iSABR: Safety and Efficacy Results from a Phase II Study of SABR in Combination with Durvalumab for Early-Stage Medically Inoperable NSCLC

Purpose/Objective(s)

SABR is standard for medically inoperable early-stage NSCLC and results in excellent outcomes. However, rate of regional and distant failures is significant. Addition of immune check point inhibitors improve disease control and overall survival in stage III and IV NSCLC and may improve outcomes in early-stage NSCLC. We report safety and efficacy results of a phase II study of SABR with durvalumab (durva) in early-stage inoperable NSCLC.

Materials/Methods

Eligible patients had newly diagnosed, biopsy proven clinical stage I or IIA NSCLC defined by AJCC 7^th edition. Patient had to be medically inoperable or refused surgery. There was a 15-patient safety lead-in cohort with pre-specified stopping rules based on incidence of grade 3 or 4 treatment-related toxicity. Patients were treated with one cycle of durva at the time of CT simulation, followed by SABR (54 Gy in 3, 50 Gy in 4, or 65 Gy in 10), then up to 4 cycles of durva (1500 mg Q4 wk). No stopping rules were met, but due to slow accrual, the study terminated prematurely in the randomized Phase II portion (1:1; SABR/durva: SABR). A total of 20 patients were enrolled from October 2017 - March 2020. Eighteen patients received SABR/durva and thus form the cohort for analysis. Local control (LC), progression-free survival (PFS), overall survival (OS), and lung cancer specific survival (LCSS) were assessed using the Kaplan Meier method. Incidences of acute (≤ 90 days) and late (> 90 days) treatment-related grade 3+ pulmonary, cardiac, and GI toxicities were tabulated.

Results

Median age was 78.6 years-old with 61% male. Median follow-up time was 2.6 years. Seventy-two percent of the patients had T1 tumor and remaining had T2. Eighty-three percent of the patients had adenocarcinoma histology and remaining had squamous cell. Eighty-nine percent of the patients were former/current smokers. Seventy-eight percent of patients received all 5 cycles of durva, 1 patient received 3 cycles, and 2 patients received 1 cycle. The 1-, 2- year LC rates were 100% and 93.8%, PFS rates were 94.4% and 83.3%, and OS rates were 94.4% and 88.9%. The 2-year cumulative incidence for LCSS was 94.4%. At 2-years, stratified by median gross tumor volume (GTV), OS was 100% (GTV ≤ 7.9 mL) vs. 77.8% (GTV > 7.9 mL), p=0.07. Acute and late grade 3+ treatment-related toxicities were pulmonary (n=3, 16.7%; n=3, 16.7%), cardiac (none; n=3, 16.7%), and GI (none). There was one case of grade 4 pneumonitis. One patient retrospectively identified as having probably fibrotic lung disease at baseline died of respiratory failure, which was conservatively assessed as possibly related to study treatment.

Conclusion

For early-stage NSCLC, SABR/durva resulted in excellent disease specific outcomes, including survival. Safety was promising, but this study underscored the importance of excluding patients with any fibrotic lung disease for safety and optimal interpretation of adverse event data. Results support ongoing phase III trials determining the benefit of SABR/durva in these patients.