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Purpose: Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma., Patients and Methods: This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety., Results: Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively., Conclusions: We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules., (©2024 American Association for Cancer Research.)

Advances in tumor molecular profiling have uncovered shared genomic and proteomic alterations across tumor types that can be exploited therapeutically. A biomarker-driven, disease-agnostic approach to oncology drug development can maximize the reach of novel therapeutics. To date, eight drug-biomarker pairs have been approved for the treatment of patients with advanced solid tumors with specific molecular profiles. Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK and mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors., (©2024 American Association for Cancer Research.)

Background: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive., Methods: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised., Results: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development., Conclusion: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations., (© 2024. The Author(s).)

PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities., Significance: Treatments for PIK3CA-mutant cancers are limited by toxicities associated with the inhibition of WT PI3Kα. Molecular dynamics, cryo-electron microscopy, and DNA-encoded libraries were used to develop RLY-2608, a first-in-class inhibitor that demonstrates mutant selectivity in patients. This marks the advance of clinical mutant-selective inhibition that overcomes limitations of orthosteric PI3Kα inhibitors. See related commentary by Gong and Vanhaesebroeck, p. 204 . See related article by Varkaris et al., p. 227 . This article is featured in Selected Articles from This Issue, p. 201., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors., Materials and Methods: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity., Results: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed., Conclusion: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development., Clinicaltrials.gov Identifier: NCT03770494., (© The Author(s) 2023. Published by Oxford University Press.)

Neuregulin 1 ( NRG1 ) fusions are oncogenic drivers that have been detected in non-small-cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. NRG1 fusions are rare, occurring in less than 1% of solid tumors. Patients with NRG1 fusion positive (NRG1+) cancer have limited therapeutic options. Zenocutuzumab is a novel, bispecific IgG1 antibody that targets both HER2 and HER3 proteins and inhibits NRG1 binding through a 'Dock & Block ® ' mechanism of action. Here, we describe the rationale and design of the phase II component of the eNRGy trial, part of the overall, open-label phase I/II, multicenter trial exploring the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of zenocutuzumab in patients with NRG1+ NSCLC, PDAC or other solid tumors.

Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting., Significance: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types or molecular subtypes may benefit from this combination., Objective: To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes., Design, Setting, and Participants: In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021., Interventions: All patients in phases 1b and 2 received avelumab plus talazoparib., Main Outcomes and Measures: The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers., Results: A total of 223 patients (mean [SD] age, 63.2 [11.0] years; 117 [52.5%] men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median [range] DOR, 11.1 [3.4-20.4] months); HR-positive, ERBB2-negative, and DDR-positive BC (median [range] DOR, 15.7 [3.9 to ≥20.6] months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients [33.6%]), thrombocytopenia (48 patients [21.5%]), and neutropenia (31 patients [13.9%])., Conclusions and Relevance: This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations., Trial Registration: ClinicalTrials.gov Identifier: NCT03330405.

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified., Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type., Design, Setting, and Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries., Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily., Main Outcomes and Measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review., Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified., Conclusions and Relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types., Trial Registration: ClinicalTrials.gov Identifier: NCT03565991.

The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers sensitivity to PARP inhibitors and platinum-therapies. Somatic reversion mutations restoring BRCA1/2 function mediate resistance, and have exclusively been reported in BRCA-associated tumors. In this study, we analyze matched tumor and normal sequencing from 31,927 patients and identify 846 (2.7%) patients with germline BRCA1/2 variants across 43 different cancer types, including 11 with somatic reversion mutations. While nine are in BRCA-associated tumors, we find two reversion mutations in non-BRCA-associated histologies, namely lung and esophagogastric adenocarcinomas. Both were detected following platinum therapy. Whole exome sequencing confirms the homologous recombination deficiency phenotype of these tumors. While reversion mutations arise in all BRCA-associated cancer types, here we show that reversion mutations arising post-platinum in non-BRCA associated histologies, while rare, may indicate BRCA1/2 mediated tumorigenesis., (© 2022. The Author(s).)

