot be removed by surgery. In the study, all patients received vemurafenib and were then randomized to also receive cobimetinib or a placebo. On average, the progression-free survival was 12.3 months in patients receiving the combination therapy compared with 7.2 months in those randomized to vemurafenib plus placebo. In addition, 65% of patients using the combination of the 2 active drugs were alive 17 months after starting therapy compared with 50% of those receiving vemurafenib alone. Furthermore, patients using the combination had an overall response rate of 70% compared with 50% among those using vemurafenib alone.

The most common side effects associated with cobimetinib in combination with vemurafenib are diarrhea, photosensitivity reaction, nausea, fever, and vomiting. Cobimetinib may cause severe side effects, including cardiomyopathy or rhabdomyolysis, new primary cutaneous malignancies, retinal detachment, severe skin rash, hepatotoxicity, hemorrhage, and severe skin rash associated with photosensitivity. Patients taking this drug should therefore avoid sun exposure, wear protective clothing, and use a broad spectrum sunscreen. Women taking this drug should use effective contraception, because it can cause harm to a developing fetus.

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Portrazza Receives FDA Approval for Metastatic Squamous NSCLC

Also in November, 2 drugs received FDA approval for lung cancer. On November 24, 2015, the FDA approved necitumumab (Portrazza; Eli Lilly), a monoclonal antibody, for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC) who have not received previous therapy for metastatic NSCLC. Necitumumab was approved for use in combination with 2 chemotherapies, gemcitabine (Gemzar) and cisplatin (Platinol). Necitumumab blocks the activity of EGFR, a common protein in squamous NSCLC tumors.

"Lung cancer tumors can be varied, so treatment options need to be tailored to the specific type of lung cancer in the patient," said Dr Pazdur. "Today's approval provides certain patients with squamous cell lung cancer a new option that may extend survival."

The safety and efficacy of necitumumab were evaluated in a multicenter, randomized, open-label clinical trial that included 1093 patients with metastatic squamous NSCLC who received chemotherapy with gemcitabine and cisplatin with or without necitumumab. Patients receiving necitumumab in combination with the 2 chemotherapies had on average an 11.5-month overall survival compared with 9.9 months among patients receiving the 2 chemotherapies alone. Necitumumab did not extend survival among patients with nonsquamous NSCLC.

The most common side effects associated with necitumumab are skin rash and hypomagnesemia, which can cause muscular weakness, seizure, and irregular heartbeats, and can be fatal. Necitumumab was approved with a boxed warning regarding the serious risks associated with this drug, including cardiac arrest, sudden death, and hypomagnesemia.

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FDA Approved Tagrisso for Patients with NSCLC and EGFR Mutation, Together with a Companion Diagnostic Test

On November 13, 2015, the FDA granted accelerated approval for the oral therapy osimertinib (Tagrisso; AstraZeneca Pharmaceuticals) for the treatment of patients with advanced non–small-cell lung cancer (NSCLC). Osimertinib was approved for patients with the EGFR mutation T790M whose disease progressed after treatment with other EGFR-blocking therapies.

The EGFR gene is a protein involved in the growth and spread of cancer cells and is a common mutation found in patients with lung cancer. Osimertinib was granted a breakthrough therapy designation, priority review, and an orphan drug status.

"Our understanding of the molecular basis of lung cancer and reasons these cancers become resistant to prior treatments is rapidly evolving," said Dr Pazdur. "This approval provides a new treatment for patients who test positive for the EGFR resistance mutation, T790M, and is based on substantial evidence from clinical trials that shows Tagrisso had a significant effect on reducing tumor size in over half of patients who were treated."

Together with the approval of osimertinib, the FDA also approved the first companion diagnostic test-cobas EGFR Mutation Test v2 (marketed by Roche Molecular Systems)–to detect EGFR T790M, a resistance mutation targeted by osimertinib. This newly approved version (v2) of the test adds the T790M mutation to the clinically relevant mutations that can be detected by the original cobas EGFR Mutation Test (v1).

"The approval of safe and effective companion diagnostic tests and drugs continue to be important developments in oncology," said Alberto Gutierrez, PhD, FDA's Director of the Office of In Vitro Diagnostics and Radiological Health. "The availability of the cobas EGFR Mutation Test v2 meets a need for the detection of this important EGFR gene mutation, which can alter treatment effectiveness."

The safety and efficacy of osimertinib were shown in 2 multicenter, single-arm clinical trials of 411 patients with advanced EGFR T790M mutation–positive NSCLC whose disease progressed after previous treatment with an EGFR-blocking medication. Overall, the objective response rates were 57% in patients in the first study and 61% in patients in the second study.

Tagrisso was approved under the agency's accelerated approval program, which allows the FDA approval of a drug for a serious or life-threatening condition based on clinical data. Continued approval for this indication may be contingent on further confirmatory studies.

The most common side effects of osimertinib are diarrhea, skin and nail conditions (eg, dry skin, rash, and infection), or redness around the fingernails. Osimertinib may cause serious side effects, including lung inflammation and injury to the heart. It may also cause harm to a developing fetus.

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