3104 Background: First-generation TRK tyrosine kinase inhibitors (TKIs) are approved in a tumor-agnostic fashion in more than 40 countries for patients with NTRK fusion-positive adult and pediatric cancers. While resistance to these agents has previously been described, the exact frequency with which major mechanisms of resistance emerges is not clearly understood. Methods: Patients with an NTRK-fusion-positive tumor who received a first-generation TRK TKI were eligible. We retrospectively identified those patients that had post-progression tumor tissue analyzed by next-generation sequencing (NGS). The pattern of serial resistance to a second-generation TKI was analyzed when available. Results: Eighteen patients were identified. The median age was 46 years (range 2-67). Nine unique fusions were detected in ten different tumor types. NTRK1, NTRK2, and NTRK3 fusions were found in eight (44%), one (6%), and nine (50%) patients, respectively. Thirteen patients (72%) were treated with larotrectinib and five patients (28%) received entrectinib. NGS (MSK-IMPACT n = 17, Foundation One n = 1) carried out on post-progression tissue revealed the following profile of acquired resistance: on-target resistance (83%, n = 15/18), off-target resistance (11%, n = 2/18), and no identifiable mechanism (6%, n = 1/18). Among patients with on-target resistance, the most common mutation involved the solvent front (87%, n = 13/15: n = 7 NTRK3 G623R, n = 4 NTRK1 G595R, n = 1 NTRK2 G639L, n = 1 NTRK3 G623E) followed by the gatekeeper region (13%, n = 2/15: n = 1 NTRK1 F589L, n = 1 NTRK3 F617I). Two patients developed off-target alterations. One acquired BRAF V600E mutation and the other MET amplification. Interestingly, solvent front mutation loss was observed in two patients who transitioned to and progressed on a second-generation TRK TKI. One patient with a baseline NTRK1 G595R mutation developed polyclonal resistance with acquisition of KRAS G12A and NTRK1 G667A alterations as well as NTRK1 G595R loss. The other patient with NTRK3 G623R developed an NTRK3 F617I gatekeeper mutation with NTRK3 G623R loss. Conclusions: In NTRK fusion-positive cancers, on-target resistance preferentially involving the solvent front is more frequent than off-target resistance to first-generation TKI therapy. Furthermore, the sequential use of second-generation therapy appears to alter the evolutionary kinetics of mutation retention and acquisition.
Introduction: The MYC gene family (MYCf), which includes MYC, MYCN, and MYCL, is deregulated in ~70% of cancers and is associated with treatment resistance. Whereas older investigational therapies for MYC amplified tumors were unsuccessful, promising novel targeted therapies are in early phase clinical trials. Unfortunately, it remains unclear how to select patients whose cancers may harbor true MYC addiction. We thus sought to characterize factors such as amplification level, focality, and clonality that may correlate with increased MYC dependence. Methods: Utilizing a center-wide next generation sequencing (NGS) program of >71,000 sequenced patients, genomic and clinical data from pediatric and adult patients with MYC, MYCN, and MYCL amplifications were identified between 2014 and 2022. Patients were characterized as harboring MYC, MYCN, and MYCL amplification based on a read-depth methodology using a DNA-based hybrid-capture NGS (MSK-IMPACT) and Fraction and Allele-Specific Copy Number Estimates from the Tumor Sequencing (FACETS). All cases underwent clinical data curation including baseline demographic, tumor characteristics, and treatment histories. Results: We identified 3911 cancers with MYCf amplification (n=3257 (82%) MYC; n=364 (9%) MYCL; n=330 (8%) MYCN) across 40 malignancies, for an overall 5.5% incidence. The most frequent tumor types with MYCf amplification were breast (22%), non-small cell lung (NSCLC) (11%), colorectal (8%), ovarian (8%), prostate (7%), brain (5%), and small cell lung cancers (SCLC) (2%). Cancers with MYC amplification had longer segment lengths than MYCL and MYCN amplification, which appeared more focal (median = 19, 4.3 and 4.5 MB, respectively, p < 0.001). MYCN amplified cancers had higher total copy number than MYC and MYCL amplified cancers (median = 19, 8, 9, respectively, p < 0.001). MYC, MYCN, and MYCL samples were predominantly clonal (median clonal fraction > 99% for all genes). Most NSCLC, squamous cell lung cancers, and pulmonary carcinoids had MYC amplifications (93%, 70%, and 67% respectively). Conversely, SCLCs most often had MYCL amplifications (49%). No concurrent targetable driver alterations were found in 33% of metastatic NSCLCs with MYC, 75% of MYCN, and 6% of MYCL amplifications. Conclusions: While MYCf amplification is observed across a broad range of cancer types, factors such as gene type (MYC, MYCN, MYCL), focality, total copy number, clonality, and concurrent oncogenic drivers vary widely. Novel MYC-directed trials may consider enrichment for a subpopulation of cancers with higher-level, focal, and clonal MYCf amplifications without concurrent other drivers. Citation Format: Monica F. Chen, Allison Richards, Patrick Evans, Patrick Lee, Adam Price, Matteo Repetto, Soo Ryum Yang, Jason Chang, Rose Brannon, Ezra Rosen, David Brown, Charles Rudin, Nitya Raj, Mark G. Kris, Jorge Reis-Filho, Mark Donoghue, Alexander E. Drilon, Noura J. Choudhury. Comprehensive clinical and genomic analysis for patients with MYC, MYCN, and MYCL amplified solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1394.
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