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Introduction: DESTINY-PanTumor02 (NCT04482309) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing [immunohistochemistry (IHC) 3+/2+] solid tumors across seven cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Subgroup analyses by HER2 status were previously reported by central HER2 IHC testing, determined at enrollment or confirmed retrospectively. Reflecting the testing methods available in clinical practice, most patients (n = 202; 75.7%) were enrolled based on local HER2 IHC testing. Here, we report outcomes by HER2 IHC status as determined by the local or central test results used for study enrollment., Methods: This phase 2, open-label study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥ 1 systemic treatment or without alternative treatments. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival., Results: In total, 111 (41.6%) and 151 (56.6%) patients were enrolled with IHC 3+ and IHC 2+ tumors, respectively. In patients with IHC 3+ tumors, investigator-assessed confirmed ORR was 51.4% [95% confidence interval (CI) 41.7, 61.0], and median DOR was 14.2 months (95% CI 10.3, 23.6). In patients with IHC 2+ tumors, investigator-assessed ORR was 26.5% (95% CI 19.6, 34.3), and median DOR was 9.8 months (95% CI 4.5, 12.6). Safety was consistent with the known profile of T-DXd., Conclusion: In line with previously reported results, T-DXd demonstrated clinically meaningful benefit in patients with HER2-expressing tumors, with the greatest benefit in patients with IHC 3+ tumors. These data support the antitumor activity of T-DXd in HER2-expressing solid tumors, irrespective of whether patients are identified by local or central HER2 IHC testing., (© 2024. The Author(s).)

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.)

Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1-4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors., (© 2024. The Author(s).)

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications., Experimental Design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model., Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and lower grades (grade 1/2, 43.2% vs. 8.1%, all P < 0.0001). The highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n = 9/9), mesonephric-like ovarian (83.3%, n = 5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival [hazard ratio (HR) = 1.3; P = 0.001]. Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN (28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS + MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy [8.4 years [(95% confidence interval (CI), 5.5-12.0) vs. 5.5 years (95% CI, 4.6-6.6); HR = 0.67; P = 0.031], this effect did not persist in multivariable analysis., Conclusions: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered., (©2024 American Association for Cancer Research.)

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories., (©2024 The Authors; Published by the American Association for Cancer Research.)

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker., Patients and Methods: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported., Results: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts., Conclusion: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Purpose: Targeted Agent and Profiling Utilization Registry (TAPUR) is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with soft tissue sarcoma with cyclin-dependent kinase 4 ( CDK4 ) amplification treated with palbociclib are reported., Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0 to 2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration (SD16+) according to RECIST v1.1. The DC rate was estimated with a 90% CI. Secondary end points included OR, progression-free survival (PFS), overall survival (OS), duration of response, duration of SD, and safety., Results: Forty-two patients with CDK4 amplification were enrolled. One patient was not evaluable for efficacy. One patient with partial response and 18 with SD16+ were observed for DC and OR rates of 46% (90% CI, 36 to 100) and 2% (95% CI, <1 to 13), respectively. Median PFS was 16 weeks (95% CI, 9 to 28) and median OS was 69 weeks (95% CI, 31 to 111) for evaluable patients. Twenty patients had at least one grade 3 to 4 adverse event (AE) at least possibly related to palbociclib, including alanine aminotransferase increase, anemia, fatigue, hypophosphatemia, leukopenia, neutropenia, and thrombocytopenia. No serious AEs were reported., Conclusion: Palbociclib met prespecified criteria to declare a signal of antitumor activity in patients with sarcoma and CDK4 amplification.

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.)

What Is This Summary About?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life., What Were the Results?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib., What Do the Results Mean?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene. Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

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.)