Background: Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors., Materials and Methods: Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers., Results: Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action., Conclusions: MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors., Competing Interests: Disclosure EB has provided advisory work for BioNTech SE and Imaging Endpoints LLC, and has participated in a speaker’s bureau for Ipsen. AMS has received fees and/or research grants from AstraZeneca, Northern Biologics, Merus, Kura Oncology, Surface Oncology, Lilly Oncology, Pfizer, Black Diamond Therapeutics, BeiGene, and Relay Therapeutics. EG has received personal fees for a consultant/advisory role from Janssen, Seattle Genetics, TFS HealthScience, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb, and MSD; and research grants from Menarini Diagnostics and Glycotope Biotechnology GmbH. IB has received research funding from Northern Biologics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, MSD, Novartis, OrionPharma, Regeneron, Seattle Genetics, Shattuck Labs, and VCN Biosciences SL; institutional grants from Cellex Foundation, La Caixa Foundation, and Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation); educational grants from Bristol Myers Squibb; consulting fees from Achilles Therapeutics PLC, Bristol Myers Squibb, Cancer Expert Now, Etherna Immunotherapies Nv, Merck Serono, MSD, and Rakuten; payment of honoraria from Bristol Myers Squibb, Merck Serono, and MSD; support from attending meetings and/or travel from Merck Serono and MSD; and has a leadership or fiduciary role in another board, society, committee, or advocacy group, paid or unpaid, with ESMO Head and Neck track, EORTC Head and Neck group, and Cancer Core Europe Clinical Taskforce. MVV has received personal fees from Roche outside the work submitted. AS has received research funding from AstraZeneca, Northern Biologics, Alkermes, Array BioPharma/Pfizer, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Janssen Oncology/Johnson & Johnson, Merck, Novartis, Regeneron Pharmaceuticals, Roche, Surface Oncology, Symphogen, Treadwell Therapeutics, and Oncorus; and personal fees from Bristol Myers Squibb, Merck, and Oncorus. MO has received personal fees from Bristol Myers Squibb, Merck, and MSD; non-financial support from Bristol Myers Squibb and MSD; and research grants from the Spanish Society of Medical Oncology, CRIS Contra el Cancer Foundation, and ASO Conquer Cancer Foundation, all outside of the work submitted. NJL has received honoraria for advisory boards from Innovent Biologics; and research funding from AstraZeneca, Northern Biologics, Alpine Immune Sciences, ALX Oncology, Apexian Pharmaceuticals, Ascentage Pharma, Alexion Pharmaceuticals, Asana, BeiGene, CytomX, Constellation Pharmaceutical, Cerulean Pharma, Formation Biologics (Forbius), Forty Seven, Ikena Oncology, Incyte Corporation, Inhibrx, Innovent Biologics, Jounce Therapeutics, Merck, Mersana Therapeutics, Pfizer, Regeneron Pharmaceuticals, Symphogen, and TaiRx. KH is a former employee and holds shares of Northern Biologics. RMH is a former employee and holds shares of Northern Biologics. DM is a former employee and holds shares of Northern Biologics. FH has received funding from Northern Biologics for the present work as part of Applied BioMath. JH has received funding from Northern Biologics for the present work as part of Applied BioMath; and owns shares of Pfizer. PG is a former employee and holds shares of Northern Biologics. JA is a former employee and holds shares of Northern Biologics. AK was a consultant to Northern Biologics at the time the study was conducted. PJV is a former employee and holds shares of Northern Biologics. RW is a former employee and holds shares of Northern Biologics. JS is a co-founder of Mosaic Biomedicals and has ownership interests from Mosaic Biomedicals and Northern Biologics; and had received grant/research support from Mosaic Biomedicals, Northern Biologics, Roche Glycart AG, and F. Hoffmann-La Roche Ltd. LLS has received financial compensation for consulting/advisory work from Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, GeneSeeq, Loxo Oncology, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Treadwell Therapeutics, Arvinas, Tessa Therapeutics, Navire Pharma, Relay Therapeutics, and Rubius Therapeutics; and research grants/support from Novartis, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattuck Labs, and Avid Radiopharmaceuticals. DMH is an employee of Loxo Oncology at Lilly, a wholly owned subsidiary of Eli Lilly (salary and equity). DVH is an employee of McKesson Corporation; he has stock or other ownership interests in Medtronic, CerRx, SynDevRx, UnitedHealthcare, Anthem Inc, Stromatis Pharma, Systems Oncology, StingRay Therapeutics, Forma Therapeutics, and Orpheus Bioscience; he has received financial compensation for consulting/advisory work from DNAtrix, Esperance Pharmaceuticals, Five Prime Therapeutics, Imaging Endpoints, Medical Prognosis Institute, Senhwa Biosciences, Tolero Pharmaceuticals, Alpha Cancer Technologies, Arvinas, Bellicum Pharmaceuticals, CanBas, Horizon Discovery, Lixte Biotechnology, Oncolyze, Translational Drug Development (TD2), Aadi Bioscience, Aptose Biosciences, BiolineRx, CytomX Therapeutics, EMD Serono, Evelo Biosciences, Fujifilm, Kura Oncology, Phosplatin Therapeutics, Sotio, Strategia Therapeutics, Synergene Therapeutics, 7 Hills Pharma, Actinium Pharmaceuticals, Cancer Prevention Pharmaceuticals, Geistlich Pharma, Huya Bioscience International, Immunophotonics, Genzada Pharmaceuticals, L.E.A.F. Pharmaceuticals, Oncology Venture, Turning Point Therapeutics, Verily Life Sciences, Athenex, Samus Therapeutics, Aeglea Biotherapeutics, Novita Pharmaceuticals, NuCana, Vicus Therapeutics, Codiak Biosciences, Agenus, Kelun, Radimmune Therapeutics, Samumed, Sobi, BioXcel therapeutics, Bryologyx, Celgene, BioPharma Services, Sirnaomics, AIMed, Boston Scientific, Corcept Therapeutics, Erimos Pharmaceuticals, Gimbal Bio, Amunix Pharmaceuticals, Pfizer, Apeiron Biologics, GiraFpharma, Axis Therapeutics, DrugCendR, ImmuneOncia, Orphagen Pharmaceuticals, Array BioPharma, MaveriX Oncology, Northern Biologics, Viracta Therapeutics, Varian Biopharma, Xerient Pharma, AlaMab Therapeutics, Avesta76 Therapeutics, Bessor Pharma, NeoTx, Decoy Biosystems, Noxxon Pharma, RefleXion Medical, and Reglagene; and has received research grants/support from Eli Lilly, Genentech, Celgene, Incyte, Merrimack Pharmaceuticals, Plexxikon, Minneamrita Therapeutics, AbbVie, Aduro Biotech, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Endocyte, Exelixis, Five Prime Therapeutics, Gilead Sciences, Merck, Pfizer, Pharmacyclics, Phoenix Biotechnology, Samumed, Strategia Therapeutics, and Halozyme. JT reports personal financial interests in the form of scientific consultancy role for Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc., HalioDx SAS, Hutchison MediPharma, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati Therapeutics, Inc., NeoPhore, Novartis, Orion Biotechnology, Peptomyc SL, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho Pharmaceutical, Tessa Therapeutics, and TheraMyc Limited., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1-expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors., (©2022 The Authors; Published by the American Association for Cancer Research.)

