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BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (Nâ =â 11 246), colorectal (Nâ =â 15 425), hepatocellular (Nâ =â 433), pancreatic (Nâ =â 5488), and urothelial (Nâ =â 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.
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Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action." The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.
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Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Metástase NeoplásicaRESUMO
Background: Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing EGFR exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with EGFR exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy. Methods: This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of EGFR exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311). Results: The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study. Conclusion: The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with EGFR-mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.
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The delivery of neoadjuvant and perioperative therapies for non-small cell lung cancer has been radically altered by significant advances and by the incorporation of targeted therapies as well as immune checkpoint inhibitors alone or alongside conventional chemotherapy. This evolution has been particularly notable in the incorporation of immunotherapy and targeted therapy into the treatment of resectable NSCLC, where recent FDA approvals of drugs such as nivolumab and pembrolizumab, in combination with platinum doublet chemotherapy, have led to considerable improvements in pathological complete response rates and the potential for enhanced long-term survival outcomes. This review emphasizes the growing importance of biomarkers in optimizing treatment selection and explores the impact of emerging studies that challenge existing treatment paradigms and investigate novel therapeutic combinations poised to redefine standard of care practices. Furthermore, the discussion extends to the unmet needs within perioperative treatment assessment and prognostication, highlighting the prospective value of biomarkers in evaluating treatment responses and prognosis.
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Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Terapia Neoadjuvante , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Terapia Neoadjuvante/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , PrognósticoRESUMO
Immune checkpoint inhibition, with or without chemotherapy, is an established standard of care for metastatic non-small cell lung cancer (NSCLC). For locally advanced NSCLC treated with chemoradiotherapy, consolidation immunotherapy has dramatically improved outcomes. Recently, immunotherapy has also been established as a valuable component of treatment for resectable NSCLC with pembrolizumab, atezolizumab, and nivolumab all approved for use in this setting. As more results read out from ongoing perioperative clinical trials, navigating treatment options will likely become increasingly complex for the practicing oncologist. In this paper, we distill key outcomes from major perioperative trials and highlight current knowledge gaps. In addition, we provide practical considerations for incorporating perioperative immunotherapy into the clinical management of operable NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia/métodos , Assistência Perioperatória/métodos , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
OBJECTIVES: Lung cancer contributes significantly to morbidity and mortality in people with HIV (PWH). We study the clinicopathologic characteristics and immune microenvironment in HIV associated lung cancer. MATERIAL AND METHODS: Clinicopathological characteristics including immunotherapy outcomes were collected for 174 PWH diagnosed with lung cancer. Immunohistochemical staining for PD-L1, CD4, and CD8 was performed. RESULTS: At diagnosis, patients with HIV associated lung cancer were significantly younger (56.9 vs. 69 years, P < .0001) and more frequently had advanced disease (70% vs. 53%, P = .01). The majority were African American (60% vs. 42%, P < .0001) and were smoking at the time of diagnosis or smoked in the past (98% vs. 86%, P = .0001). Only 10% of HIV associated lung cancer was diagnosed through the screening program. The median CD4+ lymphocyte count was 334 cells/µL, 31% had a CD4 ≤200 cells/µL and 63% of the cohort was virally suppressed. HIV associated non-small-cell lung cancer(NSCLC) was characterized by limited PD-L1 expression compared to the HIV negative cohort, 64% vs. 31% had TPS <1%, and 20% vs. 34% had TPS≥50%, respectively (P = .04). Higher CD8+ TILs were detected in PD-L1-high tumors (P < .0001). 50% of patients achieved disease control in the metastatic setting with the use of immunotherapy, and there were no new safety signals in 19 PWH treated with immunotherapy. CONCLUSION: Lung cancer in PWH demonstrates unique features highlighting the need for a specialized screening program. Despite low PD-L1 expression, immunotherapy is well tolerated with reasonable disease control. Altered immune system in lung cancer pathogenesis in PWH should be further investigated.
