Prospective Phase I/II Study of Radiation and Chemotherapy With Ipilimumab Followed by Nivolumab for Patients With Stage III Unresectable NSCLC.

Purpose/Objective(s) We hypothesized that the addition of concurrent ipilimumab (IPI) with chemoradiotherapy followed by consolidative nivolumab (NIVO) would be safe and tolerable for patients with unresectable stage III non-small cell lung cancer (NSCLC). We report early outcomes and toxicity associated with this regimen in a phase I/II clinical trial. Materials/Methods The study was designed as a prospective, multicenter phase I/II trial. Eligible patients had ECOG 0-1 and unresectable stage III NSCLC. Therapy included a platinum-based chemotherapy doublet with concurrent radiotherapy to 60 Gy in 30 fractions over six weeks and two doses of concurrent IPI (1 mg/kg) given weeks 1 and 4. Maintenance NIVO was initiated 1-3 weeks after completion of chemoradiotherapy/IPI and given every 4 weeks (480 mg) for up to 12 cycles. The primary endpoints were to evaluate the safety and tolerability of the regimen (Phase I) and the 12-month PFS (Phase II). Treatment-related toxicity was assessed according to CTCAE v5.0. Time to event analysis was performed with Kaplan Meier (KM) and Cox proportional hazard (CPH) models. Results are reported with 95% confidence intervals (CI). Results Nineteen of a planned 55 patients were enrolled in the trial which was discontinued without proceeding to the Phase II component due to exceeding the futility boundary for toxicity. The median follow-up was 21 months by the reverse KM method. The 12-month PFS estimate was 54% (CI 29-78) and the median PFS was 19 months (CI 6-not reached). The 12-month OS estimate was 60% (CI 36-84) while the median OS was not reached. Ten patients (53%, CI 29-76) experienced grade 2 or higher (G2+) pneumonitis. The median time to development of G2+ pneumonitis was 5.5 months and the risk of G2+ pneumonitis at 6- and 12-months was 57% (CI 30-84) and 74% (CI 49-99), respectively. Sixteen patients (84%, CI 68-100) had any G3+ treatment related toxicity. The most common G3+ toxicities were pulmonary (8 patients, 42%, CI 20-67) and cytopenias (7 patients, 37%, CI 16-62). Five patients (26%, CI 6-46) had possible treatment related G5 toxicity, including three patients with possible treatment related G5 pulmonary toxicity (16%, CI 0-32). There was no difference in the mean percent of lung volume receiving 20 Gy (V20) between those with and without G2+ pneumonitis (26%, CI 20-32 vs 21%, CI 16-27, P = 0.18), nor in the mean lung dose (14 Gy, CI 10-17 vs 15 Gy, CI 12-18, P = 0.35). Neither mean lung dose nor lung V20 were associated with time to G2+ pneumonitis on univariable CPH. Conclusion The combination of concurrent IPI with standard chemoradiation followed by maintenance NIVO for unresectable stage III NSCLC is associated with significant toxicity which may limit opportunities for improved outcomes, although the sample size in this trial is small. Alternative strategies or sequencing should be explored to integrate immunotherapy with cytotoxic chemotherapy and radiation for patients with unresectable stage III NSCLC.