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity-enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion-positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer were treated with Zeno. Two patients with ATP1B1-NRG1-positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74-NRG1-positive non-small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion-positive cancers., Significance: NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion-positive cancers and is thus an effective therapeutic strategy. This article is highlighted in the In This Issue feature, p. 1171., (©2022 The Authors; Published by the American Association for Cancer Research.)

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism 1-8 . The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy 7,8 . However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition., (© 2022. The Author(s).)

Background: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored., Methods: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions., Results: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value., Conclusion: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To investigate clinical and morphologic characteristics of serous retinal disturbances in patients taking extracellular signal-regulated kinase (ERK) inhibitors., Design: Single-center retrospective study of prospectively collected data., Participants: Of 61 patients receiving ERK inhibitors for treatment of metastatic cancer, this study included 40 eyes of 20 patients with evidence of retinopathy confirmed by OCT., Methods: Clinical examination, fundus photography, and OCT were used to evaluate ERK inhibitor retinopathy. The morphologic features, distribution, and location of fluid foci were evaluated serially. Visual acuity (VA) and choroidal thickness measurements were compared at baseline, fluid accumulation, and resolution., Main Outcome Measures: Characteristics of treatment-emergent choroid and retinal OCT abnormalities as compared with baseline OCT findings and the impact of toxicity on VA., Results: Of 20 patients with retinopathy, most showed fluid foci that were bilateral (100%), multifocal in each eye (75%), and with at least 1 focus involving the fovea (95%). All subretinal fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. No statistical difference was found in choroidal thickness at fluid accumulation and resolution compared with baseline. Forty-five percent of eyes showed evidence of concomitant intraretinal edema localized to the outer nuclear layer. At the time of fluid accumulation, 57.5% eyes showed a decline in VA (mainly by 1-2 lines from baseline). For all eyes with follow-up, the subretinal fluid and intraretinal edema were reversible and resolved without medical intervention, and best-corrected VA at fluid resolution was not statistically different from baseline. Concomitant intraretinal fluid was not associated with worsening of VA. No patient discontinued or decreased drug dose because of retinopathy., Conclusions: This study showed that ERK inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics. The observed foci were similar to mitogen-activated protein kinase kinase (MEK) inhibitor-associated retinopathy and distinct from central serous chorioretinopathy. However, unlike with MEK inhibitors, an increased occurrence of concomitant intraretinal fluid without significant additive visual impact seems to occur with ERK inhibitors. In this series, ERK inhibitors did not cause irreversible loss of vision or serious eye damage; retinopathy was self-limited and did not require medical intervention., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor-associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy., Objective: To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors., Design, Setting, and Participants: In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021., Main Outcomes and Measures: Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution., Results: A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor-associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was -0.1 (-0.2 to -0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (-0.03 to 0). No patient discontinued drug therapy on account of their retinopathy., Conclusions and Relevance: FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF . The BRAF V600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF -driven tubo-ovarian and primary peritoneal serous tumors., Methods: Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAF V600E oncoprotein expression was assessed by immunohistochemistry on selected cases., Results: BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAF V600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1 , and AGAP3 ). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit., Conclusion: Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection., (© 2021 by American Society of Clinical Oncology.)

