As a marker of homologous recombination deficiency, genomic loss of heterozygosity does not predict efficacy of rucaparib in advanced non–small-cell lung cancer (NSCLC).
While prior studies have shown robust efficacy leading to US Food and Drug Administration approval of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA-associated cancers, data in non–small-cell lung cancer (NSCLC) are much less clear. S1900A, a Lung-MAP substudy, evaluated the PARP inhibitor rucaparib in advanced-stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity as a phenotypic marker of homologous recombination deficiency.1
Eligible patients were required to have a deleterious mutation in BRCA1 or BRCA2 and/or high (≥21%) genomic loss of heterozygosity. Other key eligibility criteria included advanced NSCLC that progressed on or after platinum-based chemotherapy and/or PD-L1 antibody and that progressed after the most recent line of systemic therapy, Zubrod performance status of 0 or 1, adequate organ function, no grade ≥3 hypercholesterolemia, no previous PARP inhibitor exposure, and no systemic therapy within 21 days of registration. Patients were stratified by histology into 2 cohorts: squamous and nonsquamous or mixed histology. With 40 eligible patients per cohort, the design had 91% power to rule out an overall response rate (ORR) of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 patients evaluable for response per cohort required ≥3 responses to proceed to full study enrollment.1
A total of 64 patients were enrolled in the Lung-MAP Sub-Study, S1900A: 27 squamous NSCLC and 37 nonsquamous, of whom 59 were eligible for the study.1 Their median age was 66 years and most were male (56%).1 Almost all patients (98%) received 1 or 2 prior lines of treatment for stage IV disease.1 Biomarker selection included 36 (61%) patients with loss of heterozygosity only, 8 (14%) patients BRCA1 mutated, 15 (26%) patients BRCA2 mutated.1
Both cohorts were closed for futility with insufficient responses in the interim analysis populations.1 In the full study, 6 responses (4 nonsquamous and 2 squamous) were reported, such that the ORR was 10% (95% confidence interval [CI], 2%-18%).1 The disease control rate was 63% (95% CI, 50%-75%).1 The 6-month progression-free survival rate was 25% (95% CI, 4-46) in BRCA1/2-mutated patients and 50% (95% CI, 10-90) in patients with BRCA1/2-mutated homozygous NSCLC.1 Median overall survival was 7.8 months in the nonsquamous cohort and 8.2 months in the squamous cohort.1 The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%), transaminitis (5%), and thrombocytopenia (5%).1
Researchers concluded that the S1900A substudy failed to show the requisite level of efficacy for rucaparib in advanced NSCLC patients with high genomic loss of heterozygosity and/or a BRCA1/2 mutation. Genomic loss of heterozygosity as a phenotypic marker of homologous recombination deficiency does not predict sufficient activity of rucaparib in NSCLC. These results contrast with the high level of efficacy of PARP inhibitors in patients with BRCA-associated or high loss of heterozygosity in other tumor types. Underlying biologic differences in the genomic characteristics of these cancers compared with NSCLC may be responsible. Ongoing studies are examining this premise.1Reference
1. Riess JW, Redman MW, Wheatley-Price P, et al. A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A). Presented at: 2021 American Society of Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021. Abstract 9024.