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Carcinoma Pulmonar de Células não Pequenas , Infecções por HIV , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Antígeno B7-H1/metabolismo , Detecção Precoce de Câncer , Linfócitos T CD8-Positivos , Biomarcadores/metabolismo , Infecções por HIV/complicações , Linfócitos do Interstício Tumoral , Biomarcadores Tumorais/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: We report long-term outcomes from a pooled analysis of patients with previously untreated metastatic NSCLC with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) less than 1% enrolled in phase III studies of pembrolizumab plus chemotherapy versus placebo plus chemotherapy. METHODS: This exploratory pooled analysis included individual patient data from the KEYNOTE-189 global (NCT02578680) and Japan extension (NCT03950674) studies of metastatic nonsquamous NSCLC without EGFR or ALK alterations and the KEYNOTE-407 global (NCT02775435) and People's Republic of China extension (NCT03875092) studies of metastatic squamous NSCLC. Patients received pembrolizumab or placebo plus pemetrexed and cisplatin or carboplatin in KEYNOTE-189 and pembrolizumab or placebo plus carboplatin and paclitaxel or nab-paclitaxel in KEYNOTE-407. PD-L1 TPS was centrally assessed using PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA). RESULTS: Overall, 442 patients were included in this analysis (pembrolizumab plus chemotherapy, n = 255; chemotherapy, n = 187). The median follow-up was 60.7 (range, 49.9â72.0) months. Pembrolizumab plus chemotherapy improved overall survival (hazard ratio, 0.64; 95% confidence interval [CI]: 0.51â0.79) and progression-free survival (hazard ratio, 0.66; 95% CI: 0.54â0.81) versus chemotherapy. The 5-year overall survival rates (95% CI) were 12.5% (8.6%â17.3%) versus 9.3% (5.6%â14.1%). Grades 3 to 5 treatment-related adverse events occurred in 59.1% of patients for pembrolizumab plus chemotherapy and 61.3% for chemotherapy. CONCLUSION: With approximately 5 years of follow-up, pembrolizumab plus chemotherapy provided clinically meaningful and durable improvements in survival outcomes versus chemotherapy alone in patients with previously untreated metastatic NSCLC with PD-L1 TPS less than 1%. These results continue to support pembrolizumab plus chemotherapy as a standard of care in this patient population. CLINICALTRIALS: gov, NCT02578680 (KEYNOTE-189 global), NCT03950674 (KEYNOTE-189 Japan extension), NCT02775435 (KEYNOTE-407 global), NCT03875092 (KEYNOTE-407 People's Republic of China extension).
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Seguimentos , Masculino , Feminino , Pessoa de Meia-Idade , Antígeno B7-H1/metabolismo , Idoso , Adulto , Paclitaxel/administração & dosagem , Carboplatina/administração & dosagem , Cisplatino/administração & dosagemRESUMO
OBJECTIVES: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. MATERIALS AND METHODS: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. RESULTS: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm. CONCLUSION: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy. CLINICAL REGISTRATION: NCT03626545.
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Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , ImunoterapiaRESUMO
BACKGROUND: The Advancing Inclusive Research (AIR) Site Alliance is composed of clinical research centers that partner with Genentech, a biotechnology company, to advance the representation of diverse patient populations in its oncology and ophthalmology clinical trials, test recruitment, and retention approaches and establish best practices to leverage across the industry to achieve health equity. METHODS: Through a data-driven selection process, Genentech identified 6 oncology and 3 ophthalmology partners that focus on reaching historically underrepresented patients in clinical trials and worked collaboratively to share knowledge and explore original ways of increasing clinical study access for every patient, including sites co-creation of a Protocol Entry Criteria Guideline with inclusion principles. RESULTS: For patients, three publicly available educational videos about clinical trials were created in multiple languages. The AIR Site Alliance has also defined invoiceable services for sites to enhance patient support; this has been built into the new study budget templates for sustainability. For healthcare professionals (HCPs), the first-of-its-kind AIR Educational Program was developed to focus on identifying and addressing bias and engaging historically underrepresented patient populations in trials. The sites also co-created videos for HCPs and patients on why advancing inclusive research matters. Over 16 regional health equity symposia have been delivered for patients, HCPs, and community leaders. CONCLUSIONS: This AIR Site Alliance is a model for other site alliances, including Kenya, South Africa, the United Kingdom, and Canada. Such alliances will build a robust and sustainable research ecosystem that includes diverse patient groups and encourages change across the healthcare system.
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Pesquisa Biomédica , Pessoal de Saúde , Humanos , Canadá , Quênia , Oftalmologia , OncologiaRESUMO
PURPOSE: Non-small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND METHODS: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC. RESULTS: Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC (P < .01). Compared with STK11mutTP53wt, tumors with STK11mutTP53mut had higher CD8+T cells and natural killer cells (P < .01), higher TMB (P < .001) and neoantigen load (P < .001), and increased expression of MYC and HIF-1A (P < .01), along with higher expression (P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mutTP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mutTP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI. CONCLUSION: STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Intervalo Livre de Progressão , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética , Quinases Proteína-Quinases Ativadas por AMPRESUMO
PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations. METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Ten new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients without driver alterations.Additional information is available at www.asco.org/living-guidelines.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Estadiamento de Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Oncologia/normasRESUMO
PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations. METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Eight new RCTs were identified in the latest search of the literature to date. RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients based on targetable driver alterations.Additional information is available at www.asco.org/living-guidelines.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Estadiamento de Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Oncologia/normasRESUMO
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 â¼0.5%. 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.