Background: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations., Methods: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting., Findings: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis., Interpretation: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting., Funding: AstraZeneca and Daiichi Sankyo., Competing Interests: Declaration of interests BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, and Lilly. He has received academic travel support from Amgen. He is an inventor on two institutional patents at MSK (US62/685,057 and US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. He is supported by the Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. FM-B reports institutional grants or contracts from Aileron, AstraZeneca, Bayer, Calithera, Curis, CytomX, Daiichi Sankyo, Debiopharm, eFFECTOR, Genentech, Guardant, KLUS, Novartis, Puma Biotechnology, Taiho, and Takeda; personal consulting fees from AbbVie, Aduro, Alkermes, AstraZeneca, Calibr (a division of Scripps Research), Daiichi Sankyo, Debiopharm, EcoR1 Capital, eFFECTOR, F Hoffmann-La Roche, GT Apeiron, Genentech, Harbinger Health, IBM Watson, Infinity, Jackson Laboratory, Kolon Life Science, LegoChem Biosciences, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer, Protai, Samsung Bioepis, Seattle Genetics, Tallac, Tyra Biosciences, Xencor, and Zymeworks; personal meeting or travel support from the Cholangiocarcinoma Foundation, the European Organisation for Research and Treatment of Cancer, and the European Society for Medical Oncology; and personal participation on a data safety monitoring board or advisory board for Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm, Loxo Oncology, Mersana, OnCusp, Puma Biotechnology, Seattle Genetics, Sanofi, Silverback, Spectrum, Theratechnologies, and Zentalis. AB reports grants or contracts from AstraZeneca/Daiichi Sankyo, Eli Lilly, Genentech/Roche, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius/Menarini, and Sanofi; consulting fees from BioTheranostics, Daiichi Sankyo/AstraZeneca, Foundation Medicine, Genentech/Roche, Immunomedics/Gilead, Innocrin Pharma, Merck, Novartis, Pfizer, Philips, Puma Biotechnology, Radius Health, Radius/Menarini, Sanofi, and Spectrum Pharmaceuticals; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo/AstraZeneca, Genentech, Eli Lilly, Immunomedics/Gilead, Merck, Novartis, Pfizer, Radius Health, and Sanofi; personal participation on a data safety monitoring board or advisory board for AstraZeneca, Daiichi Sankyo, Eisai, Genentech, Gilead, Lilly, Menarini, Merck, Mersana, Novartis, Pfizer, and Sanofi; other personal financial or non-financial interests for AstraZeneca, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Mersana, Novartis, Pfizer, and Sanofi. YN reports institutional grants or contracts from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Ono, Pfizer, and Taiho; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Guardant, MSD, Nihon Kayaku, Novartis, Ono, PDR Pharma, Pfizer, Taiho, and Takeda. SS reports personal participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, GlaxoSmithKline, MSD, Novartis, Seagen, and T-One Therapeutics. PA reports institutional grants or contracts from Roche; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Amgen and Synthon; support for attending meetings and/or travel from Amgen, Daiichi Sankyo, MSD, Pfizer, and Roche; personal participation on a data safety monitoring board or advisory board for Amcure, Boehringer Ingelheim, Deloitte, Eisai, G1 Therapeutics, Gilead, Lilly, MacroGenics, Menarini, Novartis, Radius, Roche, and Servier. GC reports grants or contracts from Merck; consulting fees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ellipsis, Gilead, Lilly, Menarini, Merck, Novartis, Pfizer, Roche, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead, Lilly, Novartis, Pfizer, and Relay; support for attending meetings or travel from Daiichi Sankyo. MdM reports institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and MSD; and other personal financial or non-financial interests for AbbVie, Achilles, Amunix, Arcus, BioNTech, Catalym, Dizal, Furmo, Genentech, Janssen, Loxo, MSD, Novartis, Numab, PharmaMar, Replimune, Roche, and Seagen. MK reports stock or stock options from Athenex, CRISPR, Eli Lilly, Natera, and Pfizer. D-YO reports personal grants or contracts from Array, AstraZeneca, Basilea, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier; and participation on a data safety monitoring board or advisory board for Arcus, ASLAN, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, MSD, Novartis, Taiho, Turning Point, Yuhan, and Zymeworks. MK's current affiliation is Breast Medical Oncology, LifeBridge Health, Baltimore, MD, USA. JOP reports personal grants or contracts from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier; personal support for attending meetings and/or travel from Minneamrita; personal participation on a data safety monitoring board or advisory board for Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), ImmuneOncia, MediRama, MedPacto Merck, Merck Sereno, MedPacto, and Servier. SP-V reports institutional grants or contracts from AstraZeneca and IMCore Hoffman LaRoche; institutional participation on data safety monitoring board or advisory board for Amgen and Daiichi Sankyo; and other personal financial or non-financial interests for Amgen, AstraZeneca, Bristol Myers Squibb, Clovis, GlaxoSmithKline, Novartis, Oxford Biotherapeutics, PEP Therapy, and Roche. SYR reports institutional grants or contracts from ABL Bio, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bold Therapeutics, Daiichi Sankyo, Eisai, Ipsen, Leap Therapeutics, MacroGenics, MedPacto, Merck KGaA, MSD, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical, and Zymeworks; consulting fees from Individumed and LG Biochem; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Daiichi Sankyo, Eisai, Lilly, and MSD; and participation on a data safety monitoring board or advisory board for Amgen. TS reports personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Biopharm, Ono Pharmaceutical, Taiho, Takara Bio, Takeda, and Yakult Honsha; institutional payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events for Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Gilead, HUTCHMED, Merck Biopharm, Ono Pharmaceutical, Parexel, Taiho, and Yakult Honsha; and personal participation on a data safety monitoring board or advisory board for Takara Bio. IS reports institutional grants or contracts from AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; support for attending meetings or travel from AstraZeneca, Incyte, and Merck/Pfizer; and other financial or non-financial interests for AstraZeneca, Genentech, Incyte, MSD, Orion, Pfizer, Puma Biotechnology, and Roche. FM reports other personal financial or non-financial interests for AstraZeneca. AS reports personal stock or stock options for AstraZeneca and other financial or non-financial interests for AstraZeneca. KKM reports other personal financial or non-financial interests for AstraZeneca. CS reports personal participation in advisory boards or travel grants from AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F Hoffmann-La Roche Ltd, Gilead, Lilly, MediTech, MSD, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma Biotechnology, SeaGen, Synthon Biopharmaceutical, and Zymeworks. IA declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)