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Background: LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors., Materials and Methods: In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion., Results: Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site., Conclusions: LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice., Methods: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility., Results: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available., Conclusion: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer., Competing Interests: Disclosure MFM reports receipt of a fee to institution as an invited speaker from Novartis; part-time employment in PEGASCY. CBW reports receipt of a fee for participation in Advisory Board from BMS, Celgene, Rafael, RedHill, Roche, Shire/Baxalta; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Bayer, BMS, Celgene, Chugai, Falk, GSK, Janssen, Merck, MSD, Roche, Servier, Sirtex, Taiho; receipt of a fee for an expert testimony from Janssen; receipt of travel support from Bayer, Celgene, RedHill, Roche, Servier, Taiho; non-financial interest for receipt of research grant both personal and to institution from Roche; non-financial interest for serving as an officer in AIO—Arbeitsgemeinschaft Internistische Onkologie (Germany); non-financial interest for advisory role in EU Commission—DG RTD as a member of the EU Commission Mission Board for Cancer. ASt reports receipt of a fee for participation in Advisory Board from Aignostics, Amgen, AstraZeneca, Bayer, Eli Lilly, Illumina, Janssen, MSD, Pfizer, Seattle Genetics, Thermo Fisher; receipt of a fee to institution for participation in Advisory Board from BMS, Novartis, Takeda; receipt of a fee as an invited speaker from Incyte, Roche; receipt of research grant to institution from Bayer, BMS, Chugai, Incyte. FB reports receipt of a fee to institution for participation in Advisory Board from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Ignyta, Merck, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi Aventis, Seattle Genetics, Takeda; non-financial interest as a principal investigator from AstraZeneca, BMS, F. Hoffmann-La Roche Ltd., Innate Pharma, Merck, Mirati, Piere Fabre. AB reports receipt of a fee for participation in Advisory Board from Sanofi; receipt of a fee as an invited speaker from Roche. IB reports receipt of a fee as an invited speaker from AstraZeneca. JB reports receipt of a fee for participation in Advisory Board from BMS, Janssen, MSD; receipt of funding for study to institution from BMS. EC reports receipt of a fee for participation in Advisory Board from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Eli Lilly, Medscape, MSD, Novartis, Pfizer; receipt of a fee as an invited speaker from Astellas, AstraZeneca, Clovis, Janssen, Medscape, Pfizer; receipt of funding to institution from AstraZeneca; receipt of research grants to institution from Bayer, Janssen, Pfizer; receipt of a fee to institution as a local principal investigator from Janssen, MSD, Pfizer. RD reports receipt of a fee for participation in Advisory Board from Foundation Medicine, Roche; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Ipsen, Janssen, Libbs, Eli Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, Takeda; part-time employment in Oncoclinicas; owning stocks/shares in Trialing; receipt of a research grant from Merck; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis. AK reports receipt of a fee to institution for participation in Advisory Board from Roche; receipt of a fee as an invited speaker from Roche; funding to institution from Bristol Myers Squibb (BMS); non-financial interest as a principal investigator from Roche. AC reports receipt of a fee as an invited speaker from BMS, MSD, Novartis, Pierre Fabre. FMB reports receipt of a fee for participation in Advisory Board from Biovica, Eisai, Karyopharm, Protai, Seagen, Theratechnologies, Zentalis Pharmaceuticals; receipt of a fee for consultancy from AbbVie, AstraZeneca, Black Diamond Therapeutics, EcoR1, F. Hoffmann-La Roche Ltd., GT Aperion Therapeutics, Infinity Pharmaceuticals, Lengo Therapeutics, Loxo Oncology, Menarini Group, OnCusp Therapeutics, Seagen, Tallac Therapeutics, Zymeworks; non-financial interest as a coordinating principal investigator from AstraZeneca; non-financial interest as a local principal investigator from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., KLUS Pharma, Novartis, Taiho Pharmaceuticals Co.; receipt of research grants to institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Puma Biotechnology, Repare Therapeutics, Taiho Pharmaceuticals Co., Takeda Pharmaceuticals Co.; non-financial interest for serving as a Steering Committee Member from Genentech Inc.; receipt of travel support from Cholangiocarcinoma Foundation, European Organisation for Research and Treatment (EORTC), European Society for Medical Oncology (ESMO). SM reports receipt of a fee for participation in Advisory Board, Study Scientific Committee member from Roche, receipt of a fee as DSMB member from Biophytis, IQVIA, Kedrion Biopharma, Servier, Yuhan Corporation. RM reports receipt of a fee for participation in Advisory Board from GSK, AstraZeneca, Merck; receipt of a fee as an invited speaker from GSK, AstraZeneca, Clovis Oncology; receipt of a fee for expert testimony from Shionogi and Ellipses. NN reports receipt of a fee for participation in Advisory Board from Amgen, AstraZeneca, Bayer, Biocartis, Incyte, Novartis, Roche; receipt of a fee as an invited speaker from Eli Lilly, Illumina, Merck, MSD, Thermo Fisher, Roche, Novartis, Sophia Genetics, GSK, Servier; receipt of research grants to institution from AstraZeneca, Biocartis, Illumina, Incyte, Merck, QIAGEN, Roche, Thermo Fisher. JRF reports receipt of a fee for participation in Advisory Board from AstraZeneca, Bain Capital, Daiichi Sankyo, Merck, MultiplexDX, Inc., Paige.AI, Personalis, Repare Therapeutics, Roche Tissue Diagnostics; receipt of a fee for consulting from Eli Lilly, Goldman Sachs, Paige.AI, Repare Therapeutics, Saga Diagnostics; financial interest as a member of Board of Directors from Grupo Oncoclinicas, Odyssey Bio; owning stock options in Paige.AI, Repare Therapeutics; non-financial interest from a leadership role as a President of International Quality Network for Pathology (IQN Path) and a Past President of Italian Cancer Society (SIC). JR reports receipt of grants/research support from MSD, AstraZeneca; receipt of a fee to institution for participation in Advisory Board from AstraZeneca, EDIMARK; for conducting sponsored research to institution from Merck; receipt of a fee to institution as an invited speaker from AstraZeneca, Sanofi, Takeda, Janssen, Roche; non-financial interest for a leadership role as a Secretary of EORTC Lung Cancer Group. MR reports receipt of a fee for participation in Advisory Board from myMedEd; receipt of a fee as an invited speaker from Clinical Care Options, MJH Holdings, myMedEd, Physician’s Education Resource; receipt of a fee for review guideline pathways from Change Healthcare; receipt of a fee to institution as a local principal investigator from AstraZeneca, Merck, or co-principal investigator from Merck and local co-principal investigator from Pfizer; non-financial interest for serving as a Steering Committee Member from AstraZeneca, Merck; non-financial interest for advisory role in Tempus Labs, Zenith Pharmaceuticals; non-financial interest for providing editorial services for medical writing from AstraZeneca, Pfizer; non-financial interest as a member of ASCO. ER reports receipt of a fee to institution for participation in Advisory Board from Amgen, AstraZeneca, GSK, Roche; receipt of a fee to institution as an invited speaker from BMS, Clovis; receipt of funding for data base to institution from AstraZeneca. ASc