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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET -mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET -mutant MTC and RET fusion-positive TC.

Anti-angiogenic agents elicit considerable immune modulatory effects within the tumor microenvironment, underscoring the rationale for synergistic clinical development of VEGF and immune checkpoint inhibitors in advanced gastric cancer (AGC). Early phase studies involving Asian patients demonstrated encouraging anti-tumor efficacies. We report the results of the REGOMUNE phase II study, in which Caucasian patients were administered regorafenib, a multi-tyrosine kinase inhibitor, in combination with avelumab, a PD-L1-targeting monoclonal antibody. This therapeutic regimen resulted in deep and durable responses in 19% of patients, with the median duration of response not yet reached. Notwithstanding, a significant proportion of AGC patients exhibited no therapeutic advantage, prompting investigations into mechanisms of inherent resistance. Comprehensive biomarker profiling elucidated that non-responders predominantly exhibited an augmented presence of M2 macrophages within the tumor microenvironment and a marked overexpression of S100A10 by neoplastic cells, a protein previously implicated in macrophage chemotaxis. Additionally, peripheral biomarker assessments identified elevated levels of cytokines, including CSF-1, IL-4, IL-8, and TWEAK, correlating with adverse clinical outcomes, thereby accentuating the role of macrophage infiltration in mediating resistance. These insights furnish an invaluable foundation for elucidating, and potentially circumventing, resistance mechanisms in current AGC therapeutic paradigms, emphasizing the integral role of tumor microenvironmental dynamics and immune modulation., (© 2024. The Author(s).)

Background: Current systemic therapies for metastatic pancreatic ductal adenocarcinoma are associated with poor outcomes with a 5-year overall survival rate under 5%. We aimed to assess the safety and antitumour activity of mitazalimab, a human CD40 agonistic IgG1 antibody, with modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, oxaliplatin, and irinotecan), in chemotherapy-naive patients with metastatic pancreatic ductal adenocarcinoma., Methods: OPTIMIZE-1 was a single-arm, multicentre, phase 1b/2 study which enrolled adults with histologically-confirmed metastatic pancreatic ductal adenocarcinoma and European Cooperative Oncology Group performance status 0 or 1 in 14 university hospitals in Belgium, France, and Spain. The primary endpoint of phase 1b was to determine the recommended phase 2 dose of intravenous mitazalimab (450 μg/kg or 900 μg/kg) when combined with intravenous mFOLFIRINOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 150 mg/m 2 , fluorouracil 2400 mg/m 2 ). In the first 21-day treatment cycle, mitazalimab was administered on days 1 and 10, and mFOLFIRINOX on day 8. In subsequent 14-day cycles mitazalimab was administered 2 days after mFOLFIRINOX. The phase 2 primary endpoint was objective response rate. Activity and safety analyses were conducted on the full analysis set (all patients who received the combination of mitazalimab at the recommended phase 2 dose and mFOLFIRINOX for at least two treatment cycles) and safety set (all patients who received any study treatment), respectively. Enrolment is complete, and data represents a primary analysis of the ongoing trial. The trial is registered at Clinicaltrials.gov (NCT04888312)., Findings: Between Sept 29, 2021, and March 28, 2023, 88 patients were screened and 70 patients were enrolled (40 [57%] were female and 30 [43%] were male). In phase 1b, 900 μg/kg mitazalimab was determined as the recommended phase 2 dose. Overall, five patients received 450 μg/kg mitazalimab; 65 received 900 μg/kg mitazalimab. No dose-limiting toxicities were observed at 450 μg/kg, and one dose-limiting toxicity was observed at 900 μg/kg. 57 patients were evaluated for activity, and all 70 patients were included in the safety set. At data cutoff on Nov 14, 2023, median follow-up was 12·7 months (95% CI 11·1-15·7). Of the 57 patients, 29 (51%) remained on study and 18 (32%) remained on treatment. The primary endpoint (objective response rate >30%) was met (objective response rates in 23 [40%]; one-sided 90% CI ≥32 of 57 patients). The most common grade 3 or worse adverse events were neutropenia (18 [26%] of 70 patients), hypokalaemia (11 patients [16%]), and anaemia and thrombocytopenia (eight patients [11%]). Serious adverse events were reported in 29 (41%) of 70 patients, the most common being vomiting (five [7%] of 70 patients), decreased appetite (four [6%]), and diarrhoea and cholangitis (three [4%] of 70 patients for each), none considered related to mitazalimab. No treatment-related deaths were reported., Interpretation: Mitazalimab with mFOLFIRINOX demonstrated manageable safety and encouraging activity, warranting continued development in a phase 3, randomised, controlled trial. The results from OPTIMIZE-1 pave the way for further exploration and confirmation of a novel immunotherapy treatment regimen for metastatic pancreatic ductal adenocarcinoma, which is a complex and aggressive cancer with very low survival rates and restricted treatment options., Funding: Alligator Bioscience., Competing Interests: Declarations of interests J-LVL, IB, HP, AL, EM, JFeB, LP, JFB, IG, and MRG declare no competing interests. KPG has received honoraria from Ipsen, Servier, Merck, Bristol Myers Squibb (BMS), Serb, and Nordic Pharma; support for attending meetings or travel from Ipsen, and Servier, and MSD; has participated on a data safety monitoring board or advisory board for Servier, BMS, MSD, and AstraZeneca; and is Vice President for Belgian Group of Digestive Oncology. PAC has received honoraria from BMS, Boehringer Ingelheim, Brenus Pharma, Scenic Biotech; research funding to institution from AbbVie, Adlai Nortye, Alligator, Amgen, Astex, AstraZeneca, Boehringer Ingelheim, Bleuprint, C4 Therapeutics, Dragonly, Daiichi Sankyo, Exelixis, GSK, Incyte, Iteos, Janssen, Kinnate, Kazia, Lilly/Loxo, Merus, Molecular Partners, MSD, Novartis, OSE Immunotherapeutics, Pierre Fabre, Relay, Roche/Genentech, Sotio, Taiho, Tango, Toray, Turning Point/BMS, and Transgene. RAP-C received support from Alligator Bioscience for the present manuscript and reports consulting fees from Roche, BMS/Celgene, Eisai Europe, AstraZeneca Spain, Astellas Pharma, Servier, and Ipsen; payments for honoraria from BMS, Servier, AstraZeneca Spain, Astellas Pharma; payment for expert testimony from Servier; support for attending meetings or travel from Lilly, Roche, BMS; participation on data safety monitoring board or advisory board from Roche, BMS/Celgene, AstraZeneca Spain, and Servier. KES, PE, SVA, and YPdC are all employees of and have stock or stock options in Alligator Bioscience. PE is an inventor on the patents relating to mitazalimab, and KES is a co-author of patents for mitazalimab (patents owned by Alligator Bioscience). TM reports grants or contracts from MSD, Novocure, QED Therapeutics, Roche Farma, Sanofi-Aventis, Servier, Zymeworks, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios Pharmaceuticals, Amgen, Aslan Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica International, Bayer, BeiGene, BioKeralty Research Institute, BioLineRx, Blueprint Medicines, Boston Biomedical, BMS, Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-La Roche, FibroGen, Halozyme, Incyte, Ipsen Bioscience, Ipsen Pharma, Lilly, Loxo Oncology, MedImmune, Merck Sharp & Dohme, Nelum, Novartis, Novocure, OncoMed Pharmaceuticals, QED Therapeutics, VCN Biosciences, and Zymeworks; consulting fees from Ability Pharmaceuticals, Arcus Bioscience, AstraZeneca, Basilea Pharma, Baxter, BioLineRX, Celgene, Eisai, Incyte, Ipsen Bioscience; payment for honoraria from Janssen, Lilly, Esteve, Daïchi, Biontech, Novartis, Jazz Pharmaceuticals; payment for attending meetings or travel from Servier, AstraZeneca, Sanofi, Incyte, Lilly, MSD, and Roche; participation on a data safety monitoring board or advisory board for Ability Pharmaceuticals, Arcus Bioscience, AstraZeneca, Basilea Pharma, Baxter, BioLineRX, Celgene, Eisai, Incyte, and Ipsen Bioscience., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort., Methods: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock., Conclusions: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. 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).