Purpose: Although NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion-positive lung cancers in the largest and most diverse series to date., Methods: From June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed., Results: Although the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS., Conclusion: NRG1 fusion-positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1 -rearranged tumor biology is needed to develop new therapeutic strategies., Competing Interests: Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicans' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerviewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, Verastem, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Michael DuruisseauxConsulting or Advisory Role: AstraZeneca, MSD Oncology, BMS, Pfizer, Roche, Takeda, Boehringer Ingelheim, Janssen Oncology, Amgen, AbbVieTravel, Accommodations, Expenses: Boehringer Ingelheim, Merck Sharp & Dohme Ji-Youn HanHonoraria: Roche, AstraZeneca, Bristol Myers Squibb, TakedaConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Takeda, PfizerResearch Funding: Roche, Pfizer, Ono Pharmaceutical, Takeda Soo-Ryum YangConsulting or Advisory Role: Invitae Yonina R. Murciano-GoroffTravel, Accommodations, Expenses: AstraZeneca Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical, Nippon Kayaku, Chugai Pharma, Covidien, Johnson & Johnson, Daiichi Sankyo, Yakult Honsha, Lilly Japan, Nihon Medi-Physics, Pfizer, Mochida Pharmaceutical Co Ltd, Shionogi, Ono Pharmaceutical, Kyowa Hakko Kirin Miguel Angel MolinaEmployment: Pangaea OncologyResearch Funding: AstraZeneca, Merck Serono, In3Bio Marie WislezConsulting or Advisory Role: Boehringer Ingelheim, Roche, MSD Oncology, Bristol Myers Squibb, AstraZeneca, AmgenSpeakers' Bureau: Boehringer Ingelheim, Amgen, Roche, MSD Oncology, Bristol Myers Squibb, AstraZenecaTravel, Accommodations, Expenses: Roche, MSD Oncology Alexa SchrockEmployment: Foundation MedicineStock and Other Ownership Interests: Foundation Medicine, Roche Siraj AliEmployment: EQRX (I), Foundation Medicine, EQRXLeadership: Incysus Inc, Elevation Oncology, Pillar BiosciencesStock and Other Ownership Interests: Exelixis, Merus NV, PfizerConsulting or Advisory Role: Azitra (I), Princepx Tx (I)Patents, Royalties, and Other Intellectual Property:Patents via Seres Health on microbiome in non neoplastic disease (I), Foundation Medicine Valérie GounantConsulting or Advisory Role: Bristol Myers Squibb, Takeda, Roche, AstraZeneca, Boehringer Ingelheim, Novartis, Chugai Pharma EuropeTravel, Accommodations, Expenses: Takeda, Roche, Pfizer Alison M. SchramResearch Funding: Merus, Kura Oncology, Surface Oncology, AstraZeneca, Lilly, Northern Biologics, Pfizer, Black Diamond Therapeutics, BeiGene, Relay Therapeutics Isabelle MonnetTravel, Accommodations, Expenses: MSD Oncology, Roche, Takeda, Pfizer Jin-Yuan ShihHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Bristol Myers Squibb, Roche, Chugai Pharma, LillyConsulting or Advisory Role: Chugai Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Roche, AstraZeneca, Lilly, Takeda, CStone Pharmaceuticals, Janssen Oncology, Novartis, Pfizer, Ono Pharmaceutical, Merck Sharp & DohmeResearch Funding: RocheTravel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Chugai Pharma, Roche Joshua SabariConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Navire, Pfizer, Regeneron, Medscape, Takeda Maurice PérolConsulting or Advisory Role: Lilly, Roche/Genentech, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Amgen, Takeda, Chugai Pharma, Gritstone OncologyResearch Funding: AstraZeneca, Roche, Takeda, Boehringer IngelheimTravel, Accommodations, Expenses: AstraZeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Chugai Pharma Viola