Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) provides high rates of treated metastasis control, stimulates innate and adaptive immune pathways, and is safe in patients treated with anti-PD1 monotherapy. We hypothesized that SBRT may improve outcomes for patients receiving immunotherapy through direct cytoreduction and increased immunogenicity. We designed a phase 1 trial to evaluate the safety of combination immune checkpoint blockade with nivolumab and ipilimumab (N/Ip) plus sequential (Seq) or concurrent (Con) multisite SBRT as first-line therapy for patients with stage IV NSCLC.

Materials/Methods: Chemotherapy-naïve patients with metastatic NSCLC received SBRT to 1 to 4 metastases. Not all metastases were targeted, and metastases > 65mL were partially irradiated. Brain metastases were allowed, and those > 3mm were treated prior to enrollment. SBRT dose varied by anatomic site and ranged from 45 to 50 Gy in 3 to 5 fractions with predefined dose de-escalation if excess dose-limiting toxicities (DLTs) were observed. Patients in the Seq arm received N/Ip 1 to 7 days after completion of SBRT. Patients in the Con arm received N/Ip prior to completion of SBRT. N/Ip continued until progression, toxicity, or up to 2 years. To assess cytoreduction 3 months (mo) after treatment, deep learning algorithms were used to contour all metastases in patients, which were verified by radiologists.

Results: A total of 35 patients (n = 19 Seq, n = 16 Con) were enrolled and evaluable for toxicity analysis (SBRT and at least 1 cycle N/Ip). Brain metastases were present in 27% of patients. PD-L1 expression was: 0% (n = 16), 1-49% (n = 10), or >50% (n = 9). The median number of metastases treated with SBRT was 3.2. Six patients experienced DLT (4 pneumonitis), resulting in a 20% reduction in organ-at-risk constraint in the Seq arm. Median PFS by RECIST (total/Seq/Con) was 5.9mo (95% CI: 4.9-13.1)/ 6.2mo (95% CI: 3.5-12.6)/ 5.9mo (95% CI: 3.1-18.0). RECIST best response was 11% CR, 57% PR, 6% SD, and 26% PD. When comparing mean volumetric cytoreduction of non-irradiated metastases at 3mo, the Con arm was superior by 3-fold (p<0.05). Treatment past progression was allowed, and time to second-line therapy (chemotherapy) was NR/17.5mo (Seq/Con). Median OS has not been reached with median follow-up of 15mo. PD-L1 status did not impact PFS (p = 0.64) nor OS (p = 0.77).

Conclusion: Multisite SBRT and N/Ip were well tolerated, with median OS and time to chemotherapy not reached (>17mo). Fewer DLT events were observed in the Con arm. Deep learning algorithms demonstrated significant differences in cytoreduction (abscopal response) of non-irradiated metastases favoring the Con arm. Based on the lower toxicity and improved cytoreduction, the Con arm will be used in the phase 2 expansion. Clinical trial information: NCT03223155.

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