Effectiveness of PARP inhibitor maintenance therapy in ovarian cancer by BRCA1/2 and a scar-based HRD signature in real-world practice.

OBJECTIVE: To compare the effectiveness of PARP inhibitor maintenance therapy (mPARPi) in real-world practice by biomarker status (BRCA1/2 alterations [BRCAalt] and a homologous recombination deficiency signature [HRDsig]) in advanced ovarian cancer (OC). METHODS: Patients with OC receiving 1st-line platinum-based chemotherapy and either mPARPi or no maintenance were included. Patient data was obtained by a US-based de-identified OC clinico-genomic database, from ~280 US cancer clinics (01/2015-03/2023). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by biomarker status using Cox models, weighted by propensity scores. RESULTS: Of 673 patients, 160 received mPARPi [31.2% BRCAalt and 51.9% HRDsig(+)] and 513 no maintenance [15.6% BRCAalt and 34.1% HRDsig(+)]. BRCAalt patients receiving mPARPi vs. no maintenance had favorable rwPFS (HR 0.48, 95%CI 0.26-0.87, p=0.0154), as did BRCA wild-type (wt) (HR 0.76, 95%CI 0.57-1.01, p=0.0595). Favorable rwOS was not observed with mPARPi for BRCAalt or BRCAwt. HRDsig(+) patients receiving mPARPi vs. no maintenance had favorable rwPFS (HR 0.36, 95%CI 0.24-0.55, p <0.001) and numerically favorable rwOS (HR 0.46, 95%CI 0.21-1.14, p=0.0561). No differences were observed for HRDsig(-). mPARPi treatment interaction was observed for HRDsig(+) vs. HRDsig(-) (rwPFS p<0.001 / rwOS p=0.016) but not for BRCAalt vs. BRCAwt. Patients BRCAwt/HRDsig(+) receiving mPARPi had favorable rwPFS (HR 0.40, 95%CI 0.22-0.72, p=0.003), while no difference was observed for BRCAwt/HRDsig(-). CONCLUSIONS: HRDsig predicted benefit of mPARPi better than BRCAalt. HRDsig(+) patients had favorable outcomes, even among BRCAwt patients, while HRDsig(-) patients showed no enrichment for benefit with mPARPi. HRDsig might predict benefit from mPARPi regardless of BRCAalt status.

Activating Point Mutations in the MET Kinase Domain Represent a Unique Molecular Subset of Lung Cancer and Other Malignancies Targetable with MET Inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.

Association of Timely Comprehensive Genomic Profiling With Precision Oncology Treatment Use and Patient Outcomes in Advanced Non-Small-Cell Lung Cancer.

PURPOSE: Timely biomarker testing remains out of reach for many patients with advanced non-small-cell lung cancer (aNSCLC). Here, we studied the quality-of-care implications of closing the gap in timely receipt of comprehensive genomic profiling (CGP) to inform first-line (1L) decisions. METHODS: Using a real-world clinicogenomic database, we studied testing and 1L treatment patterns in aNSCLC after the approval of pembrolizumab in combination with pemetrexed and carboplatin (May 10, 2017). To estimate the association of timely CGP results with therapy selection and patient outcomes, we identified patients with no previous genomic testing beyond PD-L1 immunohistochemistry and dichotomized patients by whether CGP results were available before or after 1L therapy initiation. RESULTS: In total, 2,694 patients were included in the 1L therapy decision impact assessment. Timely CGP increased matched targeted therapy use by 14 percentage points (17% with CGP v 2.8% without) and precision immune checkpoint inhibitor (ICPI) use by 14 percentage points (18% with CGP v 3.9% without). Receipt of timely CGP resulted in an estimated 31 percentage point decrease in ICPI use among ALK/EGFR/RET/ROS1-positive patients at an expected per-patient reduction in ineffective ICPI therapy cost of $13,659.37 with timely CGP to inform 1L treatment selection. Patient benefit of CGP extended to real-world time to therapy discontinuation (median time to therapy discontinuation: 3.9 v 10 months [hazard ratio, HR, 0.54 [95% CI, 0.42 to 0.70]; P = 1.9E-06; adjusted hazard ratio [aHR], 0.50 [95% CI, 0.38 to 0.67]; P = 2.0E-06) in 1L driver-positive patients. This effect was not significant for real-world overall survival (median overall survival: 32 v 29 months [HR, 1.2 [95% CI, 0.84 to 1.67]; P = .33; aHR, 1.4 [95% CI, 0.92 to 1.99]; P = .12). CONCLUSION: Timely CGP is associated with the quality of patient care as measured by 1L matched targeted therapy use, time to therapy discontinuation, and avoidance of ineffective, costly ICPIs.

Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results.

AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible. METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6%, with AML (36.2%), MDS (19.7%), and MPN (44.5%) having higher MSAFs than DLBCL (3.9%), NHL (8.4%), HL (1.5%), PCN (2.8%), and histiocytoses (1.8%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8%), reflecting the analytical sensitivity of LBx. CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.

RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.

PURPOSE: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. EXPERIMENTAL DESIGN: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. RESULTS: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. CONCLUSIONS: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.

Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC.

BACKGROUND: Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions. MATERIALS AND METHODS: We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non-small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC. RESULTS: We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK, BRAF, FGFR2, FGFR3, NTRK1/2/3, RET, and ROS1). In NonSqNSCLC with oncogenic ALK, NTRK, RET, and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors. CONCLUSION: A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified.

Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.

PURPOSE: Studies have investigated the early use of liquid biopsy (LBx) during the diagnostic workup of patients presenting with clinical evidence of advanced lung cancer, but real-world adoption and impact has not been characterized. The aim of this study was to determine whether the use of LBx before diagnosis (Dx; LBx-Dx) enables timely comprehensive genomic profiling (CGP) and shortens time until treatment initiation for advanced non-small-cell lung cancer (aNSCLC). MATERIALS AND METHODS: This study used the Flatiron Health-Foundation Medicine electronic health record-derived deidentified clinicogenomic database of patients with aNSCLC from approximately 280 US cancer clinics. RESULTS: Of 1,076 patients with LBx CGP ordered within 30 days prediagnosis/postdiagnosis, we focused on 56 (5.2%) patients who ordered LBx before diagnosis date (median 8 days between order and diagnosis, range, 1-28). Compared with 1,020 patients who ordered LBx after diagnosis (Dx-LBx), LBx-Dx patients had similar stage and ctDNA tumor fraction (TF). LBx-Dx patients received CGP results a median of 1 day after Dx versus 25 days for Dx-LBx patients. Forty-three percent of LBx-Dx were positive for an National Comprehensive Cancer Network driver, and 32% had ctDNA TF >1% but were driver negative (presumed true negatives). In 748 patients with previously untreated aNSCLC, median time from Dx to therapy was shorter in the LBx-Dx versus Dx-LBx group (21 v 35 days; P < .001). CONCLUSION: Early LBx in anticipation of pathologic diagnosis of aNSCLC was uncommon in this real-world cohort, yet this emerging paradigm was associated with an abbreviated time to CGP results and faster therapy initiation. Forthcoming prospective studies will clarify the utility of LBx in parallel with biopsy for diagnostic confirmation for patients presenting with suspected advanced lung cancer.

Real-World comprehensive genomic profiling data for diagnostic clarity in pulmonary Large-Cell neuroendocrine carcinoma.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon subtype of lung cancer believed to represent a spectrum of tumors sharing characteristics of both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Other groups have proposed genomic LCNEC subtypes, including small cell-like, non-small cell-like, and carcinoid-like subtypes. The primary goal of this study was to better define the NSCLC-like subtype with comprehensive genomic profiling (CGP). METHODS: An institutional database was queried to identify tissue specimens (TBx, N = 1,426) and liquid biopsies (LBx, N = 39) submitted for CGP during routine clinical care (8/2014 - 7/2023) with a disease ontology of LCNEC. TBx were profiled with FoundationOne® (F1) or F1CDx, using hybrid-capture technology to detect genomic alterations (GAs). RESULTS: 1,426 LCNEC samples were genomically profiled. The presence of RB1 and TP53 genomic alterations (GAs) were used to define a SCLC-like subtype (n = 557). A carcinoid-like group was defined by the presence of MEN1 mutation in the absence of TP53 GAs (n = 25). The remaining 844 samples were compared to the SCLC-like group and GAs enriched relative to the SCLC-like samples with a false discovery rate (FDR) < 0.0001 were used to define a NSCLC-like group. These NSCLC-like subtype-defining GAs included SMARCA4, KRAS, FGF3/4/19, STK11, CDKN2A/B, MTAP, and CCND1. Under this schema, 530 samples were classified as NSCLC-like and 314 remained unclassified. CONCLUSIONS: Large-scale CGP can better characterize biologically distinct molecular subtypes in LCNEC. Further studies to define how these molecular subtypes may help inform treatment decisions in this complex and challenging malignancy are warranted.