reports receipt of a fee for participation in Advisory Board from Incyte; receipt of a fee as an invited speaker from Amgen, Aristea—MSD, Tesaro-GSK. CS reports receipt of a fee for participation in Advisory Board from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals, IDRx, Immunicum, New Bay; receipt of a fee as an invited speaker from Roche, PharmaMar; receipt of a fee as Steering Committee Member, both personal and to institution, from Deciphera, NewBay; receipt of research grants to institution from IDRx; receipt of travel grant from Bayer AG, Gilead, Pfizer, PharmaMar; non-financial interest as ESMO Faculty member and serving as a member of Board of Directors in the Spanish Group for Sarcoma Research (GEIS) and Spanish Society of Medical Oncology (SEOM). JM reports receipt of a fee for participation in Advisory Board from Amgen, Amunix Pharmaceuticals, AstraZeneca, Janssen, Pfizer, Roche; receipt of a fee to institution for participation in Advisory Board from Nuage Therapeutics; receipt of a fee as an invited speaker from AstraZeneca, GuardantHealth, MSD; receipt of research grants to institution from Amgen, AstraZeneca, Pfizer Oncology; non-financial interest from receiving product samples for access to drugs in early development for preclinical testing from AstraZeneca. FA reports receipt of a fee to institution for participation in Advisory Board from AstraZeneca, Boston Pharmaceutics, Daiichi Sankyo, Gilead, Guardant Health, Eli Lilly, N-Power Medicine, Novartis, Owkin, Pfizer, Roche, Servier; receipt of a personal fee for participation in Advisory Board from Lilly France; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, Guardant Health, Ely Lilly, Novartis, Owkin, Pfizer, Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors., Patients and Methods: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1., Results: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response., Conclusions: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials., Competing Interests: Declaration of competing interest The authors have declared all competing financial interests or personal relationships that could have appeared to influence the work reported in this paper above., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA)., Methods: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro., Results: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance., Conclusions: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi., Clinical Trial Number: NCT02052778., Impact and Implications: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone., Patients and Methods: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response., Results: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion., Conclusions: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples., Patients and Methods: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples., Results: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC., Conclusion: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Implementation of adjuvant therapies in non-metastatic melanoma improved treatment outcomes in some patients; however, adjuvant therapy can be associated with significant cost and risk of toxicity. Therefore, there is an unmet need to better identify patients at high risk of recurrence., Patients and Methods: We carried out an ultrasensitive droplet digital PCR (ddPCR)-based detection of BRAF V600E -mutated circulating tumor DNA (ctDNA) from blood samples prospectively collected before surgery, 1 hour after surgery, and then serially during follow-up., Results: In 80 patients (stages ≤III), BRAF V600E mutations were detected in 47.2% of tissue, in 37.7% of ctDNA samples collected before surgery, and in 25.9% of ctDNA samples collected 1 hour after surgery. Patients with detected ctDNA in blood collected 1 hour after surgery compared to patients without detected ctDNA had higher likelihood of melanoma recurrence (P < 0.001) and shorter median disease-free survival (P = 0.001) and overall survival (P = 0.003)., Conclusions: Ultrasensitive ddPCR can detect ctDNA in pre- and post-surgical blood samples from patients with resectable melanoma. Detection of ctDNA in post-surgical samples is associated with inferior treatment outcomes., Competing Interests: Disclosure SGC is a current employee at Tempus Labs. FM-B has research support from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo Co., Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Takeda Pharmaceutical (formerly Millennium Pharmaceutical), Novartis, Puma Biotechnology, and Taiho Pharmaceutical; provided consulting role for AbbVie, Aduro BioTech, Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, and Xencor, Zymeworks; is on the advisory committee of Black Diamond, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; received honoraria from Chugai Biopharmaceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey; and received travel-related support from Beth Israel Deaconess Medical Center. FJ has research support from Astex, Novartis, BioMed Valley Discoveries, Fore Bio, Deciphera, Bristol-Myers Squibb, Asana, Ideaya Biosciences, Sanofi, Merck, F-star, JSI Innopharm, Bioxcel, Lilly, Bicara, PureTech Health, FujiFilm Pharmaceuticals, Sotio, Synlogic, NextCure, and Hutchinson Medipharma; is on the Scientific Advisory Boards of Ideaya Biosciences, Synlogic, Sotio, Puretech Health, Deciphera, Crown Bioscience, Asana, Fore Bio, Novartis, Bicara, and PegaOne; is a paid consultant for Mersana Therapeutics, Flame Bio, Cardiff Oncology, MedinCell, and Immunomet; has ownership interests in Cardiff Oncology and Monte Rosa Therapeutics; and has the leadership position in Monte Rosa Therapeutics. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Enrolling patients with metastatic urothelial carcinoma (mUC) in phase I trials provides an opportunity to identify biological drug activity. Developing prognostic scores may aid in patient selection for phase 1 trials., Patients and Methods: We analyzed records of patients with mUC who participated in targeted therapy and immunotherapy phase I clinical trials at MD Anderson Cancer Center (MDACC). The Bellmunt and Bajorin scores were calculated as bladder cancer-specific prognostic scores. The Royal Marsden Hospital (RMH) and MDACC scores were calculated as phase I prognostic scores. Hazard ratios (HR) were calculated using the Cox proportional hazard model. The prognostic value of the Bellmunt, Bajorin, RMH, and MDACC scores were assessed using the Likelihood ratio (LR) χ2 test and the c-index., Results: Between 2015 and 2019, 43 patients were enrolled in phase I trials and 12 were enrolled in >I trial leading to a total of 57 trial participants (TPs). Ninty-seven percent of TPs received prior platinum therapy and 60% received a prior checkpoint inhibitor. Median overall survival (OS) and progression-free survival (PFS) were significantly shorter with increasing Bajorin, RMH, or MDACC scores, but not with increasing Bellmunt score. The RMH (c-index=0.658, LR χ2=11.8, P=.008) and MDACC scores (c-index =0.66, LR χ2=12.76, P=.01) outperformed the Bajorin score (c-index=0.522, LR χ2=1.22, P=.5) and the Bellmunt score (c-index=0.537, LR χ2=0.36, P=.9) in predicting overall survivalover. The Bajorin, RMH, and MDACC scores, but not the Bellmunt score, were also predictive of progression-free survival (PFS)prog. The RMH and MDACC scores again outperformed the Bajorin scoreand the Bellmunt score for predicting PFS., Conclusion: The RMH and MDACC phase I prognostic scores accurately predicted survival in patients with mUC and outperformed the bladder cancer-specific scores at time of enrollment on phase 1 clinical trials. The RMH and MDACC scores could optimize selection of patients with mUC for phase I clinical trials., (Copyright © 2021. Published by Elsevier Inc.)

