Recently, the U.S. Food and Drug Administration (FDA) granted Priority Review to agents for the treatment of refractory multiple myeloma, metastatic breast cancer, and metastatic non–small cell lung cancer (NSCLC); gave Fast Track designation to treatments for NTRK mutation–positive solid tumors and mantle cell lymphoma; and granted Orphan Drug designation to investigational drugs in chronic lymphocytic leukemia (CLL) and T-cell lymphoma.
Priority Review for Melflufen in Triple-Class Refractory Multiple Myeloma
The FDA granted Priority Review to a new drug application seeking approval of melflufen (melphalan flufenamide) in combination with dexamethasone for the treatment of adult patients with multiple myeloma whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody (ie, triple-class refractory). The FDA has set a Prescription Drug User Fee Act date, which is the target date for their review of the new drug application, of February 28, 2021.
The submission is based on the results from the pivotal phase II HORIZON study, evaluating intravenous melflufen in combination with dexamethasone in patients with relapsed or refractory multiple myeloma.
New Drug Application, Priority Review for Oral Paclitaxel and Encequidar in Metastatic Breast Cancer
The FDA accepted a new drug application for oral paclitaxel and encequidar for the treatment of metastatic breast cancer and has granted the application Priority Review. Under the Prescription Drug User Fee Act, the FDA has set a target action date of February 28, 2021. Additionally, the FDA has communicated that it is not currently planning to hold an advisory committee meeting to discuss the application.
The oral paclitaxel new drug application submission is supported by data from a single pivotal phase III study of oral paclitaxel for the treatment of metastatic breast cancer. The study is a randomized, controlled clinical trial designed to compare the safety and efficacy of oral paclitaxel monotherapy vs intravenous paclitaxel monotherapy. As previously reported, the study achieved its primary endpoint, showing statistically significant improvement in overall response rate, along with lower rates of neuropathy, for oral paclitaxel compared to intravenous paclitaxel.
New Drug Application and Priority Review for Tepotinib in Metastatic NSCLC With MET Exon 14–Skipping Alterations
The FDA has accepted and granted Priority Review to a new drug application for once-daily, orally-dosed tepotinib for the treatment of adult patients with metastatic NSCLC whose tumors have a mutation that leads to mesenchymal-epithelial transition exon 14 (MET exon 14) skipping, as detected by an FDA-approved test. Tepotinib was granted Priority Review and is being reviewed by the FDA under its Real-Time Oncology Review pilot program, which is intended to create a more efficient review process to bring safe and effective treatments to patients as early as possible. Tepotinib was granted Breakthrough Therapy designation by the FDA in September 2019 for the treatment of patients with metastatic NSCLC harboring MET exon 14–skipping alterations who progressed following platinum-based cancer therapy.
The application is based on results from the pivotal ongoing, single-arm phase II VISION study evaluating tepotinib as monotherapy in patients with advanced NSCLC with MET exon 14–skipping alterations prospectively assessed by liquid and/or tissue biopsy. Results demonstrate consistent response rate and durable antitumor activity across lines of treatment, including in patients with brain metastases and in patients assessed by both liquid biopsy and tissue biopsy.
Data from the primary analysis of the VISION study were published in The New England Journal of Medicine in May and presented during the ASCO20 Virtual Scientific Program.
Fast Track Designation for Repotrectinib in NTRK-Positive, Tyrosine Kinase Inhibitor–Pretreated Advanced Solid Tumors
The FDA granted Fast Track designation to repotrectinib for the treatment of patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with at least one prior line of chemotherapy and one or two prior TRK tyrosine kinase inhibitors and have no satisfactory alternative treatments. Repotrectinib was previously granted two Fast Rrack designations for the treatment of ROS1-positive advanced NSCLC: first for patients with one prior line of platinum-based chemotherapy and one prior ROS1-targeted tyrosine kinase inhibitor, and second for patients without prior ROS1 tyrosine kinase inhibitor treatment. There are no approved targeted therapies for patients previously treated with another ROS1 or TRK tyrosine kinase inhibitor.
