Updates on Recent Cancer Drugs Approved by the FDA

Opdivo Got Second Indication for Metastatic Lung Cancer

On October 8, 2015, the FDA expanded the indication of nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with nonsquamous metastatic non–small-cell lung cancer (NSCLC) that is progressing during or after the use of platinum-based chemotherapy. Earlier in the year (March 2015), the FDA approved nivolumab for the treatment of patients with squamous NSCLC. Nivolumab was the first immunotherapy to be approved for the treatment of patients with lung cancer. It works by blocking the PD-1/PD ligand 1 (PD-L1) immune-cell pathway. “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,” said Richard Pazdur, MD, FDA’s Director of the Office of Hematology and Oncology Products. “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.”

Onivyde Received Expedited Approval for Relapsed Metastatic Pancreatic Cancer

Using its priority review process, on October 22, 2015, the FDA approved irinotecan liposome injection (Onivyde; Merrimack Pharmaceuticals), for use in combination with fluorouracil and leucovorin, for the treatment of patients with metastatic pancreatic cancer who have received previous therapy with gemcitabine (Gemzar)-based chemotherapy. Pancreatic cancer can be difficult to diagnose early, and the treatment options are limited, especially for metastatic disease. “Many FDA staff who review drug applications are clinicians as well, so it’s especially rewarding when we are able to expedite access to new treatments for patients with unmet needs,” said Dr Pazdur. “By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.” The FDA also granted an orphan drug designation for irinotecan liposome injection. This approval is based on a randomized, open-label study of 417 patients with metastatic pancreatic cancer that progressed after chemotherapy with gemcitabine or a gemcitabine-based therapy. Overall survival was an average of 6.1 months with the combination of irinotecan liposome injection plus fluorouracil and leucovorin compared with 4.2 months with fluorouracil plus leucovorin without irinotecan liposome. No survival benefit was seen for patients who received irinotecan liposome without the combination of fluorouracil plus leucovorin. In addition, patients receiving the 3-drug combination had a delay in progression-free survival (PFS): the mean PFS was 3.1 months with the 3-drug combination compared with1.5 months with fluorouracil and leucovorin alone. The most common side effects of irinotecan liposome were diarrhea, fatigue, vomiting, nausea, decreased appetite, stomatitis, and fever. The drug also resulted in lymphopenia and neutropenia; death caused by sepsis from neutropenia has been reported with irinotecan liposome. Irinotecan liposome injection was approved with a boxed warning about the risks for severe neutropenia and diarrhea. It is not approved for use alone.

Yondelis a New Treatment Option for Patients with Soft-Tissue Sarcoma

On October 23, 2015, the FDA approved the new chemotherapy trabectedin (Yondelis; Janssen Biotech) for the treatment of patients with 2 types of unresectable or metastatic soft-tissue sarcomas, liposarcoma and leiomyosarcoma. Trabectedin is indicated for patients who previously received chemotherapy that contained anthracycline. Soft-tissue sarcomas involve cancer cells that form in soft tissues in the body, including muscles, tendons, fat, blood vessels, lymph vessels, nerves, and tissues around joints. Liposarcoma occurs in fat cells, and leiomyosarcoma occurs in smooth muscle cells. Soft-tissue sarcoma is most common in the head, neck, arms, legs, trunk, and abdomen. “The treatment of advanced or metastatic soft-tissue sarcoma represents a difficult challenge with few effective therapeutic choices available for patients,” said Dr Pazdur. “Today’s approval of Yondelis provides a treatment option for advanced or metastatic liposarcoma and leiomyosarcoma.” The effectiveness and safety of trabectedin were based on the results of a phase 3 clinical trial that included 518 patients with metastatic or recurrent leiomyosarcoma or liposarcoma. Patients were randomized to trabectedin or to dacarbazine. PFS was 4.2 months with trabectedin compared with 1.5 months with dacarbazine. Partial responses were also more common with trabectedin than with dacarbazine, but no group had complete responses. The most common adverse events with trabectedin were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes, and reduced albumin levels. This drug carries a warning box about the risk for neutropenic sepsis, rhabdomyolysis, hepatotoxicity, extravasation, tissue necrosis, and cardiomyopathy. Trabectedin is already approved in Europe for soft-tissue sarcoma and for ovarian cancer.

Imlygic, First-of-Its-Kind Oncolytic Virus Therapy Approved for Melanoma

On October 27, 2015, the first oncolytic virus therapy—talimogene laherparepvec (Imlygic; Amgen/BioVex), formerly known as T-VEC—was approved by the FDA for the treatment of patients with melanoma occurring in the skin or in lymph nodes. Skin cancer is the most common type of cancer in the United States; melanoma is the leading cause of skin cancer–related deaths. “Melanoma is a serious disease that can advance and spread to other parts of the body, where it becomes difficult to treat,” said Karen Midthun, MD, Director of the FDA’s Center for Biologics Evaluation and Research. “This approval provides patients and health care providers with a novel treatment for melanoma.” Talimogene laherparepvec is a genetically modified live oncolytic herpes virus therapy. It is injected into the melanoma lesions, where it replicates within cancer cells and kills them. This virus therapy is indicated for the treatment of unresectable melanoma lesions. After the first dose, the second injection is administered 3 weeks later, followed by additional doses every 2 weeks for at least 6 months, until another treatment is needed or until all lesions have been killed. The safety and efficacy of talimogene laherparepvec were evaluated in a multicenter study involving 436 patients with metastatic unresectable melanoma. Patients were randomized to talimogene laherparepvec or to a comparator therapy for at least 6 months or until all melanoma lesions were destroyed. Overall, 16.3% of the patients who received the new virus therapy had reductions in their melanoma lesions that lasted ≥6 months versus 2.1% of those receiving the comparator therapy. However, talimogene laherparepvec did not improve overall survival, nor did it have any impact on melanoma that metastasized to the brain, bone, liver, lungs, or other organs. The most common side effects were fatigue, chills, fever, nausea, flulike symptoms, and injection-site pain. Because this new therapy is a modified live oncolytic herpes virus, patients can be infected with this disease and should be avoided in patients with suppressed immune systems or in pregnant patients.

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, PFS 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. 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. Women taking this drug should use effective contraception, because it can cause harm to a developing fetus.

The FDA Approved 3 Myeloma Drugs in November 2015

• Darzalex First Monoclonal Antibody for Multiple Myeloma

November 2015 may be remembered as “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 Dr Pazdur. “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.

• Ninlaro First Oral Proteasome Inhibitor Approved for Multiple Myeloma

On November 20, 2015, the FDA approved ixazomib (Ninlaro; Takeda Oncology), 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) and daratumumab. 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 PFS 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.

• Empliciti Second Monoclonal Antibody Approved 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 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.” Like ixazomib, elotuzumab is approved for use in combination with lenalidomide and dexamethasone. The approval of elotuzumab was based on a randomized, open-label clinical study of 646 patients with recurrent or resistant multiple myeloma. PFS 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.

FDA Approved 2 New Drugs for Lung Cancer in November 2015

• Tagrisso Approved 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 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% of patients in the second study. Tagrisso was approved under the agency’s accelerated approval program. 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.

• Portrazza Receives FDA Approval for Metastatic Squamous NSCLC

On November 24, 2015, the FDA approved necitumumab (Portrazza; Eli Lilly), a monoclonal antibody, for the treatment of patients with metastatic squamous NSCLC who have not received previous therapy for metastatic NSCLC. Necitumumab was approved for use in combination with 2 chemotherapies, gemcitabine and cisplatin. 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.