The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies., (© 2024 Lalle et al.)

Purpose: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells., Patients and Methods: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy., Results: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%)., Conclusions: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low., (©2024 American Association for Cancer Research.)

Purpose: The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT., Methods: Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model., Results: Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence)., Conclusions: The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Early-phase clinical trials (EPCT) represent an important part of innovations in medical oncology and a valuable therapeutic option for patients with metastatic cancers, particularly in the era of precision medicine. Nevertheless, adult patients' participation in oncology clinical trials is low, ranging from 2% to 8% worldwide, with unequal access, and up to 40% risk of early discontinuation in EPCT, mostly due to cancer-related complications., Design: We review the tools and initiatives to increase patients' orientation and access to early phase cancer clinical trials, and to limit early discontinuation., Results: New approaches to optimize the early-phase clinical trial referring process in oncology include automatic trial matching, tools to facilitate the estimation of patients' prognostic and/or to better predict patients' eligibility to clinical trials. Classical and innovative approaches should be associated to double patient recruitment, improve clinical trial enrollment experience and reduce early discontinuation rates., Conclusions: Whereas EPCT are essential for patients to access the latest medical innovations in oncology, offering the appropriate trial when it is relevant for patients should increase by organizational and technological innovations. The oncologic community will need to closely monitor their performance, portability and simplicity for implementation in daily clinical practice., Competing Interests: Declaration of Competing Interest LV: reports personal fees from Adaptherapy, is CEO of RESOLVED, has received non-personal fees from Pierre-Fabre and Servier, and a grant from Bristol-Myers Squibb, all outside the submitted work. AB is the CEO and co-founder of Klinéo. PAC received consulting/honoraria by Boehringer Ingelheim Ose Immunotherapeutics, Bristol Meyer Squibb. As Principal-Investigator in the Phase 1 unit at CLB of Clinical Trials the relations are: AV with Astra Zeneca, BIONTECH RNA, EXSCIENTA LTD, Exelixis, Hoffmann La Roche Ag, IPSEN, Janssen Cilag, Kinnate Biopharma, Lilly France, Loxo Oncology, Novartis, TAKEDA. LV with Genmab, Bicycle Therapeutics, Revolution Medicine, Daiichi, Astra Zeneca, Hoffmann La Roche. PAC with Abbvie, Adlai Nortye, Alligator, Amgen, Boehringer Ingelheim, Blueprint, Bristol Meyer Squibb, Debio, Dragonfly, Exelixis, Incyte, Iteos, Janssen, Kinnate, Kazia, Lilly/Loxo, Merck Sharp Dohme, Molecular Partners, Novartis, Ose immunotherapeutics, Pierre Fabre, Relay, Roche/Genentech, Sotio, Taiho, Tango, Toray, Turning Point, Transgene. As part of the Drug Development Department (DITEP) at Gustave Roussy CB, KO, and AB declare being/having: Principal/sub-Investigator of Clinical Trials for Abbvie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astra Zeneca Ab, Astra Zeneca, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Cato Research, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, EverImmune, Exelixis, Faron Pharmaceuticals Ltd, Foghorn Therapeutics Inc, Forma Tharapeutics, Gamamabs, Genentech, Genmab, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, IGM Biosciences, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D LLC, K-Group Beta, Kinnate Biopharma, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Nuvalent, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Phio Pharmaceuticals Corp, Pierre Fabre Medicament, Pyramid Bioscience, Regeneron Pharmaceuticals, Relay Therapeutics, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor. Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Celsius, EIT Philips, GSK, INCA, IDERA, Janssen, Lombard, Merck, MedImmune, Pierre Fabre, Roche, Sanofi, Servier. Non-financial support (drug supplied) from Astrazeneca, BMS, Boringher Ingelheim, GSK, Idera, Medimmune, Merck, NH Theraguix, Roche. All other authors don’t declare any conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

CD8 + T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8 + T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8 + T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8 + T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8 + T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8 + T cells, RelA is dispensable for their protective activity in pathological contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Voisin, Plaschka, Perrin-Niquet, Twardowski, Boutemine, Eluard, Lalle, Stéphan, Bouherrou, Tonon, Pommier, Ferrari, Klein, Wencker, Baud, Cassier and Grinberg-Bleyer.)

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14 low CD16 high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L- but not GM-CSF-dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

Background: Rearranged during transfection ( RET ) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET -altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET -mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET -mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET -mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET -mutant MTC and prior C/V, 62 treatment-naïve patients with RET -mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET -mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET -mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET -mutant MTC and prior C/V, not reached in treatment-naïve patients with RET -mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET -altered thyroid cancer safety population ( N  = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET- altered thyroid cancer. Clinical Trial Registration: NCT03037385.