W. ZhuStock and Other Ownership Interests: TP TherapeuticsHonoraria: AstraZeneca, Roche/Genentech, Takeda, Blueprint Medicines, XcoveryConsulting or Advisory Role: AstraZeneca, Takeda, TP Therapeutics, Roche/Genentech, XcoverySpeakers' Bureau: AstraZeneca, Roche/Genentech, Takeda, Blueprint MedicinesTravel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, Takeda, TP Therapeutics Misako NagasakaConsulting or Advisory Role: AstraZeneca, Caris Life Sciences, Daiichi Sankyo, Takeda, Novartis, EMD SeronoSpeakers' Bureau: Blueprint MedicinesResearch Funding: TempusTravel, Accommodations, Expenses: Anheart Therapeutics Robert DoebeleEmployment: Rain TherapeuticsLeadership: Rain TherapeuticsStock and Other Ownership: Rain TherapeuticsConsulting or Advisory Role: GreenPeptide, AstraZeneca, Roche/Genentech, Bayer, Takeda, Rain Therapeutics, Anchiano, Blueprint Medicines, Foundation Medicine, Guardant HealthPatents, Royalties, and Other Intellectual Property: Abbott Molecular for Patent PCT/US2013/057495, Rain Therapeutics, Genentech (Inst), Foundation Medicine (Inst), Black Diamond (Inst), Pearl River (Inst), Voronoi (Inst)Travel, Accommodations, Expenses: Rain Therapeutics, Roche/Genentech D. Ross CamidgeHonoraria: Roche, Takeda, AstraZeneca, Daiichi Sankyo, Bio-Thera, Ribon Therapeutics, Bristol Myers Squibb, Inivata, AbbVie, Apollomics, Elevation Oncology, EMD Serono, Helsinn Therapeutics, Lilly, Nuvalent Inc, Seattle Genetics, Turning Point Therapeutics, Kestrel Labs, Amgen Astellas BioPharma, Anchiano, Eisai, GlaxoSmithKline, Janssen, OnKure, Mersana, Pfizer, QiLu Pharmaceutical, SanofiResearch Funding: Takeda Maria ArcilaHonoraria: Invivoscribe, BiocartisConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca, Invivoscribe, Raindance Technologies Sai-Hong Ignatius OuStock and Other Ownership Interests: Turning Point Therapeutics, Elevation OncologyHonoraria: Pfizer, Roche Pharma AG, Genentech/Roche, ARIAD/Takeda, AstraZenecaConsulting or Advisory Role: Pfizer, Roche/Genentech, AstraZeneca, Takeda, Jassen/JNJSpeakers' Bureau: AstraZeneca, Genentech/RocheResearch Funding: Pfizer, Roche Pharma AG, AstraZeneca/MedImmune, AstraZeneca, ARIAD, Revolution Medicines, Mirati Therapeutics, Jassen/JNJ Denis Moro-SibilotConsulting or Advisory Role: Roche/Genentech, Boehringer Ingelheim, Lilly/ImClone, Sanofi, Novartis, Amgen, Pfizer, AstraZeneca, Clovis Oncology, MSD Oncology, ARIAD, Bristol-Myers Squibb, Takeda, AbbvieResearch Funding: Abbvie (Inst), Boehr (Inst), Roche/Genentech (Inst), Bristol-Myers Squibb (Inst)Expert Testimony: MSD OncologyTravel, Accommodations, Expenses: Roche/Genentech, Lilly/ImClone, Pfizer, MSD Oncology, Bristol-Myers Squibb Lucia Anna MuscarellaTravel, Accommodations, Expenses: Boehringer Ingelheim Stephen V. LiuConsulting or Advisory Role: Genentech, Pfizer, Lilly, Bristol Myers Squibb, AstraZeneca, Takeda, Regeneron, G1 Therapeutics, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Inivata, PharmaMar, Daiichi Sankyo/UCB Japan, BeiGene, AmgenResearch Funding: Genentech/Roche, Pfizer, Corvus Pharmaceuticals, Bayer, Merck, Lycera, AstraZeneca, Molecular Partners, Blueprint Medicines, Lilly, Rain Therapeutics, Alkermes, Bristol Myers Squibb, Turning Point Therapeutics, RAPT Therapeutics, Merus, Debiopharm Group, Elevation OncologyTravel, Accommodations, Expenses: AstraZeneca, Roche/Genentech, MSD Oncology Jacques CadranelHonoraria: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Boehringer IngelheimConsulting or Advisory Role: AstraZeneca/MedImmune, Roche/Genentech, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, Merck Sharp & Dohme, Pfizer, Lilly, NovartisResearch Funding: Pfizer, Novartis, AstraZeneca/MedImmuneNo other potential conflicts of interest were reported.