Background: Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations., Patients and Methods: We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes., Results: Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048)., Conclusions: Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF., Competing Interests: Disclosure FJ has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, PIQUR, Symphogen, Bristol-Myers Squibb, Asana, and Upsher-Smith Laboratories; is or has been on the Scientific Advisory Boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Cardiff Oncology and ImmunoMet; and has ownership interests in Cardiff Oncology. MF reports grants and personal consulting fees through 06/04/18 from Seattle Genetics and salary and stocks from 10/01/18 following the start of her employment with Seattle Genetics; grants and personal fees from Takeda, Celgene, BMS, and Merck through 06/04/18; grants from ADC Therapeutics, Molecular Templates, MedImmune, Gilead, and Genentech through 06/04/18; and personal fees from Bayer and Spectrum through 06/04/18. VS has research funding/grant support for clinical trials (to institution) from Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning point therapeutics, and Boston Pharmaceuticals; travel funding from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte; and serves on the advisory board of Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, Astra-Zeneca/Medimmune, Novartis, Signant Health. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways., Patients and Methods: Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies., Results: Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling., Conclusions: The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors., Competing Interests: Disclosure TC: speaker's fees from Society for Immunotherapy of Cancer and Bristol Myers Squibb; consulting/advisory role fees from MedImmune/AstraZeneca, EMD Serono, and Bristol Myers Squibb, research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, and Bristol Myers Squibb. SAP-P: research/grant funding (institutional) from AbbVie, Inc.; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc.; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma Inc.; Chugai Pharmaceutical Co., Ltd.; Curis, Inc.; Five Prime Therapeutics; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC; Medivation, Inc.; Merck Sharp and Dohme Corp.; NewLink Genetics Corporation/Blue Link Pharmaceuticals; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Syneos Health; Taiho Oncology; Tesaro, Inc.; TransThera Bio; and Xuanzhu Biopharma. DSH: research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; funding for travel, accommodations, and expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC; consultant/advisor for Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; ownership interests in Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc. (Advisor). SF: clinical trial research support through the institution from NIH/NCI; AstraZeneca; Abbisko; Anaeropharma Science; Arrien Pharmaceuticals; BeiGene; BioAtla, LLC; Boehringer Ingelheim; Eli Lilly & Co.; Hookipa Biotech; Huya Bioscience International; IMV, Inc.; Innovent Biologics, Co., Ltd.; Lyvgen Biopharma, Co., Ltd.; MacroGenics; Medivir AB; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; Neupharma, Inc.; Novartis; OncoMed Pharmaceuticals; Parexel International, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; Tolero Pharmaceuticals; NovoCure; Turnstone Biologics; Taiho Oncology; and NCCN. AN: Research funding from NCI, EMD Serono, MedImmune, Healios, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology; on advisory board of CytomX Therapeutics, Novartis, and Genome & Company, OncoSec KEYNOTE-695, STCube Pharmaceuticals, Kymab; travel and accommodation expense from ARMO BioSciences. Spouse: Research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and Chao Physician-Scientist, and Baxalta; advisory board from Takeda, CSL Behring, Horizon Pharma. FJ: grant/research funding (institutional) from Novartis, Genentech, Biomed Valley Discoveries, Plexxikon, Deciphera, PIQUR Therapeutics, Symphogen, Bayer, Fujifilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, and Bristol Myers Squibb; advisory board member for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, IDEAYA, PureTech Health, and Jazz pharmaceuticals; consultant fees from Trovagene, Immunomet, Primmune Therapeutics, Jazz Pharmaceuticals, and SOTIO; ownership interests in Trovagene. GSF: research funding from 3-V Biosciences, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, BioAtla, Biothera, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, Delmar, eFFECTOR, Eli Lilly, EMD Serono, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, LOXO, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, VEGENICS, and Xencor; advisor fees from Fujifilm and EMD Serono; royalties from Wolters Kluwer; funding for travel from Bristol Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speaker's bureau fees from Total Health Conferencing. APC: consultant fees from Deciphera Pharmaceuticals, Guidepoint Global, Genentech, Inc., Bayer Healthcare Pharmaceuticals, OncLive, Novartis Pharmaceuticals, and Ignyta, Inc.; speaker fees from Medscape. SIS: research support from Exelixis; consultant fees from Fortress Biotech and LOXO oncology; honoraria from Eisai. FM-B: Consulting fees from Aduro Biotech Inc., Alkermes, AstraZeneca, Debiopharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee fees from Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related) from Beth Israel Deaconess Medical Center. JVH: research support from AstraZeneca, GlaxoSmithKline, and Spectrum; consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs; royalties and patents from Spectrum. VS and IMS: research funding/grant support from Novartis, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, LOXO oncology, MedImmune, ALTUM, Dragonfly therapeutics, Takeda, and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP, and UT MD Anderson Cancer Center; consultant/advisory board for Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, MedImmune, Novartis; funding for travel from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte. All other authors have declared no conflicts of interest. Data sharing The data supporting the findings presented in this manuscript are available upon reasonable academic request to the study principal investigator (VS)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Several tumour types are responsive to immunotherapy, as shown by regulatory approvals for immune checkpoint inhibitors. However, many patients either do not respond or do not have durable clinical benefit. Thus, there is great interest in developing predictors of response to immunotherapy and rational combination therapies that can enhance efficacy by overcoming primary and acquired resistance. In this Review, we provide an assessment of immunotherapy response biomarkers that can identify patients who will benefit from monotherapy rather than from combinations. We review the rationale for combination therapy and different strategies, including combinations with chemotherapy, targeted therapy, radiation therapy, intratumoural therapies, other immunomodulators, and adaptive cell therapy, including chimeric antigen T-cell receptors and other novel T-cell receptor-based therapies. There are many combination partners in development; therefore, a programmatic approach is needed to develop a framework for biomarker-driven combination therapy selection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes., Patients and Methods: Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation., Results: RET G810C/S mutations at the solvent front and RET Y806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RET M918T/V804M/L , who initially responded to selpercatinib and developed resistance. RET G810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft., Conclusions: RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations., Competing Interests: Disclosure VS: research funding/grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals; travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, Medimmune, Novartis. Other: Medscape. MH has participated in advisory boards for Blueprint Medicines Corporation, Eli Lilly and Company, and Loxo Oncology, and has served as a consultant for Veracyte. MC, receiving grant support, paid to her institution, from Eisai, Exelixis, Genentech USA, Kura Oncology, and Merck, and advisory board fees from Ignyta and Loxo Oncology. FM-B reports consulting: Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals. Sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: For patients with metastatic renal cell carcinoma (mRCC) who progress on standard-of-care therapies, there is an unmet need for novel treatments. Phase I clinical trials are designed to