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade., Competing Interests: CCL reports consulting fees from AbbVie, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi-Sankyo, Merck KGaA, Novartis, PharmaEngine; payment or honoraria from Eli Lilly, Novartis, and Roche; and support for attending meetings or travel from BeiGene, Daiichi-Sankyo, and Eli Lilly. EG reports grants or contracts from Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, and BeiGene; payment or honoraria from Roche, Genentech, F. Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, Alkermes, Thermo Fisher, BMS, MabDicovery, Anaveon, F-Star Therapeutics, Hengrui; participated on data safety monitoring board or advisory board for Roche, Genentech, Boehringer Ingelheim, Janssen Global Services, Thermo Fisher, Anaveon, MabDiscovery, Novartis and Lilly; and serves as PI or Co-PI for Affimed Gmbh. Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, Cytomx, F. Hoffmann-La Roche Ltd, F-Star Beta Limited, Genentech Inc, Genmab B.V, Hutchison Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Janssen-Cilag SA, Medimmune Llc, Merck KGaA, Novartis Farmacéutica SA, Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc, Symphogen A/S, Taiho Pharma Usa Inc PS reports grants or contracts from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA therapeutics; honoraria from Blueprint Medicines; and consulting fees from Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ biotechnology, CRT Pioneer Fund LP, Adcendo, PharmaMar, Merck Healthcare KGaA, Ysios Capital. DSH reports grants or contracts from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology; travel, accommodation, expenses from Bayer, Genmab, and Telperian; consulting fee from Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Atheneum, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm; and other ownership interests for OncoResponse (founder) and Telperian Inc (advisor). LLS reports stock ownership or equity in Agios (spouse); leadership in Treadwell Therapeutics (spouse is co-founder); and consulting fee/advisory board for Merck, Pfizer, AstraZeneca, Roche, Symphogen, GSK, Voronoi, Treadwell Therapeutics, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi-Sankyo, Coherus, Amgen, and Marengo; grant/research support (clinical trials for institution) for Novartis, BMS, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, and Avid. MigM reports honoraria from SeaGen, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, Roche; consulting fees from Roche, Novartis, AstraZeneca, Daiichi-Sankyo, SeaGen, Lilly, Sanofi; advisory board of Novartis and holds leadership roles in GEICAM (Board of Directors), TRIO. RH reports grants and contacts for clinical trials for institution from AstraZeneca, BMS, Corvus, Eli Lilly, MSD, Novartis, Olema, Oncosec, Roche, SeaGen; honoraria from AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, Roche; participates in advisory board of AstraZeneca, BMS, Eisai, Eli Lilly, Merck, MSD, Novartis, OncoSec, Pfizer, Roche, SeaGen. RAS reports grants from AstraZeneca and Boehringer Ingelheim, and personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Amgen, Bayer, Puma. TZ reports grants from Genentech Roche, OmniSeq, SeaGen, PGDx, Janssen, AstraZeneca, Pfizer, AbbVie/StemcentrX, Merck, Regeneron, Mirati Therapeutics, Novartis, Merrimack; consulting fees from Genentech Roche, Eli Lilly, Bayer, QED Therapeutics, Eisai, Calithera, Aveo Pharmaceuticals, Amgen, BMS, Dendreaon, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Merck, Exelixis; honoraria from MJH Associates, Aptitude Health, PlatformQ, Integrity CE, Vaniam Group, PeerView, and Novartis; travel support from SUO, Kidney Cancer Association, and KCCure; and leadership role in NCI GU Steering Renal Task force, KCA Medical Steering committee, and KCCure Scientific advisory board. BM reports grant from Health and Medical Research Fund, Merck Serono, Boehringer Ingelheim Inc; consulting fees from Viracta therapeutics and Y-Biologics; honoraria from MSD, Novartis, Merck, Y-Biologics, Springer, Elsevier, Daiichi, Taiho, and Pierra Fabre; holds leadership roles in ethics committee of NTEC-CUHK, ESMO Asia 2020 and ESMO 2022 (Track Chair – Paris, Singapore), ASCO 2020 (Session chair), and ESMO Asia 2019 (Co-Chair). CK reports research funding from BMS, Merus, and Gritstone Oncology. DT reports honoraria and consulting/advisory roles for Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda; consulting/advisory roles for Bayer, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and research funding for Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer, and Amgen. PAC reports research funding from AbbVie, Adlai Nortye, Alligator, Amgen, AstraZeneca, Blueprint Medicines, Boston, Bristol Myers Squibb, Celgene, Debio Pharm, Dragonfly, Exelixis, GlaxoSmithKline, Innate Pharma, Janssen, Eli Lilly, Loxo, Molecular Partners, MSD, Novartis, OSE Pharma, Relay, Roche/Genentech, Sotio, Taiho Pharmaceutical, Toray Industries, Transgene, and Turning Point Therapeutics; personal fees from AstraZeneca, Amgen, Merck Serono, Novartis, and Roche/Genentech; nonfinancial research support from AstraZeneca, Debio Pharm, MSD, Novartis, Plexxikon, and Roche/Genentech; and travel accommodation from BMS, MSD, and NETRIS Pharma. JS reports consulting/advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bayer, Eisai, Roche/Genentech, Pfizer, Immunocore, SeaGen, Novartis, Sun Pharma, EMD Serono, Amgen, Bristol-Myer Squib, Flugent Therapeutics, Exelixis, Merck, Takeda, and Array BioPharma. AW received research grants from Merck and BMS; consulting fees from Ipsen, Astella, BMS; and honoraria from Ipsen, Pfizer, BMS. RDC received research funding from Amgen, Astellis, AstraZeneca, BMS, Corvus, Ideaya, Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron, Roche/Genentech; consulting fees from Alkermes, BMS, Castle Biosciences, Eisai, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics, Trisalus; participated in data safety monitoring or advisory board of Aura Biosciences, Chimeron, and Rgenix; and stocks in Aura Biosciences, Chimeron, and Rgenix. TE reports grants for MSD, Novartis, Dainipon Sumitomo, Ono, Daiichi-Sankyo, Astellas, Astellas Amgen Biopharma, Parexel, Chugai, Quintiles, Syneos Health, Pfizer, IQVIA; and honoraria from MSD, Ono, Daiichi-Sankyo, Eli Lilly, Taiho, Chugai, and Sanofi. FR reports consulting fees from BMS and MSD; honoraria from Merck KGaA. FDB reports consulting fees from NMS Nerviano, Menarini, AstraZeneca, Incyte; honoraria from BMS, Merck Group, MDS, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte; travel support from Roche; and participated in advisory board of Pierre Fabre, AstraZeneca, MSD Serono, BMS, Roche, Sanofi, Novartis. LR is employee of Novartis. MicM, JC, JS, WA, BDB reports no conflicts of interest. TS, NRC, DG, EK and VA were employees of Novartis at the time of study conduct. EK and VA report stocks from Novartis., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Importance: Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors., Objective: To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors., Design, Setting, and Participants: The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022., Interventions: Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity., Main Outcomes and Measures: The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables., Results: Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months)., Conclusions and Relevance: In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC., Trial Registration: ClinicalTrials.gov Identifier: NCT02794571.

