Neoadjuvant N induces a 45% major pathologic response (MPR) in resected NSCLCs. We report preliminary results of NEOSTAR (NCT03158129) - a phase 2 trial evaluating neoadjuvant N or NI in resectable NSCLC pts.
Pts with stage I-IIIA (single N2) resectable NSCLC (AJCC 7th), ECOG PS 0-1, were randomized 1:1 to N (3 mg/kg IV Q2 weeks, on D1, 15, 29) or NI (N plus I, 1 mg/kg IV on D1) followed by surgery (n=22/arm). Primary endpoint is MPR (≤10% viable tumor cells at surgery), hypothesized to be higher than MPR to induction chemotherapy historical controls. Immune infiltrates were assessed by flow cytometry on checkpoint inhibitor (CPI)-treated tumors and compared to untreated resected samples (ICON set).
As of 9/6/2018, 33 pts were randomized, 17 to N, 16 to NI: mean age 65, 67% males, 21% never smokers, stage I n=10, II n=15, III n=8, 58% adenocarcinomas. 30 pts completed neoadjuvant therapy (2 ongoing, 1 G3 hypoxia [N]) & 26 had surgery (5 unresectable [2 N, 3 NI], 2 pending). Overall MPR rate was 26% (8/31). MPR rate to N and NI were 25% (4/16) and 27% (4/15), respectively. Median % of viable tumor cells was lower in tumors resected post NI vs. N (28% vs. 65%, p=0.32). There were 5 pathologic CRs (2 N, 3 NI). Radiographic ORR by RECIST v1.1 was 19% (5 PR [N], 1 CR [NI]). 19% of pts had PD (6/31, 3 N, 3 NI). Surgical complications included 1 bronchopleural fistula (BPF). Treatment-related AEs included G5 death due to BPF post steroid-treated pneumonitis (n=1, N); G3 pneumonia (n=1, N), hypoxia (n=1, N); G2 cough (n=3, NI), rash (n=1, N), fatigue (n=1, N). CPIs increased proliferative (Ki67+) & activated (ICOS+) effector CD8+ & CD4+ TILs in treated vs. untreated tumors (p<0.0001). CD27+CD28+ effector memory CD8+ TILs were higher in N vs. NI (49% vs. 33%, p=0.06). Ki67+CD103+ tissue resident effector CD8+ (98% vs. 65%, p=0.1) & CD4+ (99% vs. 40%, p=0.03) TILs and Tregs (97% vs. 47%, p=0.06) were higher in NI vs. N.
Neoadjuvant CPI is overall safe and induces a 26% MPR rate, with a trend towards less viable tumor after NI. Preliminary results suggest neoadjuvant CPIs induce higher TIL proliferation and activation vs. untreated tumors. NI may induce higher proliferation of different T cell subsets vs. N, which may lead to distinct antitumor immune responses.
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