Phase II study of combination of radiotherapy with pembrolizumab plus chemotherapy in patients with previously untreated metastatic non-small cell lung cancer: North Japan Lung Cancer Study Group 1902.

8541 Background: Radiotherapy (RT) can activate the immune system and result in an antitumor effect outside of the radiation field. Several studies showed the efficacy of an addition of RT to immunotherapy for metastatic non-small cell lung cancer (NSCLC). However, the results of RT combined with immunotherapy plus platinum-doublet chemotherapy (chemo) have not been fully examined.Thus, we conducted a multicenter phase II trial to evaluate the efficacy and safety of combination of RT with pembrolizumab (pembro) plus chemo in patients (pts) with previously untreated metastatic NSCLC. Methods: Eligible pts aged ≥ 20 years with: metastatic NSCLC without sensitizing EGFR or ALK mutations; scheduled to receive pembro plus chemo as first-line systemic therapy; lesions that can be irradiated with a total dose of 30 Gy in 10 fractions.Pts received RT and started pembro plus chemo within one week of the start of RT. Pts received 4 cycles of cisplatin or carboplatin plus pemetrexed or (nab-) paclitaxel plus pembro, followed by pembro ± pemetrexed every 3 weeks. The primary endpoint was a 12-month progression-free survival (PFS) rate from date of registration. Secondary endpoints were overall response rate (ORR), disease control rate (DCR), PFS, overall survival (OS) and toxicity profiles. Assuming a 12-month PFS rate under the null hypothesis set at 30% and the alternative hypothesis at 50% with a one-side α = 0.05 and β = 0.2, the required total sample size was 37. Considering potential ineligible pts after enrollment, the sample size was set at 40. Results: Between July 2019 and May 2023, 40 pts were enrolled. Thirty-seven and 38 pts were analyzed for efficacy and safety, respectively. Their median age was 68 (47-81) years; 9 (23.7%) female; 22 (57.9%) ECOG PS 0 and 16 (42.1%) PS 1; 29 (76.3%) adenocarcinoma; PD-L1 tumor proportion score 6 (15.8%) <1%, 14 (36.8%) 1-49%, 14 (36.8%) ≥50% and 4 (10.5%) unknown. The most common sites of radiotherapy were bone 20 (52.6%), followed by lymph nodes 8 (21.1%) and lung 5 (13.2%). At the primary end point, the 12-month PFS rate was 44.3% (90% CI, 30.3%-57.3%). Median PFS was 8.4 months (95% CI, 5.7-22.2) and median OS was 30.1 months (95% CI, 22.3-not reached). ORR was 67.6% and DCR was 89.2%. Grade 3 or 4 adverse events (AEs) occurred in 25 pts (65.8%), and one treatment-related death (pneumonitis) occurred. The most common ≥ grade 3 AEs were neutropenia, leukopenia and anemia. Pneumonitis was reported in ten (26.3%), with two pts having grade 3 and one patient having grade 5. AEs with potential immunological cause occurred in 17 pts (44.7%). Of these, 10 pts (26.3%) were ≥ grade 3. Conclusions: The addition of RT to pembro plus chemo showed promising efficacy for pts with previously untreated metastatic NSCLC, although caution should be exercised with regard to pneumonitis. Clinical trial information: UMIN000036856.