Phase 2 study of pembrolizumab plus pemetrexed for older patients with non-squamous non-small cell lung cancer with PD-L1 tumor proportion score of less than 50%: CJLSG1901.

8540 Background: Immune checkpoint inhibitor plus platinum-containing chemotherapy is the standard of care for patients with advanced non-small cell lung cancer (NSCLC). Pembrolizumab combined with pemetrexed and cisplatin/carboplatin is approved as first line treatment for patients with metastatic non-squamous NSCLC based on the results of KEYNOTE-189. However, data on the efficacy and safety of this regimen are limited for patients aged ≥75 years. In preclinical models, anti-PD-L1 antibody with pemetrexed enhanced the antitumor effect more than the combination of pemetrexed with carboplatin. These results suggest that pembrolizumab plus pemetrexed can be effective while potentially sparing severe side effects by omitting carboplatin. Methods: This multicenter, open-label, phase 2 trial was conducted at 42 institutions in Japan to evaluate the efficacy and safety of pemetrexed plus pembrolizumab. Eligible patients had metastatic/recurrent non-squamous NSCLC without sensitizing EGFR or ALK mutations, were aged ≥75 years, had a PD-L1 TPS of less than 50%, had received no prior systemic chemotherapy, and had an ECOG performance status of 0 or 1. Patients received pemetrexed (500 mg/m 2 ) plus pembrolizumab (200 mg/body) on day 1 of each 21-day cycle. Treatment continued until radiographic progression or unacceptable toxicity was observed. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. This trial is registered with ClinicalTrials.gov (NCT04396457) and the Japan Registry of Clinical Trials (jRCTs041200012). Results: From July 2020 to May 2022, 49 patients were enrolled in this study. The median follow-up time was 15.4 months. The median age was 79.0 years (range 75-91), 77.6% of the patients were male, and 57.1% had a PD-L1 TPS ≥1%. The ORR was 36.7% (95% CI 23.4-51.7), and the disease control rate was 65.3% (95% CI 50.4-78.3%). The median PFS was 7.6 months (95% CI 4.8-16.2), and the median OS was 19.4 months (95% CI 11.8- not reached). The most common grade 3 or 4 adverse events were neutropenia (31.3%), leukopenia (20.8%), and anemia (12.5%). Serious adverse events were observed in 14 patients (4 with pneumonitis, 2 with decreased appetite, 2 with febrile neutropenia). No treatment-related deaths were observed. Conclusions: Pembrolizumab plus pemetrexed demonstrated an ORR of 36.7% and met the primary endpoint. The safety profile was tolerable and manageable. This combination therapy is a promising candidate as a novel first line treatment strategy for older patients with metastatic non-squamous NSCLC. Clinical trial information: NCT04396457 .