Purpose: Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1 . Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically., Experimental Design: A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping ( n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS)., Results: Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion ( F11R - NRG2 ). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS -mutant IMAs, NRG1 -rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival ( P < 0.0001)., Conclusions: This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1 -rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset., (©2021 American Association for Cancer Research.)

Background: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents., Patients and Methods: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0., Results: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab., Conclusions: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies., Competing Interests: Disclosure AM has an advisory board role in AstraZeneca, receives research funding from Incyte, and is supported by a Dermatology Foundation Career Development Award. EQ receives royalties from UpToDate. SAF receives research funding from AstraZeneca and Genentech/Roche, has a consulting/advisory relationship with Merck, and has ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, InconOVir and Vida Ventures. MHV reports receiving commercial research support from Pfizer and honoraria from Pfizer, Exelixis, Eisai, Calithera Biosciences, and Corvus Pharmaceuticals. AD discloses honoraria/advisory board participation for Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, and MORE Health; associated research funding paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, and PharmaMar; research for Foundation Medicine; royalties from Wolters Kluwer; expenses from Merck and Puma; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, and Research to Practice. MDH receives research funding from Bristol Myers Squibb; is a paid consultant to Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Achilles Therapeutics, PACT Pharma, Immunai, and Shattuck Labs; receives travel support/honoraria from AstraZeneca, Eli Lilly, Merck, and BMS; and a patent has been filed by MSK related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. EAC reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, and Heron Therapeutics. DYML has been a consultant for Genentech and Novartis. MEL has a consultant role with Johnson and Johnson, Novocure, QED, Bicara, Janssen, Novartis, F. Hoffmann-La Roche AG, EMD Serono, Astrazeneca, Innovaderm, Deciphera, DFB, Azitra, Kintara, RBC/La Roche Posay, Trifecta, Varsona, Genentech, Loxo, Seattle Genetics, Lutris, OnQuality, Azitra, Roche, NCODA, Apricity, Oncoderm Labs, Hoth Therapeutics. Dr. Lacouture also receives research funding from Lutris, Paxman, Novocure, J&J, US Biotest, OQL, Novartis and AZ. All other authors have declared no conflicts of interest., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKA G667 and TRKC G696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion-positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation. This article is highlighted in the In This Issue feature, p. 1 ., (©2020 American Association for Cancer Research.)

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease., (© 2020 by The American Society of Hematology.)

Background: Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge., Methods: This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge., Results: Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035)., Conclusions: In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives., (© 2020 American Cancer Society.)

The molecular characterization of tumors now informs clinical cancer care for many patients. This advent of molecular oncology has been driven by the expanding number of therapeutic biomarkers that can predict sensitivity to both approved agents and investigational agents. Beyond its role in driving clinical-trial enrollments and guiding therapy in individual patients, large-scale clinical genomics in oncology also represents a rapidly expanding research resource for translational scientific discovery. Here we review the progress, opportunities, and challenges of scientific and translational discovery from prospective clinical genomic screening programs now routinely conducted for patients with cancer., (© 2020. Springer Nature America, Inc.)

