The U.S. Food and Drug Administration (FDA) recently granted Priority Review to nivolumab as either adjuvant or first-line therapy in several types of gastric cancers, as well as to a novel PD-1 inhibitor for locally advanced or metastatic squamous cell carcinoma of the anal canal. The FDA also issued several other designations for treatments for urothelial cancer, melanoma, soft-tissue sarcoma, and liver cancer.
Priority Review for Nivolumab as Adjuvant Therapy for Patients With Resected Esophageal or Gastroesophageal Junction Cancer
The FDA accepted a supplemental biologics license application for nivolumab for the treatment of patients with resected esophageal or gastroesophageal junction cancer in the adjuvant setting, after neoadjuvant chemoradiotherapy. The FDA granted the application Priority Review and assigned a Prescription Drug User Fee Act goal date of May 20, 2021.
The filing was based on results from the phase III CheckMate-577 trial, which is the first trial to show positive results in the adjuvant setting in this group of patients. CheckMate-577 is a randomized, multicenter, double-blind study evaluating nivolumab as an adjuvant therapy in patients with resected esophageal or gastroesophageal junction cancer who have received neoadjuvant chemoradiotherapy and have not achieved a pathologic complete response. The primary endpoint of the trial is disease-free survival, and the secondary endpoint is overall survival.
Following neoadjuvant chemoradiotherapy and complete tumor surgical resection, a total of 794 patients were randomly assigned to receive placebo (n = 262) or nivolumab (n = 532) at 240 mg by intravenous infusion every 2 weeks for 16 weeks followed by placebo or nivolumab at 480 mg every 4 weeks until disease recurrence, unacceptable toxicity, or withdrawal of consent, with a maximum total treatment duration of 1 year. The study met its primary endpoint of disease-free survival in patients with esophageal or gastroesophageal junction cancer, following neoadjuvant chemoradiotherapy and tumor resection. Follow up for overall survival is ongoing. The safety profile of nivolumab as adjuvant therapy in the CheckMate-577 trial was consistent with that reported in previous studies.
Priority Review for Nivolumab Combined With Chemotherapy as First-Line Treatment in Metastatic Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
The FDA also accepted a supplemental biologics license application for nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma, based on results from the CheckMate-649 trial. The FDA granted the application Priority Review and assigned a Prescription Drug User Fee Act goal date of May 25, 2021.
CheckMate-649 is a phase III, randomized, multicenter, open-label study evaluating nivolumab plus chemotherapy or a combination of nivolumab plus ipilimumab compared to chemotherapy alone in patients with previously untreated, HER2-negative, advanced or metastatic gastric/gastroesophageal junction cancer or esophageal adenocarcinoma. The primary endpoints of the trial are overall survival in PD-L1–positive patients with a combined positive score (CPS) ≥ 5 treated with nivolumab plus chemotherapy, and progression-free survival in CPS ≥ 5 patients treated with nivolumab plus chemotherapy compared to chemotherapy alone.
Patients in the nivolumab plus chemotherapy arm received 240 mg of nivolumab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) every 2 weeks or 360 mg of nivolumab plus capecitabine and oxaliplatin (CAPOX) every 3 weeks. Patients in the nivolumab/ipilimumab arm received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for four cycles followed by nivolumab at 240 mg every 2 weeks. Patients in the chemotherapy arm received FOLFOX or CAPOX every 2 or 3 weeks, respectively. All patients continued treatment for up to 2 years or until disease progression, unacceptable toxicity, or withdrawal of consent.
First-line treatment with nivolumab plus FOLFOX or CAPOX led to a statistically significant improvement in overall survival and progression-free survival for patients with unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma whose tumors express PD-L1 with a CPS ≥ 5, compared to treatment with chemotherapy alone. A statistically significant overall survival benefit was also observed in the all-randomized population. The safety profile of nivolumab plus chemotherapy was consistent with the known safety profile of the individual treatments.
Priority Review for Retifanlimab in Squamous Cell Carcinoma of the Anal Canal
The FDA accepted for Priority Review a biologics license application for retifanlimab, an intravenous PD-1 inhibitor, as a potential treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal who have had disease progression on, or who are intolerant of, platinum-based chemotherapy. The Prescription Drug User Fee Act target action date for retifanlimab is July 25, 2021.