test the safety, toxicity and optimal dosing of novel agents. Herein, we analysed the outcomes of patients with mRCC enrolled in phase I trials and assess the utility of prognostic scores., Methods: Patients with all histologies of mRCC were included if they received treatment on a phase I clinical trial at MD Anderson Cancer Center (MDACC). Survival outcomes were calculated using Cox proportional hazard model. Prognostic value of the International Metastatic RCC Database Consortium (IMDC), Royal Marsden Hospital (RMH) and MDACC scores was assessed using the likelihood ratio (LR) χ 2 test and the c-index., Results: Among 82 patients with mRCC who received treatment, 21 patients participated in more than one trial, resulting in 106 trial participants (TP). Median prior therapies was two. For all TPs, median overall survival (OS) was 31.2 months, progression-free survival (PFS) was 5.9 months and objective response rate was 22%. Median OS and PFS were significantly shorter with increasing IMDC, RMH and MDACC scores. The RMH and MDACC scores outperformed the IMDC score for predicting OS (RMH LR χ 2 =8.64; MDACC LR χ 2 =7.74; IMDC LR χ 2 =2.36) and PFS (RMH LR χ 2 =17.5; MDACC LR χ 2 =20.3; IMDC LR χ 2 =4.28)., Conclusions: The RMH and MDACC prognostic scores can be used to predict OS for patients with mRCC in phase I trials and may guide patient selection. Patients with mRCC should be considered for phase I trials., Competing Interests: Competing interests: AWH, OA, EC, HL and JR have no conflicts to disclose. PM reports consultancy/honoraria to Pfizer, Bristol-Myers Squibb, Mirati, Exelixis and Axiom Healthcare Strategies; research funding to his institution from Mirati, Takeda, Bristol-Myers Squibb and Gateway for Cancer Research. FM-B reports consulting to Aduro BioTech, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer, Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor and Zymeworks. She reports honoraria from Chugai Biopharmaceuticals, Mayo Clinic and Rutgers Cancer Institute of New Jersey. She reports research funding to her institution from Aileron Therapeutics AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Debiopharm International, eFFECTOR Therapeutics, Genentech, Guardant Health, Millennium Pharmaceuticals, Novartis, Puma Biotechnology and Taiho Pharmaceutical. AN reports consulting to CytomX Therapeutics, Novartis, Kymab and Genome. He reports travel and accommodation expenses from ARMO BioSciences. He reports research funding to his institution from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus and Immune Deficiency Foundation (Spouse). EJ reports research funding to his institution from Exelixis, Merck and Pfizer. He reports consulting for Eisai, Exelixis, Novartis, Merck, Pfizer, Roche. Sarina Piha-Paul reports research funding to her institution from AbbVie, ABM therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol Myers Squib, Chugai Pharmaceutical, Daichi Sankyo, Eli Lilly, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, Medimmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Taiho Oncology, Tesaro and TransThera Bio. NMT reports consultancy and honoraria from Pfizer, Novartis, Bristol-Myers Squibb, Exelixis, Nektar, Eisai, Ono Pharmaceutical, Eli Lilly, Oncorena, Ipsen, Surface Oncology and Neolukin Therapeutics. He reports research funding to his institution from Bristol-Myers Squibb, Exelixis, Pfizer, Nektar Therapeutics, Calithera Bioscience, Eli Lilly, Mirati Therapeutics, Arrowhead Pharmaceuticals, Takeda, Epizyme and Eisai. He reports travel expenses from Pfizer, Novartis, Nektar, Bristol-Myers Squibb, Eisai, Onco Pharmaceuticals, Oncorena, Surface Oncology, Lilly Oncology, Ipsen, and Neolukin Therapeutics. David S. Hong reports research funding to his institution from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, GSK, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics. He reports travel expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC. He reports consulting for Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD. He reports ownership interests in Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc (Advisor). Shubham Pant reports research funding to his institution from Mirati Therapeutics, Eli Lilly, Red Hill Biopharma Ltd., Xencor, Five Prime Therapeutics, Novartis, Rgenix, Sanofi-Aventis, Arqule, Bristol-Myers Squibb, Onco Response, Sanofi US Services Inc., and GlaxoSmithKline. Timothy Yap reports research funding to his institution from: AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius/Formation Biologics, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Sanofi, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. He reports consultancy from Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Kyn Therapeutics, Merck, Pfizer, Roche, Seattle Genetics, and Zai Labs.Vivek Subbiah reports research funding to his institution from LOXO Oncology, Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Amgen, Multivir, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, Turning Point Therapeutics, and Boston Pharmaceuticals. He reports consultancy for Helsinn, Incyte, and QED Pharma. He reports travel expenses from Helsinn, Incyte, ASCO and ESMO., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology., Competing Interests: Disclosure JR: advisory: Merck Sharp & Dohme (MSD), Boehringer, Bristol-Myers Squibb (BMS), AstraZeneca, Roche; speaker's bureau: Pfizer; travel support: OSE Immunotherapeutics SA, BMS, AstraZeneca, Roche. JM: advisory board: Amgen, AstraZeneca, Clovis Oncology, Janssen, MSD and Roche-Foundation Medicine; research funding: AstraZeneca and Pfizer Oncology; principal investigator of several industry sponsored clinical trials. CBW: personal and speakers' fees, reimbursement for travel and accommodation and honoraria for participance in advisory boards from Bayer, Celgene, Ipsen, MedScape, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta and Taiho; scientific grant support by Roche. FB: personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda. MPL: research grants (to hospital): MSD, Astellas, JnJ, Sanofi; advice: Roche, Bayer, Amgen, JnJ, Sanofi, Servier, Pfizer, Incyte. NN: speaker's fee and/or advisory boards: Amgen, AstraZeneca, Bayer, Biocartis, BMS, Boehringer Ingelheim, Eli Lilly, Ilumina, Incyte, MERCK, MSD, Qiagen, Roche, Thermofisher, Sanofi; institutional financial interests (financial support to research projects): AstraZeneca, Biocartis, BMS, Illumina, Merck, Qiagen, Roche, Sysmex, Thermofisher; non-financial interests: President of the International Quality Network for Pathology (IQN Path); President of the Italian Cancer Society (SIC). ASc: speakers bureau: Ypsen, Astra Zeneca, Amgen, MSD, GSK; consulting: INCYTE Biosciences. MR: consulting or advisory: AstraZeneca (uncompensated), Change Healthcare, Daiichi-Sankyo (uncompensated), Epic Sciences (uncompensated), Merck (uncompensated), Pfizer (uncompensated); research funding: AbbVie (institution), AstraZeneca (Institution), Invitae (Institution, in-kind), Merck (Institution), Pfizer (institution); travel, accommodation, expenses: AstraZeneca, Merck; editorial services: AstraZeneca, Pfizer. FM-B: consulting: Aduro BioTech Inc., Alkermes, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd, Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee: Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research: Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd, Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related): Beth Israel Deaconess Medical Center. NW: research grant from Puma Biotechnology; scientific advisory board and stockholder for Relay Therapeutics; advisor to Eli Lilly. ASt: advisory board/speakers bureau: Astra Zeneca, Eli Lilly, Bayer, BMS, Illumina, Janssen, MSD, Pfizer, Roche, Seattle Genetics, Thermo Fisher; Grants: Bayer, BMS, Chugai. JB: travel support: BMS; consulting fees: BMS, MSD, Astellas. SM: statistical advice: IDDI and Janssen Cilag; Independent Data Monitoring Committee member: Hexal, Steba, IQVIA, Roche, Sensorion, Biophytis, Servier, Yuhan. IB: speaker’s fee: AstraZeneca. ER: board participation: AstraZeneca, BMS, Roche; travel funding: AstraZeneca, BMS. JSR-F: paid consultant: Goldman Sachs, REPARE Therapeutics, and Paige.AI; member of the scientific advisory board: REPARE Therapeutics, Paige.AI, and Volition Rx; member of the Board of Directors: Group Oncoclinicas; ad hoc member of the scientific advisory board: Roche Tissue Diagnostics, Roche, Genentech, Novartis, and Invicro; owns shares: REPARE Therapeutics. RD: advisory: Roche, Boehringer Ingelheim; speaker’s fee: Roche, Ipsen, Amgen, Servier, Sanofi, Merck Sharp & Dohme; research grants: Merck and Pierre Fabre. FA: research grants and talks/advisory boards compensate to the hospital: Roche, Pfizer, Novartis, AstraZeneca, Daiichi Sankyo, Lilly. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. All rights reserved.)

Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents., Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines., Results: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line., Conclusions: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+)., Methods: A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation., Results: Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation., Conclusion: Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours., Competing Interests: Competing interests: VS reports grants and other from Loxo Oncology/ Eli Lilly, grants from Roche/ Genentech, grants and other from Novartis, grants from Bayer, grants from GlaxoSmithKline, grants from Nanocarrier, grants from Vegenics, grants from Celgene, grants from Northwest Biotherapeutics, grants from Berghealth, grants from Incyte, grants from Fujifilm, grants and other from Pharmamar, grants from D3, grants from Pfizer, grants from Multivir, grants from Amgen, grants from Abbvie, grants from Alfa-sigma, grants from Agensys, grants from Boston Biomedical, grants from Idera Pharma, grants from Inhibrx, grants from Exelixis, grants from Blueprint medicines, grants and other from Medimmune, grants from Altum, grants from Dragonfly therapeutics, grants from Takeda, grants from National Comprehensive Cancer Network, grants from NCI-CTEP and UT MD Anderson Cancer Center, grants from Turning point therapeutics, grants from Boston Pharmaceuticals, other from Helsinn, from R-Pharma US, other from INCYTE, other from QED pharma, other from ASCO, other from ESMO, other from Medscape, during the conduct of the study. FM-B reports other from Arduro BioTech, other from DebioPharm, grants and other from eFFECTOR Therapeutics, other from F. Hoffman-La Roche Ltd, grants and other from Genentech, other from IBM Watson, other from Jackson Laboratory, other from Kolon Life Science, other from OrigiMed, other from PACT Pharma, other from Parexel International, other from Pfizer, other from Samsung Bioepis, other from Seattle Genetics, other from Tyra Biosciences, other from Xencor, other from Zymeworks, other from Alkermes, other from Immunomedics, other from Inflection Biosciences, other from Mersana Therapeutics, grants and other from Puma Biotechnology, other from Silverback Therapeutics, other from Spectrum Pharmaceuticals, grants from Aileron Therapeutics, grants from AstraZeneca, grants from Bayer Healthcare Pharmaceutical, grants from Calithera Biosciences, grants from Curis, grants from CytomX Therapeutics, grants from Daiichi Sankyo Co Ltd, grants from Debiopharm International, grants from Novartis, grants from Taiho Pharmaceutical Co, other from Chugai Biopharmaceuticals, other from Mayo Clinic, other from Rutgers Cancer Institute of New Jersey, other from Beth Israel Deaconess Medical Center, outside the submitted work. MIH reports other from Blueprint Medicines, other from Loxo Oncology, other from Eli Lilly and Co, outside the submitted work. JL reports personal fees from Foundation Medicine, during the conduct of the study; personal fees from Foundation Medicine, other from Roche, outside the submitted work., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: Futibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors., Patients and Methods: Following a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.)., Results: A total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%)., Conclusions: Futibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D., Clinical Trial Registration: FOENIX-101 (ClinicalTrials.gov, NCT02052778)., Competing Interests: Disclosure RB does not have conflicts of interests to disclose. FM-B reports research support from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., K Group, Millennium Pharmaceuticals Inc., Novartis, Pfizer Inc., PPD Investigator Services LLC, Puma Biotechnology Inc., Seattle Genetics, Taiho Pharmaceutical Co., and Zymeworks Inc.; has served on the advisory committees of ClearLight Diagnostics, Darwin Health, Grail, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, and Silverback Therapeutics, Spectrum Pharmaceuticals; has a consulting role for eFFECTOR Therapeutics, PACT Pharma, Zymeworks, Jackson Laboratory, Genentech Inc., F. Hoffman-La Roche Ltd., Parexel International, Pfizer Inc., IBM Watson, Samsung Bioepis, Aduro Biotech Inc., Kolon Life Science, OrigiMed, Sumitomo Dainippon Pharma Co., Seattle Genetics Inc., DebioPharm, Dialectica, Piers Pharmaceuticals, Xencor, and Tyra Biosciences; and has received fees/honoraria from Chugai Biopharmaceuticals, Dialectica, Mayo Clinic, and Sumitomo Dainippon Pharma. LG has a consulting/advisory role for Debiopharm, H3 Biomedicine, Incyte, QED, Alentis, Pieres, Agios, and Sirtex; serves on the IDMC for AstraZeneca; has received research funding from Taiho; and has received reimbursement for travel, accommodation, and other expenses from Taiho. BT has served in an advisory role at Amgen, Astellas, Bayer, Sanofi, BMS, Janssen-Cilag, MSD, Novartis, Tolmar, Ipsen; has received research funding from Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen-Cilag, Pfizer, and Servier; has served on the Speaker Bureau for Amgen, Astellas, BMS, and Janssen-Cilag; and has received travel expenses from Amgen, Astellas, Bayer, and Sanofi. BT's institution receives funding from Amgen, Aslan, Akeso, AstraZeneca, Aptevo, GSK, MSD, Novartis, Servier, and Taiho. YH, KAB, and IY are full-time employees at Taiho Oncology. KAB was an employee at Eli Lilly and owns stock in Eli Lilly. HTA is an investigator in studies sponsored by Taiho and reports an advisory role in Guardant, Roche, and Servier. IM has no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics., Patients and Methods: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR)., Results: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred., Conclusions: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions., Patients and Methods: This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity., Results: Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose., Conclusions: Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients., Clincaltrials.gov Number: NCT02122913., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis., Patients and Methods: We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes., Results: Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016)., Conclusions: Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.

Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference., Patients and Methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR., Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response., Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab., Clinicaltrials.gov Identifiers: NCT00513292, NCT00353483., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Exosomes arise from viable cancer cells and may reflect a different biology than circulating cell-free DNA (cfDNA) shed from dying tissues. We compare exosome-derived DNA (exoDNA) to cfDNA in liquid biopsies of patients with pancreatic ductal adenocarcinoma (PDAC)., Patients and Methods: Patient samples were obtained between 2003 and 2010, with clinically annotated follow up to 2015. Droplet digital PCR was performed on exoDNA and cfDNA for sensitive detection of KRAS mutants at codons 12/13. A cumulative series of 263 individuals were studied, including a discovery cohort of 142 individuals: 68 PDAC patients of all stages; 20 PDAC patients initially staged with localized disease, with blood drawn after resection for curative intent; and 54 age-matched healthy controls. A validation cohort of 121 individuals (39 cancer patients and 82 healthy controls) was studied to validate KRAS detection rates in early-stage PDAC patients. Primary outcome was circulating KRAS status as detected by droplet digital PCR. Secondary outcomes were disease-free and overall survival., Results: KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic PDAC patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Higher exoKRAS MAFs were associated with decreased disease-free survival in patients with localized disease. In the validation cohort, mutant KRAS exoDNA was detected in 43.6% of early-stage PDAC patients and 20% of healthy controls., Conclusions: Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy., Patients and Methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care., Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001)., Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting., Materials and Methods: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected at baseline and, following 14 days of treatment, prior to or during surgery. The primary objective was to assess antiproliferative response per Ki67 levels in Arms 2 and 3 compared with Arm 1. Additional assessments included safety, pharmacokinetics, and genetic profiling., Results: Mean decreases in the Ki67-positive cell fraction from baseline were: Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% (range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent with single-agent data. The ribociclib plus letrozole combination was well tolerated, with no Grade 3/4 adverse events over the treatment., Conclusion: The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229)., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed., Patients and Methods: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays., Results: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002., Conclusions: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials., Clinical Trials Number: The study NCT number is NCT01196130., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Next-generation sequencing in cancer research may reveal germline variants of clinical significance. We report patient preferences for return of results and the prevalence of incidental pathogenic germline variants (PGVs)., Patients and Methods: Targeted exome sequencing of 202 genes was carried out in 1000 advanced cancers using tumor and normal DNA in a research laboratory. Pathogenic variants in 18 genes, recommended for return by The American College of Medical Genetics and Genomics, as well as PALB2, were considered actionable. Patient preferences of return of incidental germline results were collected. Return of results was initiated with genetic counseling and repeat CLIA testing., Results: Of the 1000 patients who underwent sequencing, 43 had likely PGVs: APC (1), BRCA1 (11), BRCA2 (10), TP53 (10), MSH2 (1), MSH6 (4), PALB2 (2), PTEN (2), TSC2 (1), and RB1 (1). Twenty (47%) of 43 variants were previously known based on clinical genetic testing. Of the 1167 patients who consented for a germline testing protocol, 1157 (99%) desired to be informed of incidental results. Twenty-three previously unrecognized mutations identified in the research environment were confirmed with an orthogonal CLIA platform. All patients approached decided to proceed with formal genetic counseling; in all cases where formal genetic testing was carried out, the germline variant of concern validated with clinical genetic testing., Conclusions: In this series, 2.3% patients had previously unrecognized pathogenic germline mutations in 19 cancer-related genes. Thus, genomic sequencing must be accompanied by a plan for return of germline results, in partnership with genetic counseling., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Residual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes-resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer., Methods: A phase II study in patients with residual cancer burden II or III randomized to ixabepilone versus observation was conducted. Circulating tumor cells (CTCs) were measured at baseline and at 9 and 18 weeks. Survival probabilities were estimated by Kaplan-Meier product limit. Toxicities were reported as proportions in the ixabepilone arm., Results: Accrual was stopped because of ixabepilone toxicity. Sixty-seven patients were registered; 43 were randomized, 19 received ixabepilone, and 24 went to observation. One patient (9.1%) in the observation arm versus 2 patients (18.2%) in the ixabepilone arm had CTCs at 18 weeks (P = 1.0). Three-year recurrence-free survival and overall survival were 94% and 82%, and 100% and 79% in the observation and ixabepilone arms (P = .35 and .18), respectively. Most common adverse events (AEs) included fatigue, pain, neuropathy, constipation, nausea, rash, anorexia, and diarrhea. Serious AEs included pain (63.2%), fatigue (31.6%), and neuropathy (31.6%)., Conclusions: Adjuvant ixabepilone in patients with significant RD after neoadjuvant chemotherapy was difficult to administer because of AEs and did not change the presence of CTC or affect survival outcomes. NCT00877500., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: We carried out a phase I trial of the vascular endothelial growth factor inhibitor pazopanib and the histone deacetylase inhibitor vorinostat to determine the safety and efficacy. Because these agents are known to target factors activated by TP53 mutation and facilitate mutant p53 degradation, a subgroup analysis may be interesting in patients with TP53 mutant malignancies., Patients and Methods: Patients with advanced solid tumors (n = 78) were enrolled following a 3 + 3 design, with dose expansion for those with responsive tumors. Hotspot TP53 mutations were tested when tumor specimens were available., Results: Adverse events of ≥grade 3 included thrombocytopenia, neutropenia, fatigue, hypertension, diarrhea and vomiting. Overall, the treatment produced stable disease for at least 6 months or partial response (SD ≥6 months/PR) in 19% of the patients, median progression-free survival (PFS) of 2.2 months, and median overall survival (OS) of 8.9 months. In patients with detected hotspot TP53 mutant advanced solid tumors (n = 11), the treatment led to a 45% rate of SD ≥6 months/PR (1 PR and 3 SD ≥6 months), median PFS of 3.5 months, and median OS of 12.7 months, compared favorably with the results for patients with undetected hotspot TP53 mutations (n = 25): 16% (1 PR and 3 SD ≥6 months, P = 0.096), 2.0 months (P = 0.042), and 7.4 months (P = 0.1), respectively., Conclusion: The recommended phase II dosage was oral pazopanib at 600 mg daily plus oral vorinostat at 300 mg daily. The preliminary evidence supports further evaluation of the combination in cancer patients with mutated TP53, especially in those with metastatic sarcoma or metastatic colorectal cancer., Clinical Trial Registration: www.clinicaltrials.gov, NCT01339871., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To evaluate the frequency of receptor change from pretreatment to residual breast cancer after NCT and their correlation with outcomes., Patients and Methods: Three hundred ninety-eight women were identified retrospectively. Estrogen receptor, progesterone receptor, and HER2 were reviewed. Patients were classified as not having receptor change versus any receptor change. Kaplan-Meier was used to estimate survival outcomes according to changes. Cox proportional hazards models were used to determine the association of receptor status changes with outcomes after adjustment for patient and tumor characteristics., Results: One hundred sixty-two (40.7%) patients had a change in at least 1 of the receptors from pretreatment to residual disease. Patients who had no change in receptor status had a significantly greater triple-negative breast cancer (TNBC) rate at baseline (P = .0001). Of the 193 hormone receptor (HR)-positive tumors, 9 (4.7%) and 29 (15.1%) became HER2-positive and TNBC, respectively. Of the 72 HER2-positive tumors, 20 (27.8%) and 9 (12.5%) became HR-positive and TNBC, respectively. Of the 128 TNBC tumors, only 2 (1.6%) and 33 (25.8%) became HER2-positive and HR-positive, respectively. At a median follow up of 40 months, 5-year overall survival (OS) was 73% and 63%; and 5-year relapse-free survival (RFS) was 63% and 48% for patients with or without any receptor change (P = .07 and P = .003), respectively. Any receptor change was associated with better RFS (hazard ratio, 0.63; 95% confidence interval [CI], 0.44-0.9) but not OS. (hazard ratio, 0.79; 95% CI, 0.53-1.18)., Conclusion: Changes in receptor status between the pretreatment and residual disease after NCT are frequent and appear to be associated with improved RFS because of the receptor stability of TNBC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine the prevalence of MET amplification and mutation among GU malignancies and its association with clinical factors and responses to c-MET inhibitors., Patients and Methods: Patients with GU malignancies referred to our Phase I Clinical Trials Program were evaluated for MET mutation and amplification and outcomes using protocols with c-MET inhibitors., Results: MET amplification was found in 7 of 97 (7.2%) patients (4/27 renal [all clear cell], 1/18 urothelial, and 2/12 adrenocortical carcinoma), with MET mutation/variant in 3 of 54 (5.6%) (2/20 renal cell carcinoma [RCC] [1 clear cell and 1 papillary] and 1/16 prostate cancer). No demographic characteristics were associated with specific MET abnormalities, but patients who tested positive for mutation or amplification had more metastatic sites (median, 4 vs. 3 for wild type MET). Median overall survival after phase I consultation was 6.1 and 11.5 months for patients with and without a MET alteration, respectively (hazard ratio, 2.8; 95% confidence interval, 1.1 to 6.9; P = .034). Twenty-nine (25%) patients were treated according to a c-MET inhibitor protocol. Six (21%) had a partial response (prostate and RCC) and 10 (34%) had stable disease as best response. Median time to tumor progression was 2.3 months (range, 0.4-19.7) for all treated patients with no responses in patients with a MET abnormality or single-agent c-MET inhibitor treatment., Conclusion: MET genetic abnormalities occur in diverse GU malignancies and are associated with a worse prognosis in a phase I setting. Efficacy of c-MET inhibitors was more pronounced in patients without MET abnormalities and when combined with other targets/drugs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

Background: c-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit., Methods: We reviewed the electronic medical records of all patients with advanced BC tested for MET amplification, mutation, or both who were referred to the Department of Investigational Cancer Therapeutics at MD Anderson., Results: A total of 107 patients with advanced BC were analyzed for MET mutation/variant (88 patients) or amplification (63 patients). Of these, 49 were tested for both genetic abnormalities. Three of 63 patients (4.7%) demonstrated MET gene amplification by fluorescence in situ hybridization (2 in primary tissue; 1 in metastatic site). MET mutation/variant was detected in 8 of 88 patients (9%). High-grade tumors were characteristic of all patients harboring MET amplification and were present in 7 of 8 (87.5%) of those with MET mutation. Metastatic sites were greater in MET-amplified compared with wild-type patients (median of 7 vs. 3 sites). Five of 8 patients (62.5%) with MET mutations had triple negative BC compared with 46% in controls. In addition, patients with positive test results for MET aberrations (n = 11) had inferior overall survival (OS) from Phase I consult compared with wild-type patients (n = 37), although this was not statistically significant (median OS = 9 vs. 15 months, P = .43)., Conclusions: In this cohort of patients with BC who were referred to our Phase I Department, MET aberrations were associated with higher metastatic burden and high-grade histology. We could not demonstrate differences in survival outcomes because of a small sample size., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: KRAS mutations in codons 12 and 13 are present in ∼40% of all colorectal cancers (CRC). Activating mutations in codons 61 and 146 of KRAS and in codons 12, 13, and 61 of NRAS also occur but are less frequent. The clinicopathologic features and gene expression profiles of this latter subpopulation of RAS-mutant colorectal tumors have not yet been clearly defined but in general are treated similarly to those with KRAS 12 or 13 mutations., Patients and Methods: Records of patients with metastatic CRC (mCRC) treated at MD Anderson Cancer Center between December 2000 and August 2012 were reviewed for RAS (KRAS or NRAS) and BRAF mutation status, clinical characteristics, and survival outcomes. To study further with an independent cohort, data from The Cancer Genome Atlas were analyzed to define a gene expression signature for patients whose tumors feature these atypical RAS mutations and explore differences with KRAS 12/13-mutated colorectal tumors., Results: Among the 484 patients reviewed, KRAS 12/13, KRAS 61/146, NRAS, and BRAF mutations were detected in 47.7%, 3.0%, 4.1%, and 7.4%, respectively, of patients who were tested for each of these aberrations. Lung metastases were more common in both the KRAS 12/13-mutated and atypical RAS-mutated cohorts relative to patients with RAS/BRAF wild-type tumors. Gene expression analyses revealed similar patterns regardless of the site of RAS mutation, and in silico functional algorithms predicted that KRAS and NRAS mutations in codons 12, 13, 61, and 146 alter the protein function and drive tumorgenesis., Conclusions: Clinicopathologic characteristics, survival outcomes, functional impact, and gene expression profiling were similar between patients with KRAS 12/13 and those with NRAS or KRAS 61/146-mutated mCRC. These clinical and bioinformatic findings support the notion that colorectal tumors driven by these RAS mutations are phenotypically similar., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC)., Patients and Methods: Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity., Results: Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred., Conclusion: The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group., Clinical Trial Number: NCT00499603., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Guidelines for the use of chemotherapy and endocrine therapy recently recommended that estrogen receptor (ER) status be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. In clinical practice, a range of thresholds are used; a common one is 10% positivity. Data addressing the optimal threshold with regard to the efficacy of endocrine therapy are lacking. In this study, we compared patient, tumor, treatment and survival differences among breast cancer patients using ER-positivity thresholds of 1% and 10%., Methods: The study population consisted of patients with primary breast carcinoma treated at our center from January 1990 to December 2011 and whose records included complete data on ER status. Patients were separated into three groups: ≥10% positive staining for ER (ER-positive ≥10%), 1%-9% positive staining for ER (ER-positive 1%-9%) and <1% positive staining (ER-negative)., Results: Of 9639 patients included, 80.5% had tumors that were ER-positive ≥10%, 2.6% had tumors that were ER-positive 1%-9% and 16.9% had tumors that were ER-negative. Patients with ER-positive 1%-9% tumors were younger with more advanced disease compared with patients with ER-positive ≥10% tumors. At a median follow-up of 5.1 years, patients with ER-positive 1%-9% tumors had worse survival rates than did patients with ER-positive ≥10% tumors, with and without adjustment for clinical stage and grade. Survival rates did not differ significantly between patients with ER-positive 1%-9% and ER-negative tumors., Conclusions: Patients with tumors that are ER-positive 1%-9% have clinical and pathologic characteristics different from those with tumors that are ER-positive ≥10%. Similar to patients with ER-negative tumors, those with ER-positive 1%-9% disease do not appear to benefit from endocrine therapy; further study of its clinical benefit in this group is warranted. Also, there is a need to better define which patients of this group belong to basal or luminal subtypes.