Purpose: To evaluate tipapkinogene sovacivec (TG4001), a viral immunotherapeutic vaccine expressing human papillomavirus (HPV)16 E6/E7 non-oncogenic proteins and IL-2, in combination with avelumab in HPV16+ cancer patients., Patients and Methods: In this open-label, phase Ib/II, multicenter study, HPV16+ advanced cancer patients received subcutaneous TG4001 at two dose levels (DL) in phase Ib and at the recommended phase II dose (RP2D) in phase II weekly for 6 weeks, then every 2 weeks (q2Wk) until 6 months, thereafter every 12 weeks, in combination with avelumab q2Wk starting from day 8. Exploratory end-points included immunomonitoring from sequential tumour and blood samples., Results: Forty-three patients, mainly heavily pretreated (88% ≥ 1 previous line), were included in the safety analysis, with a majority of anal cancer (44%). No dose-limiting toxicities were reported, and DL2 (5 × 10 7 Plaque forming units (PFU)) was selected as the RP2D. Treatment-related adverse events to TG4001 occurred in 93% of patients, mostly grade 1/2, with grade 3 anaemia in one patient and no grade 4/5. Overall response rate (ORR) was 22% (8/36) and 32% (8/25) in all and patients without liver metastases, respectively. Median progression-free survival (PFS) and Overall Survival (OS) were 2.8 months (95% CI: 1.4-5.6) and 11.0 months (95% CI:7.5-16.7) in the total population and 5.6 months (95% CI:1.6-9.6) and 13.3 months (95% CI:8.7-32.7) in patients without liver metastases. Antigen-specific T-cell response was identified in 7/11 patients by IFNγ ELISpot., Conclusions: TG4001 in combination with avelumab is safe, demonstrated antitumour activity in heavily pre-treated HPV16+ cancer patients, and is currently being evaluated in a randomised phase II trial in patients with incurable anogenital cancer and limited hepatic involvement., Gov Identifier: NCT03260023., Competing Interests: Declaration of Competing Interest EB received honoraria from Eisai, MSD, Sandoz, Amgen; Meetings/travel grants and non-financial support from Daiichi Sankyo, Eisai, Amgen, Sandoz, MSD, Bristol-Myers Squibb, Novartis, Pfizer, Roche; has consulted for Egle Tx. CLT participated in advisory boards from MSD, BMS, Merck, Astra Zeneca, Celgene, Seattle Genetics, Roche, Novartis, Rakuten, Nanobiotix, and GSK. JPD participated in advisory boards for MSD, Roche, Genentech, BMS, Novartis, Merck, Pierre Fabre, MHCom, all of them to the benefit of his Institution and received research grant from Genentech, MSD, BMS, Astra Zeneca, Transgene, Amgen, all of them to the benefit of his Institution. PC received honoraria from ITeos Therapeutics, Amgen, Janssen, participated in advisory boards for OSE Immunotherapeutics, and Travel/accommodations support from Netris Pharma, Amgen, Merck, Roche, MSD, AstraZeneca. EP is co-founder of Egle Tx and has consulted for Transgene. MB, AT, HM, KB are employees of Transgene. The other authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Netrin-1 is upregulated in cancers as a protumoural mechanism 1 . Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care 2 , we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments., (© 2023. The Author(s).)

Background: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes., Methods: The MOST-plus trial used a randomized discontinuation design. After 12 weeks of sorafenib (400 mg, po BID), patients with progressive disease discontinued study, patients with objective response were proposed to continue sorafenib, whereas patients with stable disease (SD) were randomly assigned (1:1) to the maintenance or interruption of treatment. The primary endpoint was RECIST version 1.1 progression-free rate at 16 weeks after randomization (PFR-16w). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analyses used a sequential Bayesian approach with interim efficacy analyses. The enrolment could be stopped in the case of a 95% probability for the estimated PFR-16w to be higher in the maintenance than in the interruption arm (NCT02029001)., Results: 151 patients were included, of whom 35 had SD at 12 weeks of Sorafenib. For the 35 patients with SD on sorafenib, the PFR-16w was 65% [95% credibility interval 43.4-83.7] in the continuation arm and 25% [7.8-48.1] in the interruption arm. Median PFS and OS were improved in the maintenance versus the interruption arm (mPFS: 5.6 [95%CI 1.97-6.77] months versus 2.0 [95%CI 1.61-3.91] months ( p = 0.0231) and mOS: 14.3 [95%CI 8.9-23.8] versus 8.0 months [95%CI 3.5-15.2] ( p = 0.0857))., Conclusion: Sorafenib showed activity in progressive patients with solid tumors harboring somatic genomic alterations in sorafenib-targeted genes. Continuing sorafenib when SD is achieved improves PFR compared to interruption.

Background: Alterations in fibroblast growth factor receptor 2 ( FGFR2 ) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR -altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors., Methods: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes., Results: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment., Conclusions: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects., Methods: I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics., Results: Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2)., Conclusion: This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors., Clinicaltrials: gov Identification Number: NCT02784795., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET-altered solid tumors. Twenty-nine patients with 12 different RET fusion-positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35-77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib's potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion-positive solid tumors., (© 2022. The Author(s).)

Objective: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients., Methods: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response., Results: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR., Conclusions: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting., (Copyright © 2022. Published by Elsevier Inc.)

