FDA Issues Complete Response Letter for Retifanlimab + Chemotherapy in Metastatic NSCLC
The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) for the supplemental biologics license application (sBLA) seeking approval of retifanlimab-dlwr (Zynyz) in combination with platinum-based chemotherapy for the treatment of metastatic non–small cell lung cancer (NSCLC).
Importantly, the FDA’s decision was not related to the drug’s clinical efficacy or safety. Instead, the CRL cited inspection findings at the Catalent Indiana fill-finish facility, a third-party manufacturing site referenced in the application.
According to the agency, regulatory compliance issues at the facility were the sole approvability concern. No additional issues were raised regarding the clinical data supporting retifanlimab or the drug-substance manufacturer.The developer, Incyte, stated that it plans to work closely with the FDA and Catalent to resolve the manufacturing concerns and support a future resubmission of the application.
“Lung cancer is the leading cause of cancer deaths globally, with the high majority of cases being NSCLC. I am encouraged by the observed safety and efficacy profile of retifanlimab when added to platinum-based chemotherapy in this patient population and believe the positive results from the POD1UM-304 trial support retifanlimab in combination with chemotherapy as an additional treatment option for previously untreated metastatic NSCLC,”
Saied Shun Lu, MD, PhD, from Shanghai Chest Hospital
POD1UM-304 Trial
The submission was supported by results from the phase III POD1UM-304 trial, a randomized, international, double-blind study evaluating retifanlimab plus platinum-based chemotherapy as first-line treatment for metastatic NSCLC.
The trial enrolled 583 patients with previously untreated metastatic nonsquamous or squamous NSCLC who did not harbor actionable driver alterations such as EGFR, ALK, BRAF, or ROS1. Participants were randomized in a 2:1 ratio to receive retifanlimab plus chemotherapy or placebo plus chemotherapy.
Treatment regimens differed by histology. Patients with nonsquamous disease received pemetrexed plus cisplatin or carboplatin, followed by maintenance pemetrexed. Those with squamous histology received carboplatin combined with paclitaxel or nab-paclitaxel. Retifanlimab was administered at 375 mg every three weeks for up to two years.
Survival and Response Outcomes
The addition of retifanlimab to platinum-based chemotherapy significantly improved clinical outcomes compared with chemotherapy alone.
Median overall survival (OS) reached 18.1 months in the retifanlimab arm versus 13.4 months in the placebo arm, corresponding to a 25% reduction in the risk of death. Median progression-free survival (PFS) was 7.7 months with the combination compared with 5.5 months with chemotherapy alone.
Response outcomes also favored the investigational regimen. The objective response rate (ORR) was approximately 52% with retifanlimab plus chemotherapy compared with 39% in the control arm. Median duration of response (DOR) was 12.7 months with retifanlimab versus 6.1 months with chemotherapy alone.
Safety Profile
The safety profile of the combination was generally consistent with that observed for other PD-1 immune checkpoint inhibitors combined with chemotherapy. Higher rates of grade 3 or higher treatment-emergent adverse events were observed in the retifanlimab arm, which investigators attributed largely to longer treatment exposure in patients who derived clinical benefit.
Importantly, no increase in fatal or serious COVID-19–related adverse events was observed with the addition of retifanlimab.
Clinical Implications
Investigators concluded that adding retifanlimab to platinum-based chemotherapy significantly improved overall survival and other key clinical endpoints in patients with metastatic NSCLC without targetable driver mutations. If approved, the regimen could represent a new first-line immunotherapy option for this patient population.
However, the FDA’s CRL highlights that manufacturing and regulatory compliance issues—rather than clinical efficacy—currently remain the primary barrier to approval. Resolution of these issues could allow the application to move forward.
What Happens Next?
Incyte indicated that it will address the manufacturing inspection findings and work toward a potential resubmission of the application to the FDA.If approved in the future, retifanlimab plus platinum chemotherapy could represent a new first-line immunotherapy combination option for patients with metastatic NSCLC.