Recently, the U.S. Food and Drug Administration (FDA) accepted applications for agents aiming to treat non–small cell lung cancer (NSCLC), differentiated thyroid cancer, renal cell carcinoma (RCC), hypersensitive acute lymphoblastic leukemia (ALL), mucosal melanoma, and endometrial carcinoma.
Priority Review for Atezolizumab in NSCLC With Tumor PD-L1 ≥ 1%
The FDA accepted a supplemental biologics license application and granted Priority Review to atezolizumab as adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumours express PD-L1 ≥ 1%, as determined by an FDA-approved test. The FDA is reviewing the application under the Real-Time Oncology Review pilot program; the FDA is expected to make a decision on approval by December 1, 2021.
Atezolizumab is a monoclonal antibody designed to bind with PD-L1, which is expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.
The application is based on disease-free survival results from an interim analysis of the phase III IMpower010 study. The study showed that treatment with atezolizumab, following surgery and platinum-based chemotherapy, reduced the risk of disease recurrence or death by 34% (hazard ratio [HR] = 0.66, 95% confidence interval [CI] = 0.50–0.88) in people with stage II to IIIA NSCLC whose tumors express PD-L1 ≥ 1%, compared with best supportive care. In this population, median disease-free survival was not yet reached for atezolizumab compared with 35.3 months for best supportive care. Follow-up on the IMpower010 trial will continue with planned analyses of disease-free survival in the overall intent-to-treat population, including stage IB patients, which at the time of analysis did not cross the threshold, and overall survival data, which were immature at the time of interim analysis. Safety data for atezolizumab were consistent with its known safety profile, and no new safety signals were identified. Results from the IMpower010 trial were presented at the 2021 ASCO Annual Meeting (Abstract 8500).
Priority Review for Cabozantinib in Previously Treated Radioactive Iodine–Refractory Differentiated Thyroid Cancer
The FDA accepted a supplemental new drug application for cabozantinib, a tyrosine kinase inhibitor, as a treatment for patients 12 years and older with differentiated thyroid cancer whose disease has progressed following prior therapy and are radioactive iodine–refractory (if radioactive iodine is appropriate). The FDA granted Priority Review designation and assigned a Prescription Drug User Fee Act target action date of December 4, 2021.
The application is based on the results of COSMIC-311, a phase III pivotal trial evaluating cabozantinib vs placebo in patients with radioactive iodine–refractory differentiated thyroid cancer whose disease progressed after up to two prior vascular endothelial growth factor receptor–targeted therapies. At a planned interim analysis, cabozantinib met one of the trial’s primary endpoints, demonstrating a significant improvement in progression-free survival vs placebo. In February 2021, the FDA granted Breakthrough Therapy designation to cabozantinib as a potential treatment for patients with differentiated thyroid cancer that has progressed following prior therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate) based on these results. Detailed study findings were presented at the 2021 ASCO Annual Meeting (Abstract 3001) and were published in The Lancet Oncology in July 2021.
Priority Review for Pembrolizumab as Adjuvant Therapy in Certain Patients With RCC Following Surgery
The FDA has accepted and granted Priority Review to new supplemental biologics license application for pembrolizumab, an anti–PD-1 therapy, for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. The FDA has set a Prescription Drug User Fee Act, or target action, date of December 10, 2021.
The application is based on data from the pivotal phase III KEYNOTE-564 trial, in which pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in disease-free survival compared to placebo. These data were presented at the 2021 ASCO Annual Meeting (Abstract LBA5).
KEYNOTE-564 is a randomized, double-blind, phase III trial evaluating pembrolizumab monotherapy for the adjuvant treatment of patients with RCC who have undergone nephrectomy and who have intermediate-high risk, high risk, or M1 no evidence of disease (M1 NED) RCC with clear cell component. The study enrolled 994 patients who were randomly assigned to receive either pembrolizumab (200 mg intravenously [IV] on day 1 of each 3-week cycle for up to 17 cycles) or placebo (saline solution IV on day 1 of each 3-week cycle for up to 17 cycles). The primary endpoint is disease-free survival and the secondary endpoints include overall survival and safety.
Fast Track Designation for Eryaspase in Hypersensitive ALL
The FDA granted eryaspase fast track designation for the treatment of patients with ALL who have developed hypersensitivity reactions to Escherichia coli–derived pegylated asparaginase.
Asparaginase has been an integral component of ALL treatment for several years, but is associated with treatment-limiting hypersensitivity in up to 30% of patients. Discontinuation of asparaginase therapy in patients with ALL has been associated with inferior event-free survival, highlighting the need for additional asparaginase-based treatment options.
In December 2020, positive results from a phase II trial evaluating the safety and enzyme activity of eryaspase in primarily pediatric patients with ALL who developed hypersensitivity reactions to pegylated asparaginase were presented by the Nordic Society of Pediatric Hematology and Oncology at the 2020 American Society of Hematology Annual Meeting & Exposition (Abstract 614). This data demonstrated that eryaspase in combination with chemotherapy administered every 2 weeks provided a sustained asparaginase enzyme activity level and was generally well tolerated, with few hypersensitivity reactions.
Fast Track Designation for Nemvaleukin in Mucosal Melanoma
The FDA granted fast track designation to nemvaleukin alfa (nemvaleukin), an investigational engineered interleukin-2 (IL-2) variant immunotherapy, for the treatment of mucosal melanoma. Earlier this year, the FDA also granted Orphan Drug designation to nemvaleukin for the treatment of mucosal melanoma.
Nemvaleukin is an investigational, novel, engineered fusion protein comprised of modified IL-2 and the high-affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of nemvaleukin is designed to leverage the proven antitumor effects of existing IL-2 therapy, while mitigating certain limitations.
The manufacturer, Alkermes, recently initiated enrollment in ARTISTRY-6 (ClinicalTrials.gov identifier: NCT04830124), a global phase II trial evaluating the antitumor activity, safety, and tolerability of nemvaleukin monotherapy in patients with melanoma who have been previously treated with anti–PD-1/-L1 therapy. The study is evaluating intravenously administered nemvaleukin in patients with mucosal melanoma and subcutaneously administered nemvaleukin in patients with advanced cutaneous melanoma.
Supplemental Biologics Application for Pembrolizumab as a Single Agent for Certain Patients With MSI-H/dMMR Advanced Endometrial Carcinoma
The FDA has accepted for review a new supplemental biologics license application seeking approval for pembrolizumab as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting, and who are not candidates for curative surgery or radiation. The application is based on overall response data from cohorts D and K of the KEYNOTE-158 trial, which will be presented for the first time at the European Society for Medical Oncology (ESMO) Congress 2021 (Abstract #795P). The FDA has set a Prescription Drug User Fee Act date of March 28, 2022.
KEYNOTE-158 (ClinicalTrials.gov identifier: NCT02628067) is an ongoing global, open-label, nonrandomized, multicohort, multicenter phase II study evaluating pembrolizumb in patients with multiple types of advanced solid tumors, including endometrial carcinoma, that have progressed on standard of care therapy. Cohort K enrolled 79 patients with MSI-H endometrial carcinoma, and cohort D enrolled 11 patients with MSI-H endometrial carcinoma for a total of 90 pooled patients who received pembrolizumab as monotherapy (200 mg fixed-dose every 3 weeks). The primary endpoint was overall response rate as evaluated by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints are progression-free survival, overall survival, duration of response, and safety.