Background: In the KEYNOTE-158 study (NCT02628067), pembrolizumab showed a high objective response rate and durable clinical benefit for patients with previously treated, unresectable/metastatic microsatellite instability-high (MSI-H)/mismatch repair‒deficient (dMMR) non-colorectal solid tumours. We present health-related quality of life (HRQoL) results from the MSI-H/dMMR population (cohort K)., Patients and Methods: Eligible patients had previously treated MSI-H/dMMR advanced non-colorectal solid tumours, measurable disease per RECIST v1.1, and ECOG performance status ≤1. Patients received pembrolizumab 200 mg Q3W for 35 cycles (2 years). The EORTC Quality of Life Questionnaire (QLQ-C30) and EQ-5D-3L were administered at baseline, at regular intervals throughout treatment, and 30 days after treatment discontinuation. Prespecified analyses (exploratory endpoints) included the magnitude of change from baseline to post-baseline timepoints in all patients and by the best overall response for QLQ-C30 global health status (GHS)/QoL, QLQ-C30 functional/symptom scales/items, and EQ-5D-3L visual analogue scale (VAS) score., Results: At data cutoff (October 5, 2020), 351 patients were enrolled, of whom 311 and 315 completed baseline QLQ-C30 and EQ-5D-3L questionnaires, respectively. QLQ-C30 GHS/QoL scores improved from baseline to week 9 (mean [95% CI] change, 3.07 [0.19-5.94]), then remained stable or improved by week 111, with greater improvements observed in patients with a best response of complete response (CR) or partial response (PR) (10.85 [6.36-15.35]). Patients with CR/PR showed improvements in physical (5.58 [1.91-9.25]), role (9.88 [3.80-15.97]), emotional (5.62 [1.56-9.68]), and social (8.33 [2.70-13.97]) functioning, and stable cognitive functioning (1.74 [-1.45 to 4.94])., Conclusions: Pembrolizumab generally improved or preserved HRQoL in patients with previously treated MSI-H/dMMR advanced non-colorectal solid tumours., Competing Interests: Conflict of Interest Statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests. Michele Maio: study funding to the institution from Merck Sharp & Dohme LLC, and Merck & Co., Inc., Rahway, NJ, USA, to support study conduct; honoraria for serving as a speaker from MSD, Roche, Bristol Myers Squibb (BMS), Sanofi, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GlaxoSmithKline (GSK), Sciclone, Alfasigma, and Merck Serono; personal fees for advisory boards from Merck Sharp & Dohme LLC, Roche, BMS, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, Sanofi, GSK, Alfasigma, and Merck Serono; stockholder in Epigen Therapeutics and Theravance. Mayur M. Amonkar: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Owns stock in Merck & Co., Inc., Rahway, NJ, USA. Josephine M. Norquist: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Owns stock in Merck & Co., Inc., Rahway, NJ, USA. Paolo A. Ascierto: research funding from Bristol Myers Squibb, Roche-Genentech, Array, and Sanofi; personal fees for advisory/consultant role for Bristol Myers Squibb, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Nektar, Italfarmaco, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, and Seagen; personal fees for travel support from MSD; unpaid consultant for Takis. Ludmila Manzyuk: nothing to disclose. Daniel Motola-Kuba: research funding from Roche/Genentech, Novartis, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Eli Lilly, AstraZeneca, and MSD. Nicolas Penel: study funding to the institution from MSD to support study conduct; research funding to the institution from Bayer-HealthCare. Philippe A. Cassier: research funding from Roche/Genentech, Novartis, Amgen, Bristol Myers Squibb, Blueprint Medicines, GlaxoSmithKline, Janssen, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, Celgene, AbbVie, Toray Industries, Transgene, Innate Pharma, and Loxo; personal fees from Roche/Genentech, Novartis, Amgen, Merck Serono, and AstraZeneca; nonfinancial support from Roche/Genentech, Novartis, AstraZeneca, MSD, and Plexxikon; travel accommodations from NETRIS Pharma. Giovanni Mendonca Bariani: research funding from mAbxience, MSD, and Bristol Myers Squibb; advisory role for Libbs. Ana De Jesus Acosta: research funding from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA; consulting for Merck & Co., Inc., Rahway, NJ, USA. Toshihiko Doi: honoraria from AbbVie, Astellas Pharma, Bristol Myers Squibb Japan, Oncolys BioPharma, Ono Pharmaceutical, and Taiho Pharmaceutical; consulting or advisory role for AbbVie, Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Otsuka, Rakuten Medical, Sumitomo Dainippon, Taiho Pharmaceutical, and Takeda; research funding to the institution from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Lilly Japan, Merck Serono, MSD, Novartis, Pfizer, Quintiles, Sumitomo Group, and Taiho Pharmaceutical. Federico Longo: honoraria from Amgen, Bayer, Bristol Myers Squibb, Celgene, Ferrer, Lilly, Merck, MSD, Roche, Sanofi, and SERVIER; consulting or advisory role for Amgen, Bayer, Bristol Myers Squibb, Lilly, MSD, Roche, and SERVIER; travel expenses from Amgen, Bayer, Bristol Myers Squibb, Celgene, Ferrer, Lilly, Merck, MSD, Roche, Sanofi, and SERVIER. Wilson H. Miller, Jr.: consulting role for Bristol Myers Squibb, Merck & Co., Inc., Rahway, NJ, USA, Roche, Novartis, Amgen, GSK, Mylan, and EMD Serono; honoraria from BMS, Merck, Roche, GSK, Novartis, Amgen, Mylan, and EMD Serono; grants to the institution from Merck, CIHR, CRS, Terry Fox Research Institute, Samuel Waxman Cancer Research Foundation, and CCSRI; current or past (within the prior two years) investigator in clinical trials for BMS, Novartis, GSK, Roche, AstraZeneca, Methylgene, MedImmune, Bayer, Amgen Merck, Incyte, Pfizer, Sanofi, Array, MiMic, Ocellaris Pharma, Astellas, and Alkermes. Do-Youn Oh: consultant or advisory board member for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, and Turning Point; research grant from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok. Maya Gottfried: nothing to disclose. Ruixue Wang: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Owns stock in Merck & Co., Inc., Rahway, NJ, USA. Kevin Norwood: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Owns stock in Merck & Co., Inc., Rahway, NJ, USA. Aurelien Marabelle: funding to institution during the conduct of the study from MSD; honorarium from MSD and Sanofi; research grants from Foundation MSD Avenir, Sanofi, and Bristol Myers Squibb; personal fees for speakers bureau from Bristol Myers Squibb, Sanofi, and MSD., (Copyright © 2022 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study., Methods: Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067., Findings: Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5-36·4). 