NeoRad(Low): A phase 2 trial of neoadjuvant (NA) ipilimumab + nivolumab (ipi+nivo) with low dose stereotactic body radiation therapy (SBRT) as an immune stimulant in patients with resectable stage IB-III non-small cell lung cancer (NSCLC).

e20081 Background: Standard NA immune checkpoint blockade for patients with resectable NSCLC targets PD1 only and must be combined with platinum-based chemotherapy. In a randomized phase 2 NA study, ipi + nivo demonstrated greater immune-mediated efficacy compared to nivo alone with major pathologic response (MPR) 50% vs. 24%, Cascone T, et al. Nat Med. 2021;27(3):504-14). Preclinical and clinical studies have demonstrated that low doses of radiation enhance immune response by multiple mechanisms (dsDNA breaks, induction of STING, transcription of pro-inflammatory proteins, increased expression of neoantigens while sparing effector T cells). An approach incorporating low dose radiation as an immune stimulant potentially may improve immune-mediated efficacy and shorten the duration of NA treatment compared to approaches that use combined cytotoxic chemotherapy. Methods: This single-arm trial tested NA ipi (1 mg/kg d1) + nivo (3mg/kg d1, 15, 29) plus low-dose SBRT delivered as 2 fractions (4Gy x 2) to the gross primary tumor and nodal disease immediately following day 1 infusion and completed by day 3 in patients with medically operable stage IB-III NSCLC Patients went on to surgical resection between days 49 -63. The primary efficacy outcome measure was pathologic response (including MPR, and complete PR (CPR)). Secondary outcome measures included safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design was employed to stop the study for lack of efficacy if fewer than 3 of the first 9 evaluable patients achieved MPR or experienced undue toxicity. Results: Patients were treated on study: 4 men, 5 women, aged 40-71, stage IB (2), IIB (5), IIIA (1), IIIB (1); adenocarcinoma 7 (all EGFR,ALK -), squamous 2; ECOG PS 0-1 (9); all were former smokers. There were no dose limiting toxicities. Study-related toxicities were ≤ grade 2 including rash (2) and abdominal pain (1). There were no study-related surgical complications. One patient (IIIA, T1N2) experienced clinical and radiologic progression during study treatment and was confirmed to have pleural metastases at surgery. Of 7 patients resected to date, there was 1 CPR, 0 further MPR and 1 patient with surgery pending. All resected patients had some treatment effect, 3 were down staged and these elected not to receive adjuvant cytotoxic chemotherapy. The only patient to progress in 8 months med f/u was the patient progressing during NA therapy. Conclusions: Low-dose radiation with concurrent NA ipi + nivo was safe and well tolerated in this small cohort but did not improve MPR compared to historical phase 2 data of ipi + nivo alone. Standard and exploratory biomarkers of immune response will be presented to determine if patient selection played a role in these results. Clinical trial information: NCT04933903 .