Background: Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC., Patients and Methods: A total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period., Results: Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit., Conclusion: Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit., Competing Interests: Disclosure PR has received honoraria for consulting/advisory board for Novartis, AstraZeneca, Foundation Medicine and institutional research support from GRAIL, Inc. MS has received research funds from Puma Biotechnology, AstraZeneca, Daiichi Sankyo, Immunomedics, Targimmune, and Menarini Ricerche. He is in the scientific advisory board (SAB) of Menarini Ricerche and Bioscience Institute and is a cofounder of Medendi.org. ML has received honoraria for ad hoc advisory board participation from Merck, Astra-Zeneca, Bristol Myers Squibb, Takeda, Lilly Oncology and Bayer, and research support from LOXO Oncology, Merus, and Helsinn Therapeutics. DMH has received personal fees from Chugai Pharma, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, and Genentech/Roche, as well as grants from Bayer, AstraZeneca, Puma Biotechnology, and Loxo Oncology, and employment and equity in Eli Lilly. All personal fees and grants are for work outside the submitted work. AD has honoraria from Medscape, OncLive, PeerVoice, Physician Education Resources, Tyra Biosciences, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView, AstraZeneca, Ignyta/Genentech/Roche, Bayer; consulting roles at Ignyta, Loxo/Lilly, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, 14ner/Elevation Oncology, GlaxoSmithKline, Exelixis, Teva, Taiho, Merck, Puma, Merus, Boeringer Ingelheim, PharmaMar, and Bayer. RB has received a grant from Archer, honoraria for advisory board participation from Loxo oncology and speaking fees from Illumina. SC has received honoraria for ad hoc consulting for Eli Lilly, Sermonix, BMS, Paige AI, Context Therapeutics, Revolution Medicine, and Novartis; research support to the institution from Daiichi Sankyo, Novartis, Eli Lilly, Genentech, and Sanofi. JFH has received honoraria from Medscape, Cor2Ed, ClearView Healthcare Partners, Illumina, and Axiom Healthcare Strategies, as well as research funding from Bayer, Eli Lilly, and Boehringer Ingelheim. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Prospective molecular characterization of cancer has enabled physicians to define the genomic changes of each patient's tumor in real time and select personalized therapies based on these detailed portraits. Despite the promise of such an approach, previously unrecognized biological and therapeutic complexity is emerging. Here, we synthesize lessons learned and discuss the steps required to extend the benefits of genome-driven oncology, including proposing strategies for improved drug design, more nuanced patient selection, and optimized use of available therapies. Finally, we suggest ways that next-generation genome-driven clinical trials can evolve to accelerate our understanding of cancer biology and improve patient outcomes., Competing Interests: Declaration of Interests Y.R.M.-G. acknowledges receipt of support for travel, accommodation, and expenses from AstraZeneca and has received training through a K30 grant (CTSA UL1TR00457). B.S.T. reports receiving honoraria and research funding from Genentech and Illumina and advisory board activities for Boehringer Ingelheim and Loxo Oncology, a wholly owned subsidiary of Eli Lilly. D.M.H. reports paid consulting work for Chugai, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech/Roche, and Fount Therapeutics, and research grants from AstraZeneca, Puma Biotechnology, Loxo Oncology, and Bayer. D.M.H. is currently employed by Loxo, a wholly owned subsidiary of Eli Lilly. A.M.S. has no financial interests to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers., Experimental Design: Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes., Results: We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers ( P < 0.001) and lower tumor mutation burden ( P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response., Conclusions: TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors., (©2019 American Association for Cancer Research.)

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2 -mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer. This article is highlighted in the In This Issue feature, p. 161 ., (©2019 American Association for Cancer Research.)

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition 1-8 . With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors 9-11 . Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.

Purpose: Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and MET exon 14 ( MET ex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers., Experimental Design: Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq., Results: As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) MET ex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6 MET ex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Megabase (mut/Mb)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions ( P < 0.0001)., Conclusions: Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq. See related commentary by Davies and Aisner, p. 4586 ., (©2019 American Association for Cancer Research.)

