Impact of genomic aberrations and additional therapies on survival outcomes of patients with operable non-small cell lung cancer (NSCLC) from the NEOSTAR study.
Authors: Zhou Nicolas , Sepesi Boris , Leung Cheuk Hong , Lin Heather Y. , William William Nassib , Weissferdt Annikka , Pataer Apar , Godoy Myrna , Fossella Frank V. , Blumenschein George , Le Xiuning , Tsao Anne S. , Zhang Jianjun , Hofstetter Wayne L. , Swisher Stephen , Vaporciyan Ara A. , Lee J. Jack , Gibbons Don Lynn , Heymach John , Cascone Tina 
Published: June 2021

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Background: The NEOSTAR study compared nivolumab (N) vs. nivolumab plus ipilimumab (NI) with major pathological response (MPR; ≤10% viable tumor) as primary outcome. We report updated rates of treatment failure (TF), including in patients whose tumors harbored genomic aberrations, and outcomes of additional treatments. Methods: Patients (pts) with stage I-IIIA resectable NSCLC (AJCC 7th) were randomized to either neoadjuvant N or NI followed by surgery (n = 44). TF was defined as radiographic and/or biopsy-proven recurrence from primary lung cancer and/or death (treatment or cancer-related). Additional systemic therapy at recurrence included immuno-oncology (IO)-based therapy (IO or chemo-IO), targeted therapy (TT), or chemotherapy. Disease control rate (DCR) was defined as the proportion of pts with radiographic objective responses and stable disease at first restaging. Cox proportional hazards model was used to associate baseline characteristics and time to TF. Results: A total of 44 randomized pts were evaluated, the median follow-up was 35 months (mts) as of February 4, 2021. Among the 12 TF pts (12/44, 27%), 42% (5/12) did not undergo surgery on trial, 9 (9/44, 20%) experienced recurrence and 6 (6/44, 14%) died (1 non-cancer-related, 5 cancer-related). TF was less likely in smokers vs. never smokers (hazard ratio = 0.20, 95% confidence interval = 0.06-0.65, p = 0.007). Among pts with pathological specimen resected on trial, MPR was achieved in 40% (12/30) of non-TF pts. Only 1 (1/7, 14%) TF pt achieved MPR, but died of a non-cancer related cause. TF-free survival rate at 2 years was 92% in MPR and 78% in non-MPR pts. Eight (8/9, 89%) pts had tumors with canonical oncodriver aberrations (5 EGFR mutations, 1 with STK11+ KRAS Q61H mutations, 1 ALK translocation and 1 RET fusions). Of the 9 recurrences, 44% (4/9) were treated with IO therapy, and all 7 pts with targetable aberrations were treated with TT (3 after retreatment with IO therapies). Of the 4 pts retreated with IO therapy, duration between end of neoadjuvant and retreatment were 20, 17, 23, and 19 mts. Duration from retreatment until progression (PD) were 1, 1, and 2 mts, respectively. Last pt was treated without PD for 2 mts but switched to TT due to discovery of genomic aberration. IO retreatment achieved 25% DCR (1/4). In comparison, the DCR for TT treated pts was 71% (5/7, p = 0.242). Median time to treatment was 21 mts, and median time to PD was not reached. Among 32 non-TF pts, 12 had genomic analysis and 7 aberrations were found in 6 pts (2 STK11, 2 ERBB2, 1 STK11 + 1 KRAS G12C, and 1 KRAS G12C mutation). Conclusions: A 27% TF rate was observed after neoadjuvant IO. TF was less likely to occur in smokers and MPR pts, and 42% of TF pts did not undergo curative-intent surgery on trial. Genomic aberrations were common in pts with recurrence (89%), and treatment with TT achieved 71% DCR vs. 25% DCR with IO-based retreatment. Clinical trial information: NCT: 03158129.