12 (11%, 95% CI 6-18) patients had an objective response, including 11 (15%, 8-25) of 75 patients with PD-L1-positive tumours and one (3%; 0-17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3-4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths., Interpretation: Pembrolizumab monotherapy is a possible treatment option with a favourable benefit-risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests AM received institutional research funding from Merck Sharp & Dohme (MSD); a grant from Fondation MSD Avenir outside the topic of the manuscript; and honoraria and travel expenses for participation in a scientific advisory board from MSD outside the topic of the submitted work. PAC received financial support (paid to their institution) for conduct of clinical study from MSD, AbbVie, Amgen, Bayer, Bristol Myers Squibb, Merck Serono, Novartis, Roche/Genentech, GlaxoSmithKline, Janssen, Lilly, AstraZeneca, Celgene, Taiho, Toray, Transgene, Loxo, and Innate Pharma; grants from MSD and Novartis; personal fees from Blueprint (for advisory board), Amgen, Merck Serono, Novartis, and Roche/Genentech; non-financial support from MSD, Novartis, AstraZeneca, and Plexxikon; and travel and accommodations from MSD, Novartis, Roche/Genentech, and Netris Pharma. MF received honoraria from Amgen; personal fees for an advisory role for Amgen, Array BioPharma, Bayer, and BGB Group/GlaxoSmithKline; personal fees for speaker bureau participation for Amgen and Guardant360; and personal fees for consulting for Pfizer, Bayer, Taiho Oncology, Seattle Genetics, Zhuhai Biotech, and Incyte. SK received research funding (paid to their institution) from MSD; personal fees (paid to their institution) from Bristol Myers Squibb, Pfizer, Roche, AstraZeneca, Takeda, Boehringer Ingelheim, and Specialised Therapeutics; and grants to institution from AstraZeneca. AI reports grants from MSD, Merck, Bayer, Roche, AstraZeneca, and Bristol Myers Squibb; personal fees from Bayer, Roche, and Springworks; and non-financial support from Seven and Eight. MGJV received institutional research funding from MSD. GMB received research funding from mAbxience, MSD, and Bristol Myers Squibb. PAA received research funding from Bristol Myers Squibb, Roche-Genentech, Array, and Sanofi; received personal fees for advisory and consultancy roles for Bristol Myers Squibb, Roche-Genentech, MSD, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Nektar, Italfarmaco, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, and Seagen; received personal fees for travel support from MSD; and served as an unpaid consultant for Takis. AS is on the advisory board for Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD; does consultancy for Arqule and Sanofi; and is on the speaker's bureau for Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD. MS received research grants from MSD and Eli Lilly. ST received grants from MSD, Eisai, Novartis, Taiho, AstraZeneca, Chugai, Bayer, and Daiichi-Sankyo; and personal fees from Eisai, Novartis, Taiho, Chugai, Bayer, and Daiichi-Sankyo. SAP-P received clinical trial research support (paid to their institution) from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Bristol Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical, Curis, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Therapeutics, Gene Quantum, Genmab, GlaxoSmithKline, Helix BioPharma Corp, Incyte Corp, Jacobio Pharmaceuticals, MedImmune, Medivation, MSD, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Bio, NCI/NIH P30CA016672–Core Grant (CCSG Shared Resources), Cyclacel Pharmaceuticals, F-Star Beta, HiberCell, and Synologic; and received clinical trial research support from BioMarin Pharmaceutical and Boehringer Ingelheim. PAO received grants from Bristol Myers Squibb, Genentech, Celldex, Cytomx, Pfizer, Neon Therapeutics, Armo Biosciences, and AstraZeneca; and personal fees from Bristol Myers Squibb, Genentech, Celldex, Cytomx, Pfizer, Alexion, Amgen, Novartis, Neon Therapeutics, and Array. AC, FJ, and KN are employees of MSD, and have stock ownership in Merck & Co. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Molibresib is an orally bioavailable, selective, small molecule BET protein inhibitor. Results from a first time in human study in solid tumors resulted in the selection of a 75 mg once daily dose of the besylate formulation of molibresib as the recommended Phase 2 dose (RP2D). Here we present the results of Part 2 of our study, investigating safety, pharmacokinetics, pharmacodynamics and clinical activity of molibresib at the RP2D for nuclear protein in testis carcinoma (NC), small cell lung cancer, castration-resistant prostate cancer (CRPC), triple-negative breast cancer, estrogen receptor-positive breast cancer and gastrointestinal stromal tumor. The primary safety endpoints were incidence of adverse events (AEs) and serious AEs; the primary efficacy endpoint was overall response rate. Secondary endpoints included plasma concentrations and gene set enrichment analysis (GSEA). Molibresib 75 mg once daily demonstrated no unexpected toxicities. The most common treatment-related AEs (any grade) were thrombocytopenia (64%), nausea (43%) and decreased appetite (37%); 83% of patients required dose interruptions and 29% required dose reductions due to AEs. Antitumor activity was observed in NC and CRPC (one confirmed partial response each, with observed reductions in tumor size), although predefined clinically meaningful response rates were not met for any tumor type. Total active moiety median plasma concentrations after single and repeated administration were similar across tumor cohorts. GSEA revealed that gene expression changes with molibresib varied by patient, response status and tumor type. Investigations into combinatorial approaches that use BET inhibition to eliminate resistance to other targeted therapies are warranted., (© 2021 UICC.)