Purpose: Matching patients to investigational therapies requires new tools to support physician decision making. We designed and implemented Precision Insight Support Engine (PRECISE), an automated, just-in-time, clinical-grade informatics platform to identify and dynamically track patients on the basis of molecular and clinical criteria. Real-world use of this tool was analyzed to determine whether PRECISE facilitated enrollment to early-phase, genome-driven trials., Materials and Methods: We analyzed patients who were enrolled in genome-driven, early-phase trials using PRECISE at Memorial Sloan Kettering Cancer Center between April 2014 and January 2018. Primary end point was the proportion of enrolled patients who were successfully identified using PRECISE before enrollment. Secondary end points included time from sequencing and PRECISE identification to enrollment. Reasons for a failure to identify genomically matched patients were also explored., Results: Data were analyzed from 41 therapeutic trials led by 19 principal investigators. In total, 755 patients were accrued to these studies during the period that PRECISE was used. PRECISE successfully identified 327 patients (43%) before enrollment. Patients were diagnosed with 29 tumor types and harbored alterations in 43 oncogenes, most commonly ERBB2 (21.3%), PIK3CA (14.1%), and BRAF (8.7%). Median time from sequencing to enrollment was 163 days (interquartile range, 66 to 357 days), and from PRECISE identification to enrollment 87 days (interquartile range, 37 to 180 days). Common reasons for failing to identify patients before enrollment included accrual on the basis of molecular alterations that did not match pre-established PRECISE genomic eligibility (140 [33%] of 428) and external sequencing not available for parsing (127 [30%] of 428)., Conclusion: PRECISE identified 43% of all patients accrued to a diverse cohort of early-phase, genome-matched studies. Purpose-built informatics platforms represent a novel and potentially effective method for matching patients to molecularly selected studies., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Ezra Y. RosenResearch Funding: BayerJaclyn F. HechtmanHonoraria: Medscape Consulting or Advisory Role: Navigant Consulting, Axiom Biotechnologies Research Funding: BayerJames J. HardingConsulting or Advisory Role: Bristol-Myers Squibb, CytomX Therapeutics, Eli Lilly, Eisai Research Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst), Eli Lilly (Inst), Novartis (Inst), Incyte (Inst), Calithera Biosciences (Inst), Polaris (Inst)Lillian M. SmythHonoraria: AstraZeneca, Pfizer Consulting or Advisory Role: AstraZeneca, Genentech Research Funding: AstraZeneca (Inst), Genentech (Inst), Puma Biotechnology (Inst) Travel, Accommodations, Expenses: Pfizer, Genentech, Puma BiotechnologyKomal L. JhaveriConsulting or Advisory Role: Novartis, Pfizer, Spectrum Pharmaceuticals, AstraZeneca, Taiho Pharmaceutical, Jounce Therapeutics, ADC Therapeutics, Synthon, Intellisphere, Bristol-Myers Squibb Research Funding: Novartis (Inst), Genentech (Inst), Debio Pharmaceuticals (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Eli Lilly (Inst), Zymeworks (Inst) Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca Other Relationship: Novartis, Pfizer, Taiho Pharmaceutical, Jounce TherapeuticsAlexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, Peerview Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda, ARIAD Pharmaceuticals, Millennium Pharmaceuticals, BerGenBio, MORE Health, Eli Lilly Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Wolters Kluwer (royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, Teva Pharmaceuticals, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma BiotechnologyMarc LadanyiHonoraria: Merck (I) Consulting or Advisory Role: National Comprehensive Cancer Network/AstraZeneca Tagrisso RFP Advisory Committee, Takeda, Bristol-Myers Squibb, Bayer, Merck (I) Research Funding: Loxo (Inst), Helsinn TherapeuticsDavid B. SolitStock and Other Ownership Interests: Loxo Consulting or Advisory Role: Pfizer, Loxo, Illumina, Intezyne Technologies, Vivideon Therapeutics Travel, Accommodations, Expenses: MerckMichael F. BergerConsulting or Advisory Role: Roche Research Funding: IlluminaDavid M. HymanConsulting or Advisory Role: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech Research Funding: AstraZeneca, Puma Biotechnology, Loxo, Bayer Travel, Accommodations, Expenses: Genentech, Chugai Pharma No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Kinase fusions are rare and poorly characterized in colorectal carcinoma, yet they present unique opportunities for targeted therapy. In this study, we characterized kinase fusions from patients with advanced colorectal carcinoma who had MSK-IMPACT testing of their tumors between January 2014 and June 2018. Patients were analyzed for the presence of fusions, microsatellite instability (MSI), and RAS/BRAF mutations. Mismatch repair (MMR), IHC, and promoter hypermethylation status of MLH1 (MLH1ph) in microsatellite instability-high (MSI-H) colorectal carcinoma with fusions were investigated. Fusion transcripts were confirmed using a targeted RNA-seq panel assay. Of 2,314 colorectal carcinomas with MSK-IMPACT testing, 21 harbored kinase fusions. Overall 57% (12/21) of colorectal carcinoma fusions were MSI-H/MMR-D. Loss of MLH1 and MLH1ph was confirmed in all 12 and all 10 cases with available material, respectively. Fusions were present in 5% of MSI-H/MMR-D colorectal carcinoma compared with 0.4% of MSS/MMR-P colorectal carcinoma ( P < 0.001) and 15% of MSI-H/MMR-D colorectal carcinoma with wild-type RAS/BRAF . Of 24 total MLH1-deficient colorectal carcinomas with MLH1ph and wild-type RAS/BRAF , 10 (42%) harbored kinase fusions. Kinase fusions in MSI-H colorectal carcinoma were associated with sporadic MLH1ph rather than with Lynch syndrome, and these patients may be eligible for kinase inhibitors, particularly following resistance or toxicity in response to immunotherapy. These findings identify a molecular subset of colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors. Significance: A high frequency of targetable kinase fusions in BRAF/RAS wild-type, MSI-H colorectal carcinoma offers a rationale for routine screening to identify patients with colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors. See related commentary by Valeri, p. 1041 ., (©2019 American Association for Cancer Research.)

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.

Background: This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours., Methods: This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response., Results: 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%)., Conclusions: The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.

Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors. The variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD predicted for increased morbidity across cancer types, including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers, independently of established clinical prognostic factors. We conclude that WGD is highly common in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types.