Comprehensive cfDNA testing impacted clinical decisions in one-quarter to one-third of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.

Background Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non‐small cell lung cancer (NSCLC). Methods A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next‐generation sequencing in 01/2015‐8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression‐free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log‐rank and Cox regression analyses. Results Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum‐based chemotherapy. Conclusion Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively.

Background Data regarding the prevalence and clinical relevance of BRCA mutations in non-small cell lung cancer (NSCLC) is limited. Our objective was to evaluate the impact of pathogenic BRCA variants detected by tumour next-generation sequencing (NGS) on disease course and response to therapy. Methods We performed a retrospective analysis of all consecutive NSCLC patients with available NGS reports in a single institution between 01/2015 and 08/2020. Pathogenicity of identified mutations was determined according to American College of Medical Genetics (ACMG) guidelines. Log rank and cox regression analyses were used to determine the association between BRCA mutation status, overall survival (OS) and progression-free survival (PFS) under various front-line treatment modalities for advanced disease. Results Out of 445 patients with NGS data (54% tissue, 46% liquid), 109 (24.5%) patients had a documented BRCA variant; 5.6% (25/445) had a pathogenic/likely pathogenic variant ( pBRCA ). Forty percent (10/25) of pBRCA patients had no co-occurring NSCLC driver mutations. Patients with pBRCA NSCLC had a less prominent smoking history [mean 42.6 (29.2) vs. 25.7 (24.0) pack years; P=0.024]. Median PFS with first-line chemo-immunotherapy was significantly prolonged for pBRCA patients (n=7) compared with wild-type BRCA ( wtBRCA ) patients (n=30) (HR =0.279; P=0.021, 95% CI: 0.094–0.825). Conclusions pBRCA -mutated NSCLC can represent a specific subtype of pulmonary carcinoma. Patients whose tumours harbor pBRCA mutations present with a less prominent smoking history and exhibit prolonged PFS with chemo-immunotherapy combinations compared with wtBRCA controls. In a subset of these patients, pBRCA is the sole identifiable putative driver mutation, hinting at a significant role for BRCA loss in oncogenesis.

Background: The next-generation ALK inhibitor brigatinib is approved for use postcrizotinib in ALK+ mNSCLC based on phase II trial (ALTA) data. The phase III ALTA-1L trial showed that brigatinib improves progression-free survival (PFS) vs crizotinib (HR¼0.49, 95% CI 0.35e68; P<0.0001 based on blinded independent review) in ALK TKI-naïve patients (pts). We report final data from the UVEA-Brig study of brigatinib use in clinical practice.Methods: UVEA-Brig is a retrospective chart review of pts who started brigatinib between 06/16 and 12/17 in Italy, Norway, Spain and the UK in an Expanded Access Program. Adults with ALK+ mNSCLC, including those with brain lesions, who were resistant to or intolerant of 1 prior ALK TKI and with ECOG performance status 3 were eligible. Pts received brigatinib 180 mg once daily with a 7-day lead-in at 90 mg. The primary objective was to describe baseline characteristics, prior therapy, clinical outcomes and safety with brigatinib.Results: Data for 104 pts (male: 43.3%; median age: 53 [29e80] years; never smoker: 50.0%; adenocarcinoma: 95.2%; metastatic at diagnosis: 86.5%; brain lesions at brigatinib initiation: 62.5%) were analysed. Pts had received a median of 2 (1e6) lines of systemic therapy prior to brigatinib (37.5% had received 3) and a median of 1 (1e 5) prior ALK TKI (crizotinib 83.7%; ceritinib 50.0%; alectinib 6.7%; lorlatinib 4.8%). At the time of analysis, 77 pts had discontinued brigatinib (progression: 71.4%; adverse event: 5.2% [pneumonitis (2), asthenia/fatigue, amylase and creatine kinase increase]; other: 23.4%). 32 pts continued brigatinib beyond progression. Pt outcomes with brigatinib are shown in the table. 53 pts received subsequent systemic therapy; 42 had an ALK inhibitor, most commonly lorlatinib (n¼36).Conclusions: These real-world data indicate the substantial activity and tolerability of brigatinib in pts with ALK+ mNSCLC who were more heavily pretreated than pts included in clinical trials.