Background: In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy., Patients and Methods: Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample., Results: Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 × AKT + 0.2501 × IGFBP2 - 0.6745 × LKB1+1.0692 × S6 + 1.4086 × stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001)., Conclusions: We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease.

Background: We sought to determine the prognostic value of pathologic response to neoadjuvant chemotherapy with concurrent trastuzumab., Patients and Methods: Two hundred and twenty-nine women with HER2/neu (HER2)-overexpressing breast cancer were treated with neoadjuvant chemotherapy plus trastuzumab between 2001 and 2008. Patients were grouped based on pathologic complete response (pCR, n = 114) or less than pCR (

Background: The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes., Methods: Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results., Results: Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets., Conclusions: We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.

Background: The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established., Patients and Methods: MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes., Results: Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS., Conclusions: MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Aim: This article evaluates the risk of recurrence for patients who have small node-negative breast cancer by age and tumor subtype., Methods: One thousand twelve patients with a T1a,bN0 breast cancer diagnosed between 1990 and 2002 who did not receive chemotherapy or trastuzumab were included. Patients and tumor characteristics were compared using the χ(2) or Wilcoxon's rank sum tests. Survival outcomes were estimated with the Kaplan-Meier method and compared using the log-rank statistic. Cox proportional hazards models were used to determine association of breast cancer subtypes and age at diagnosis with other covariates., Results: Median age was 51.5 years. There were 771 hormone receptor (HR)-positive, 98 HER2-positive, and 143 triple-negative breast cancers (TNBC). Six hundred ninety-three patients were > 50 years, and 33 patients were ≤ 35 years. For 5-year survival estimates, there were 118 deaths and overall survival was 94.6% (95% confidence interval [CI] = 93.2%, 96.1%). After adjusting for breast cancer subtype and other tumor characteristics, patients ≤ 35 had 2.51 (95% CI = 1.21-5.22) times greater risk of worse recurrence-free survival (RFS), and 2.60 (95% CI = 1.05-6.46) times greater risk of worse distant RFS (DRFS) compared to patients > 50 years old. Compared to patients with HR-positive disease, patients with HER2-positive breast cancer had 4.98 (95% CI = 2.91-8.53) times the risk of worse RFS and 4.70 (95% CI = 2.51-8.79) times greater risk of worse DRFS, and patients with TNBC had 2.71 (95% CI = 1.59-4.59) times greater risk of worse RFS and 2.08 (95% CI = 1.04-4.17) times greater risk of worse DRFS., Conclusions: In this cohort, patients with T1a,bN0 breast cancer, young age and breast cancer subtype were significantly associated with RFS and DRFS., (Copyright © 2011. Published by Elsevier Inc.)

Background: Previous studies suggested that sentinel lymph node (SLN) identification rates are lower in older breast cancer patients. This study was undertaken to compare identification rates in patients 70 years of age and older versus those younger than 70 years in a large cohort undergoing sentinel lymph node dissection (SLND)., Study Design: Patients undergoing SLND between August 1993 and December 2006 were identified and grouped by age. Clinicopathologic data and details regarding the procedure were reviewed., Results: Of the 3995 patients undergoing SLND, 3406 (85.3%) were under 70 years of age, and 589 (14.7%) were 70 years or older. Age was significantly associated with clinical stage (P = .001) and tumor grade (P < .0001). A greater proportion in the older group had clinical stage I disease (74.7% vs. 66.8%), and a lower proportion had grade 3 tumors (24.0% vs. 36.1%). There were no significant differences by age in the mapping method or site of injection. Overall SLN identification rate was 97.2% and did not differ significantly by age. The SLN was positive in 23.1% of younger patients and 18.2% of older patients (P = .01)., Conclusion: Sentinel lymph node dissection can be performed with high identification rates regardless of patient age. Breast cancer patients 70 years and older with clinically negative axillary lymph nodes should be offered SLND, as the presence of lymph node metastasis may alter adjuvant therapy recommendations.

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple cellular functions critical to tumor initiation, progression, and outcomes, including growth and proliferation, metabolism, motility, migration, invasion, angiogenesis, survival, and autophagy. Tight regulation of this pathway is paramount to ensure that multiple cellular inputs are integrated for appropriate cellular outcomes. Frequent deregulation and aberrations of this pathway have been implicated in breast cancer development and progression. This review focuses on the biology of this pathway and its role in breast cancer pathogenesis. The role of therapies directed at targeting mTOR in the PI3K/Akt/mTOR pathway, which are currently being evaluated in clinical trials, will also be reviewed.

Background: We evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis., Methods: A total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters., Results: Discordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2-FISH scores was higher., Conclusions: Concordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.

Background: We investigated the expression of CXCR4, CCR7, estrogen receptor (ER), progesterone receptor (PR) and HER2-neu in human metastatic breast cancers to determine whether these biological biomarkers were preferentially expressed in any organ-specific metastases., Materials and Methods: CXCR4, CCR7, ER, PR and HER2-neu expression levels were evaluated by immunohistochemical staining using paraffin-embedded tissue sections of metastatic breast cancers (n = 41) obtained by either diagnostic biopsy or surgical resection., Results: The metastatic sites included the following: bone (n = 15), brain (n = 14), lung (n = 6), liver (n = 2), and omental metastases (n = 2). CXCR4 was expressed in 41% of cases, CCR7 expression was demonstrated in 10%, and HER2-neu overexpression was present in 27%. CXCR4 was more likely to be expressed in bone metastases than visceral metastases (67% versus 26%, P = 0.020). Visceral sites demonstrated a lower rate of CXCR4 positivity (33% and 23%, respectively, for lung and brain metastases). Similarly, CCR7 was more likely to be found in bone metastases than visceral sites (27% versus 0%, P = 0.037)., Conclusions: These results indicate that CXCR4 can contribute to the homing of breast cancer cells to the bone. This finding might have important clinical implications since patients with metastatic bone disease may achieve the highest benefit from a CXCR4-targeted therapy.