Abstract 1046P
Background
Poly (ADP-ribose) polymerase inhibitors (PARPi) have received approval in BRCA-associated cancers and shown efficacy in ovarian cancers exhibiting genomic scarring or HRD mutational signatures. Despite these successes, PARPi trials in BRCA1/2 mutant or high genomic loss of heterozygosity (gLOH) NSCLC have shown little clinical activity. We hypothesize that HRDsig would improve patient selection for PARPi treatment in NSCLC.
Methods
Targeted next generation sequencing was performed on 48,344 NSCLC specimens. HRDsig was called using a machine learning based algorithm (AACR 2022 #1249). A gLOH high cutoff of 21% was based off TCGA data and was utilized as a selection biomarker in the S1900A LUNGMAP sub-study (NCT03845296). Comparisons of proportions were made with chi-squared test. A non-parametric Mann–Whitney U test was used to compare continuous variables. All reported comparisons have a p-value < 0.001.
Results
In 48,344 NSCLC cases, HRDsig(+) was observed in 2,201 cases (4.6%) and was enriched in NCCN driver negative cases (6.2% v 2.6%). HRDsig(+) NSCLC were more frequently squamous histology (37% v 25), gLOH high (41% v 10%) and had higher tumor mutational burden (median 10 mut/mb v 7.5 mut/mb) when compared to HRDsig(-) NSCLC. Alterations (alts) in BRCA1/2 were enriched in HRDsig(+): BRCA2 (17% v 1.5%), BRCA1 (5.5% v 1.4%). BRCA1/2 biallelic inactivation was strongly associated with HRDsig(+) (365/486, 75%) while biallelic BRCA1/2 alts in HRDsig(-) NSCLC were less frequent (265/1286, 21%). BRCA1/2 alts detected in gLOH high NSCLC were not as frequently biallelic (255/403, 63%), particularly when focusing on HRDsig(-) cases (55/168, 33%).
Conclusions
HRDsig(+) NSCLC represents a distinct genomic subset and is often mutually exclusive with NCCN driver alts. Most BRCA1/2 alts are monoallelic in NSCLC, but biallelic inactivation is associated with HRDsig(+) and improved clinical outcomes to PARPi were noted in the subset of patients whose tumors had biallelic inactivation (ASCO 2021 #9024). This data suggests HRDsig may perform better when selecting NSCLC patients who may benefit from PARPi, however, further prospective clinical trials are needed.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Foundation Medicine Inc.
Funding
Foundation Medicine Inc.
Disclosure
J.W. Riess: Financial Interests, Institutional, Research Grant: Merck, Novartis, AstraZeneca, Revolution Medicines, Spectrum; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals, Boehringer Ingelheim, Novartis, Regeneron, Janssen, Daichi-Sankyo, EMD Serono, Sanofi, BMS, BeiGene, Turning Point, Blueprint. R.W. Madison, K. Tolba, A.B. Schrock, G.R. Oxnard: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc; Financial Interests, Personal, Stocks/Shares: Roche. E.S. Sokol: Financial Interests, Personal, Full or part-time Employment, Employee: Foundation Medicine; Financial Interests, Personal, Stocks/Shares, Stocks and stock options: Roche.