The submission is based on data from the phase II POD1UM-202 trial, which is evaluating retifanlimab in previously treated patients with locally advanced or metastatic squamous cell carcinoma of the anal canal who have progressed on, or are intolerant of, standard platinum-based chemotherapy. The trial enrolled 94 patients, including several with well-controlled human immunodeficiency virus (HIV) infection. Retifanlimab was administered intravenously at 500 mg every 4 weeks.
The study, which was recently presented at the European Society for Medical Oncology Virtual Congress 2020 (Abstract 1089P), resulted in an objective response rate of 14% for retifanlimab monotherapy as determined by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. Responses were observed regardless of PD-L1 status, presence of liver metastases, age, or HIV status, and were durable (median = 9.5 months). Grade 3 or worse treatment-related adverse events occurred in 11.7% of patients; grade 3 or worse immune-related adverse events occurred in 6.4% of patients. The most common adverse reactions (incidence ≥ 20%) were fatigue and diarrhea.
POD1UM-303/InterAACT 2, a phase III trial of retifanlimab in combination with carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal, is now open and recruiting patients.
Fast Track Designation for Padeliporfin ImPACT in High-Grade Upper Tract Urothelial Cancer
The FDA granted Fast Track designation for padeliporfin ImPACT for the treatment of adult patients with low-grade and unifocal high-grade upper tract urothelial cancer. This follows clearance of the investigational new drug application granted in December 2020 allowing initiation of a phase III clinical trial of padeliporfin ImPACT in patients with low-grade upper tract urothelial cancer, expected to begin enrollment in the first quarter of 2021.
Padeliporfin ImPACT (Immune Photo Activated Cancer Therapy) offers surgery-like efficacy combined with organ preservation. ImPACT is an oncology platform comprising the intravenous delivery of an inactive drug, padeliporfin. Upon activation, the drug rapidly triggers the constriction of the blood supply in the illuminated area only, resulting in targeted tumor necrosis that activates antitumor immunity, which enhances cancer cell eradication.
Fast Track Designation for Toripalimab in Mucosal Melanoma
The FDA granted toripalimab Fast Track designation for the first-line treatment of mucosal melanoma. The FDA also approved an investigational new drug application for a global phase III trial of toripalimab in combination with axitinib vs pembrolizumab for the first-line treatment of patients with advanced mucosal melanoma. Toripalimab is an anti–PD-1 monoclonal antibody.
The Combination Clinical Trial is an international, multicenter, randomized phase III study designed to evaluate the efficacy and safety of toripalimab in combination with axitinib vs pembrolizumab as a first-line treatment in patients with unresectable, locally advanced, or metastatic mucosal melanoma. The trial intends to enroll 220 patients who will be randomly assigned 1:1 into two study arms. The primary endpoint of the Combination Clinical Trial is progression-free survival; secondary endpoints include objective response rate, duration of response, overall survival, and safety.
The combination of toripalimab plus axitinib for patients with mucosal melanoma was previously studied in a phase Ib trial, the results of which were published by Sheng et al in the Journal of Clinical Oncology. The study showed that in the first-line setting, the combination achieved an overall response rate of 48.3% and a disease control rate of 86.2%, with a manageable safety profile. The median progression-free survival was 7.5 months.
Orphan Drug Designation for Ilixadencel in Soft-Tissue Sarcoma
The FDA granted Orphan Drug designation to ilixadencel for the treatment of soft-tissue sarcoma. The designation recognizes results from a phase I/II clinical trial of gastrointestinal stromal tumors, a rare and difficult-to-treat cancer.
Ilixadencel is an off-the-shelf cell-based cancer immunotherapy developed for the treatment of solid tumors. Its active ingredient is activated allogeneic dendritic cells derived from healthy blood donors. Injection of these cells in the patient’s tumor generates an inflammatory response, which in turns leads to tumor-specific activation of the patient’s cytotoxic T cells.
Orphan Drug Designation for Uttroside-B in Liver Cancer
The FDA has granted Orphan Drug designation to Uttroside-B, a small-molecule chemotherapeutic, for the treatment of hepatocellular carcinoma. In preclinical studies, Uttroside-B was up to 10 times more potent against hepatocellular carcinoma cells than sorafenib.