Purpose: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers., Patients and Methods: Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1., Results: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively., Conclusions: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies., (©2021 The Authors; Published by the American Association for Cancer Research.)

Introduction: Local control in sarcoma is rarely achieved with exclusive radiotherapy (RT). We aim to assess the feasibility and safety of sunitinib continuously administrated with concomitant RT in inoperable non-GIST sarcomas patients., Methods: This multicentric French 3 + 3 dose escalation study included patients with inoperable locally advanced or recurrent sarcoma, ECOG-PS <2, ≤2 metastatic sites and no brain metastases, adequate organ functions and absence of uncontrolled hypertension, who had never received sunitinib or radiotherapy. The escalation phase planned to use sunitinib dose levels (DL1: 25; DL2: 37.5; DL3: 50 mg/day) with standard RT (60 Gy, 30 fractions, 5 fractions/week/6 weeks). The primary endpoint was to determine the incidence of dose-limiting toxicities (DLT) in the first 14 weeks and the maximal tolerated dose (MTD). Secondary endpoints included safety (acute and late toxicities), local control at 6 months including local progression free rate (L-PFR) progression free survival (PFS), overall survival (OS), proportion of patients eligible for surgery after treatment., Results: From May 2011 to April 2016, the dose-escalation phase enrolled 10 patients (DL1 N = 4; DL2 N = 6). No DLT was observed in at DL1. One DLT (grade 4 thrombopenia) occurred at DL2. The 19 patients treated at DL2 (including the 13 patients from the expansion phase) received sunitinib for a median duration of 42.7 (2.8-79.1) days, and radiotherapy for 6.4 (1-8) weeks; all but 3 patients received 60 Gy (40 Gy, early progression (N = 1); 8 Gy, early death (N = 1), prescribed dose, 50 Gy (N = 1)). With a median follow-up of 19.5 (14-36.5) months, the median PFS was 6.5 (1.9-31.1) months. Median OS was not reached. At 6 months, L-PFR was 73.3% (95%CI 44.9%-92.2%). One patient was amendable to surgery after treatment. Sunitinib-related grade ≥ 3 adverse events occurred in 58% of the patients treated at DL2 (Escalation N = 4; Expansion N = 7). Seven (36.8%) deaths related to disease progression were reported., Conclusion: This is the first trial assessing the combination of continuous administration of sunitinib 37.5 mg with exclusive RT in non-GIST sarcoma. Whereas this combination was found feasible, efficient, further investigations of combinations of more recent multikinase inhibitors with RT need to be explored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158., Methods: Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety., Results: As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events)., Conclusion: Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer., Competing Interests: David M. O'MalleyConsulting or Advisory Role: Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute, Agenus, Marker Therapeutics, Eisai, Genelux, Iovance Biotherapeutics, Ambry Genetics, Tarveda Therapeutics, Leap Therapeutics, Myriad Genetics, GlaxoSmithKline, Regeneron, Sorrento Therapeutics, Rubius Therapeutics, Elevar Therapeutics, Novartis, Seattle Genetics, BBI Healthcare, Arquer Diagnostics, Toray Medical, Takeda, InxMed, Celsion, Roche Diagnostics MSAResearch Funding: Amgen (Inst), AstraZeneca (Inst), Genentech/Roche (Inst), Regeneron (Inst), Immunogen (Inst), Janssen Research & Development (Inst), Clovis Oncology (Inst), EMD Serono (Inst), Ergomed (Inst), Ajinomoto (Inst), Immunogen (Inst), Cerulean Pharma (Inst), PharmaMar (Inst), Array BioPharma (Inst), Bristol Myers Squibb (Inst), Agenus (Inst), Tesaro (Inst), TRACON Pharma (Inst), Genmab (Inst), Seattle Genetics (Inst), Iovance Biotherapeutics (Inst), Leap Therapeutics (Inst), Merck (Inst), AbbVie/Stemcentrx (Inst), AbbVie (Inst), Mersana (Inst), Eisai (Inst), BBI Healthcare (Inst), Sumitomo Dainippon Pharma Oncology (Inst) Giovanni Mendonca BarianiConsulting or Advisory Role: LibbsResearch Funding: mAbxience, Merck Sharp & Dohme, Bristol Myers SquibbTravel, Accommodations, Expenses: Lilly Philippe A. CassierHonoraria: Novartis, Roche/Genentech, Amgen, AstraZeneca, Merck SeronoResearch Funding: Novartis (Inst), Roche/Genentech (Inst), Lilly (Inst), Blueprint Medicines (Inst), Bayer (Inst), AstraZeneca (Inst), Celgene (Inst), Plexxikon (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Merck Serono (Inst), Merck Sharp & Dohme (Inst), Taiho Pharmaceutical (Inst), Toray Industries (Inst), Transgene (Inst), Loxo (Inst), GlaxoSmithKline (Inst), Innate Pharma (Inst), Janssen (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Bayer, Merck Serono Aurelien MarabelleStock and Other Ownership Interests: PEGASCY (Inst), HiFiBiO Therapeutics, Shattuck Labs, Centessa Pharmaceuticals (Inst)Honoraria: Bristol Myers Squibb, AstraZeneca/MedImmune, OncovirConsulting or Advisory Role: Lytix Biopharma, EISAI, Pierre Fabre, AstraZeneca, Servier, Roche, Redx Pharma, Sotio, Innate Pharma, ImCheck therapeutics, MSD, OSE Immunotherapeutics, HiFiBiO Therapeutics, MedinCell, Centessa PharmaceuticalsSpeakers' Bureau: BMSResearch Funding: Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Transgene (Inst), MSD (Inst)Patents, Royalties, Other Intellectual Property: Monoclonal antibodies against CD81 (Stanford University)Travel, Accommodations, Expenses: MSD, AstraZeneca Aaron R. HansenConsulting or Advisory Role: Merck, GlaxoSmithKline, Bristol Myers Squibb, Eisai, Novartis, AstraZenecaResearch Funding: Karyopharm Therapeutics (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim, GlaxoSmithKline (Inst), Roche/Genentech (Inst), Janssen (Inst), AstraZeneca/MedImmune (Inst), Astellas Pharma (Inst), BioNTech (Inst), Pfizer/EMD Serono (Inst), Neoleukin Therapeutics (Inst) Ana De Jesus AcostaConsulting or Advisory Role: MerckResearch Funding: Merck (Inst), AstraZeneca (Inst) Wilson H. Miller JrHonoraria: Bristol Myers Squibb Foundation, Merck, Roche, Novartis, GlaxoSmithKline, Mylan, EMD Serono, AmgenConsulting or Advisory Role: Bristol Myers Squibb, Merck, Roche, Novartis, Amgen, GlaxoSmithKline, Mylan, EMD SeronoResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Roche (Inst), AstraZeneca (Inst), Merck (Inst), MethylGene (Inst), Bayer (Inst), Amgen (Inst), MedImmune (Inst), Pfizer (Inst), Esperas Pharma (Inst), Astellas Pharma (Inst), Sanofi (Inst), Incyte (Inst), Array BioPharma (Inst), Exelixis (Inst), Mimic Technologies (Inst), Ocellaris Pharma (Inst), Canadian Institutes of Health Research (CIHR) (Inst), Canadian Research Society (Inst), Terry Fox Research Institute (Inst), Samuel Waxman Cancer Research Foundation (Inst), Canadian Cancer Society Research Institute (CCSRI) (Inst) Antoine ItalianoHonoraria: Bayer, Daiichi Sankyo, Lilly, Epizyme, Novartis, Roche, IPSENConsulting or Advisory Role: Roche, Daiichi Sankyo, Immune Design, Epizyme, Bayer, LillyResearch Funding: Roche, Bayer, AstraZeneca/MedImmune, PharmaMar, MSD Oncology, Merck SeronoPatents, Royalties, Other Intellectual Property: BMS Lei XuEmployment: MerckStock and Other Ownership Interests: Merck Fan JinEmployment: MerckStock and Other Ownership Interests: MerckTravel, Accommodations, Expenses: Merck Kevin NorwoodEmployment: Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA Hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, AlfasigmaNo other potential conflicts of interest were reported.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016)., Patients and Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments., Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts., Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing., (© 2021. The Author(s).)