Early interim data was recently reported from the phase II TRIDENT-1 study of repotrectinib, showing a confirmed objective response rate of 50% in the cohort of NTRK-positive, tyrosine kinase inhibitor–pretreated patients with advanced solid tumors. A total of 40 patients are planned for enrollment in this cohort, and the FDA recently provided guidance that 6 months of follow-up from the last response in this cohort may be sufficient to support potential approval (previous guidance was 12 months).
Fast Track and Orphan Drug Designations for VLS-101 in Mantle Cell Lymphoma
The FDA has granted Fast Track and Orphan Drug designations to VLS-101 for the treatment of patients with mantle cell lymphoma. VLS-101 is a ROR1-directed antibody-drug conjugate that is currently being studied in a first-in-human phase I clinical trial in patients with relapsed or refractory hematologic cancers.
BCL2 Inhibitor APG-2575 Granted Orphan Drug Designation for CLL
The FDA granted APG-2575, a novel BCL2 inhibitor, Orphan Drug designation for the treatment of CLL.
APG-2575 is a novel, orally administered BCL2 selective inhibitor currently in development. APG-2575 is designed to treat a variety of hematologic malignancies by selectively blocking BCL2 to restore the normal apoptosis process in cancer cells. APG-2575 has received clearances and approvals for multiple phase IB/II clinical studies in China, Australia, and the United States in a range of hematologic malignancies, including a global phase IB/II clinical study of APG-2575 as a single agent or in combination with other therapeutic agents in patients with relapsed or refractory CLL/small lymphocytic lymphoma.
Orphan Drug Designation for Tolinapant in T-Cell Lymphoma
The FDA granted Orphan Drug designation to tolinapant (formerly known as ASTX660), a novel, orally administered nonpeptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), for the treatment of T-cell lymphoma.
Inhibitors of apoptosis proteins are frequently overexpressed in tumor cells and contribute to tumor cell survival and chemoresistance. By inhibiting inhibitors of apoptosis proteins, tolinapant promotes cell death. Tolinapant also acts via a newly described immunomodulatory mechanism which works to enhance an antitumor immune response in T-cell lymphomas. Tolinapant was designed using a fragment-based drug design technology.
Tolinapant is being evaluated in a phase I/II clinical study for the treatment of advanced solid tumors and lymphomas.
FDA Approves Label Changes to Hydrochlorothiazide to Describe Small Risk of Nonmelanoma Skin Cancer
The FDA has approved changes to the hydrochlorothiazide (HCTZ) drug label to inform health-care professionals and patients about a small increased risk of nonmelanoma skin cancer (basal cell skin cancer or squamous cell skin cancer) associated with HCTZ use and to encourage patients to protect their skin from the sun. Hydrochlorothiazide is a diuretic used to treat high blood pressure and other conditions.
Specifically, the labeling changes include the following:
- Adverse Reactions, Postmarketing Experience: Information has been added about an increased risk of nonmelanoma skin cancer associated with HCTZ
- Patient Counseling Information: Information has been added instructing patients to protect their skin from the sun and undergo regular skin cancer screenings.
The overall risk for nonmelanoma skin cancer increases as individuals age and as they spend more time in the sun. The increased risk of developing nonmelanoma skin cancer while taking HCTZ, a drug associated with photosensitivity, is small.
An FDA Sentinel Initiative study found that the increased risk was mostly for squamous cell carcinoma. In the overall study population, the increased risk for squamous cell carcinoma in patients on HCTZ was approximately 1 additional case per 16,000 patients per year.
In addition, treatment for nonmelanoma skin cancer is typically local and successful, with very low rates of death. Meanwhile, the risks of uncontrolled blood pressure can be severe and include life-threatening heart attacks or stroke. Given this information, patients should continue to use HCTZ and take protective skin care measures to reduce their risk of nonmelanoma skin cancer unless directed otherwise by their health-care provider.
