Over the past week, the U.S. Food and Drug Administration (FDA) granted Priority Review to an immunotherapeutic agent for solid tumors with a high tumor mutational burden and to a combination treatment for the first-line treatment of metastatic or recurrent non–small cell lung cancer. The agency also granted Fast Track designations for treatments in urothelial, cervical, and central nervous system cancers, as well as gave avelumab Breakthrough Therapy designation in locally advanced or metastatic bladder cancer.
Priority Review for Pembrolizumab Based on Biomarker, Regardless of Tumor Type
The FDA accepted and granted Priority Review to a new supplemental Biologics License Application (sBLA) for the anti–programmed cell death protein 1 (PD-1) therapy pembrolizumab. The application seeks the accelerated approval of pembrolizumab monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden–high (TMB-H; ≥ 10 mutations/mb), as determined by an FDA-approved test, whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. The FDA has set a Prescription Drug User Fee Act (PDUFA) date of June 16, 2020.
The application was based in part on results from the phase II KEYNOTE-158 trial. Data from the TMB-H patient population of KEYNOTE-158 were presented at the European Society for Medical Oncology (ESMO) 2019 Congress.
KEYNOTE-158 is a multicenter, multicohort, nonrandomized, open-label trial evaluating pembrolizumab, dosed at 200 mg every 3 weeks, in patients with solid tumors. Tissue TMB status was determined using the FoundationOne CDx assay. Tumor response was assessed every 9 weeks per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), by independent, central, blinded radiographic review.
The major efficacy outcome measures were objective response rate and duration of response as assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Priority Review for First-Line Nivolumab/Ipillimumab Combined With Limited Chemotherapy in NSCLC
The FDA accepted an sBLA for nivolumab plus ipilimumab administered concomitantly with a limited course of chemotherapy for the first-line treatment of patients with metastatic or recurrent non–small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations. The FDA granted this application Priority Review with a PDUFA goal date of August 6, 2020, in addition to granting Fast Track designation.
The applications were based on results from the phase III CheckMate 9LA trial. In October 2019, the trial met its primary endpoint of superior overall survival at a prespecified interim analysis.
CheckMate 9LA is an open-label, multicenter, randomized phase III trial evaluating nivolumab/ipilimumab combined with two cycles of chemotherapy vs chemotherapy alone (up to four cycles, followed by optional pemetrexed maintenance therapy if eligible) as first-line treatment in patients with metastatic NSCLC regardless of programmed cell death ligand 1 (PD-L1) expression and histology. Patients in the experimental arm were treated for up to 2 years or until disease progression or unacceptable toxicity. Patients in the control arm were treated with up to four cycles of chemotherapy and optional pemetrexed maintenance (if eligible) until disease progression or toxicity.
The primary endpoint of the trial was overall survival in the intent-to-treat population. Secondary endpoints included progression-free survival, overall response rate, and efficacy measures according to biomarkers.
Fast Track Designation for Sacituzumab Govitecan for Locally Advanced or Metastatic Urothelial Carcinoma
The FDA granted Fast Track designation for sacituzumab govitecan for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting, including patients who are platinum-ineligible and have previously received a PD-1 or PD-L1 inhibitor in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.
Sacituzumab govitecan is currently being evaluated in the phase II TROPHY U-01 study of patients with metastatic urothelial carcinoma. Interim results from 35 patients included in the 100-patient cohort of cisplatin-eligible patients who have relapsed or are refractory to PD-1 or PD-L1 inhibitors and platinum-based chemotherapy were presented at the ESMO 2019 Congress and showed an overall response rate of 29%, consistent with previously reported data in this population.
Enrollment for the full cohort of 100 patients with prior platinum-based and PD-1 or PD-L1 inhibitor therapies has been completed, with topline data expected to be available in the second half of 2020. While enrollment for the second cohort of 40 cisplatin-ineligible patients is expected to be completed later this year, the study has recently been broadened to include a third cohort of PD-1 or PD-L1 inhibitor-naive patients to assess the combination of sacituzumab govitecan and pembrolizumab.
Fast Track Designation for Balstilimab/Zalifrelimab in Advanced Cervical Cancer
The FDA granted Fast Track designation for the combination of balstilimab, a PD-1 inhibitor, and zalifrelimab, an anti–CTLA-4 agent, in the treatment of cervical cancer.
Updated data from a preplanned interim analysis found the combination of balstilimab and zalifrelimab showed activity in patients with relapsed or refractory metastatic cervical cancer. Patients treated with the combination demonstrated a 26.5% objective response rate (with four complete responses and five partial response reported), with the median response not yet reached. For patients treated with balstilimab monotherapy, the objective response rate was 14.3% (with one complete response and five partial responses) in an all-comer, nonbiomarker-selected population of patients with refractory cervical cancer in whom prior platinum chemotherapy, with or without bevacizumab, has failed.
Fast Track Designation for Tozuleristide in Pediatric Central Nervous System Tumors
The FDA granted Fast Track designation to tozuleristide (also known as BLZ-100)—a tumor-targeting optical imaging agent designed to provide real-time, high-resolution visualization of cancer cells during surgery, potentially enabling more effective removal of cancerous tissue while sparing healthy tissue. Tozulerisitide and the high-sensitivity Canvas Imaging System are currently being tested in a phase II/III clinical trial enrolling patients aged 0 to 30 years undergoing surgery for pediatric central nervous system tumors.
Tozuleristide consists of a targeting peptide and a fluorescent dye, which emits light in the near-infrared range. Tozulerisitide has been tested in four phase I clinical trials and has demonstrated clinical proof-of-concept in brain, breast, and skin cancers.
Breakthrough Therapy Designation for Avelumab in Locally Advanced or Metastatic Urothelial Carcinoma
The FDA accepted the submission of an sBLA for avelumab for the first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma. The FDA also granted Breakthrough Therapy designation to avelumab for this indication, and the sBLA is being reviewed by the FDA under its Real-Time Oncology Review pilot program.
The application is based on positive results from an interim analysis of the phase III JAVELIN Bladder 100 trial, which met its primary endpoint of overall survival. In this study, avelumab plus best supportive care as first-line maintenance therapy significantly extended the survival of patients with previously untreated locally advanced or metastatic urothelial carcinoma whose disease did not progress on induction chemotherapy compared with best supportive care only.
A statistically significant improvement was demonstrated in both co-primary populations: all randomly assigned patients and patients with PD-L1–positive tumors. The safety profile for avelumab in the trial was consistent with that in the JAVELIN monotherapy clinical development program. Detailed results from the JAVELIN Bladder 100 study will be presented at an upcoming medical congress.