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design., Competing Interests: Vincent Ribrag received honoraria from Gilead, Infinity, ArgenX, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Roche, and AstraZeneca; served as a consultant or advisor for Servier; and received research funding from ArgenX. Julio C. Chavez served as a consultant or advisor for Novartis, Celgene, a Bristol‐Myers Squibb Company, Bayer, Morphosys, Karyopharm, AstraZeneca, Verastem, Pfizer, and Genentech; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Jason Kaplan served as a consultant or advisor for and received research funding from Seattle Genetics, and received travel funding from Curis. Jason C. Chandler served as a consultant or advisor for Janssen and Axess Oncology. Armando Santoro served as a consultant or advisor for ArQule, Sanofi, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and Merck Sharpe and Dohme; and served on the speaker's bureau for Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, a Bristol‐Myers Squibb company, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, and Merck Sharpe and Dohme. Paolo Corradini received honoraria from Janssen, Gilead, AbbVie, Takeda, Roche, Novartis, and Celgene, a Bristol‐Myers Squibb Company; served as a consultant or advisor for Novartis, Janssen, Celgene, a Bristol‐Myers Squibb company, and Gilead; received travel funding from Novartis, AbbVie, and Gilead; and served on the speaker's bureau for Novartis. Ian W. Flinn received research funding from AbbVie, Acerta, Agios, ArQule, BeiGene, Calithera, Celgene, a Bristol‐Myers Squibb Company, Constellation, Curis, Forma, Forty‐Seven Inc, Genentech, Gilead, Incyte, Infinity, Janssen, Karyopharm, Kite, Merck, Novartis, Pfizer, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, and Verastem. Ranjana Advani served as a consultant or advisor for AstraZeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech/Roche, Gilead Kite Pharma, Kyowa, Seattle Genetics, and Takeda; and received research funding from Agensys, Celgene, a Bristol‐Myers Squibb company, Forty‐Seven Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seattle Genetics. Philippe A. Cassier received honoraria from Amgen, AstraZeneca, Blueprint Medicines, Novartis, and Roche/Genentech; received research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, GlaxoSmithKline, Innate Pharma, Janssen, Lilly, Loxo, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries, and Transgene; and received travel funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Novartis, and Roche. Randeep Sangha received honoraria from Pfizer, Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, and Takeda; served as a consultant or advisor for Boehringer Ingelheim, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, Takeda, and Teva; and received research funding from Bristol Myers Squibb, AbbVie, Takeda, Pharmacyclics, Morphosys, Roche, Merck, Celgene, a Bristol‐Myers Squibb company, and Novartis. Iris Isufi served as a consultant or advisor for AstraZeneca, Celgene, a Bristol‐Myers Squibb company/Jazz Pharmaceuticals, and Kite Pharma; and received travel funding from Celgene, a Bristol‐Myers Squibb company, and Kite Pharma. Shailaja Uttamsingh, Patrick R. Hagner, Anita K. Gandhi, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Harald Haeske has equity ownership with Pieris AG and served as a consultant or advisor for Celgene, a Bristol‐Myers Squibb company, and 4SC AG. Kristen Hege is employed by and holds patents with Bristol Myers Squibb; has equity ownership with Bristol Myers Squibb, Arcus Biosciences, and Mersana Therapeutics; and served on the Board of Directors for Arcus Biosciences, Mersana Therapeutics, and the Society for Immunotherapy of Cancer. John Kuruvilla received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, Gilead, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, and Seattle Genetics; and served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche, and Seattle Genetics; and received research funding from Janssen and Roche. All other authors declare no conflict of interest., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents., Methods: In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program., Results: Adenocarcinoma (n = 86, 59%), signet-cell (n = 37, 25%) and squamous-cell (n = 21, 14%) were the dominant histology amongst 147 patients. Genomic analyses could be performed for 114 (78%) patients. The most common genomic alterations involved ERBB2 (15%), KRAS (12%), CCND1 (7%), FGFR1-3 (8%), EGFR (5%) and MET (3%), TP53 (51%) and CDKN2A/B (10%). ERBB2, MET and FGFR alterations were found exclusively in the adenocarcinoma and signet-cell subtypes, while CCND1 amplification, TP53 mutations and CDKN2A/B loss were found in both adenocarcinoma and squamous-cell subtypes. Nine patients (8%) received therapy matched to their genomic alteration, with 5 of them achieving disease control. In an exploratory analysis, patients with stage IV disease at diagnosis who had an actionable alteration had longer overall survival compared to those without., Conclusion: Genomic profiling for patients with advanced gastroesophageal cancers allows the identification of actionable alterations in large proportion of patients. Increased accessibility to molecularly matched therapy may improve survival in this disease., (Copyright © 2021. Published by Elsevier Inc.)

Bispecific therapies targeting CD3, so-called T-cell engagers (TCE), belong to the new spectrum of anti-tumor immunotherapies stimulating T-lymphocytes. TCE are unique constructs targeting the MHC-independent CD3 epsilon subunit (CD3e) and a tumor antigen. To date, only blinatumomab have reached market agreements in lymphoid malignancies with constructs targeting CD3exCD19. Other TCE are in advances development, with promising results targeting CD20 and BSMA in lymphoma and myeloma. These successes have relaunched the development of TCE in solid tumors, bringing mixed results so far (notably in terms of tolerance). Still, TCE pave the way to new immunotherapy in tumors considered to be refractory to inhibitors of immune checkpoints such as prostate cancer or colorectal cancer., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525)., Methods: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics., Results: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined., Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors., Translational Relevance: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity., (© 2021. The Author(s).)

Background: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC., Methods: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis., Findings: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population., Interpretation: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC., Funding: Blueprint Medicines., Competing Interests: Declaration of interests JFG reports personal fees from Bristol-Myers Squibb (BMS), Roche–Genentech, Merck, Takeda, LOXO Oncology–Lilly, Blueprint Medicines, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Novartis, and Moderna, grants from Takeda and Novartis, and institutional research support from BMS, LOXO Oncology–Lilly, Blueprint Medicines, Novartis, Moderna, Alexo, Tesaro, Jounce, Adaptimmune Therapeutics, and an immediate family member who is an employee of and holds equity in Ironwood Pharmaceuticals, all outside the submitted work. GC reports personal fees from Roche, Pfizer, Novartis, Eli Lilly, Foundation Medicine, BMS, Samsung, AstraZeneca, Daiichi-Sankyo, Boehringer Ingelheim, GlaxoSmithKline (GSK), and Seagen, non-financial support from Roche and Pfizer, grants from Merck, and other support from Ellipsis, all outside the submitted work. D-WK reports grants and non-financial support from Blueprint Medicines during the conduct of the study; grants from Alpha Biopharma, Amgen, AstraZeneca–Medimmune, Boehringer Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Meurs, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche–Genentech, Takeda, Turning Point Therapeutics, Xcovery, and Yuhan, and non-financial support from Amgen and Daiichi-Sankyo, all outside the submitted work. DHL reports personal fees from AstraZeneca, Boehringer Ingelheim, BMS, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, MSD, Mundipharma, Novartis, Ono Pharmaceutical, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie, Takeda, Genexine, Menarini, and BC Pharma, and non-financial support from Takeda and Blueprint Medicines, all outside the submitted work. BB reports grants from AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche–Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, 4D Pharma, Aptitude Health, and Cergentis. CSB reports grants from Blueprint Medicines, Daiichi-Sankyo, Celgene, Pfizer, Lilly Oncology, AbbVie, Rain Therapeutics, and Spectrum Pharmaceuticals, and personal fees from AstraZeneca, Turning Point Therapeutics, National Comprehensive Cancer Network, and Takeda, all outside the submitted work. RCD reports consulting–advisory roles for Blueprint Medicines, Rain Therapeutics, Roche–Genentech, Green Peptide, Anchiano, Takeda, AstraZeneca, and Bayer, and travel support from Blueprint Medicines, Rain Therapeutics, Roche–Genentech, Green Peptide, and Takeda, holds stock or has other ownership in Rain Therapeutics, and has patents–royalties from Rain Therapeutics and Abbott Molecular, all outside the submitted work. PAC reports other support from Blueprint Medicines during the conduct of the study; personal fees from Blueprint Medicines, Amgen, Merk Serono, Novartis, and Roche–Genentech, non-financial support from MSD, Novartis, AstraZeneca, and Plexxikon, grants from MSD and Novartis, and other support from AbbVie, Amgen, Bayer, BMS, Merck Serono, MSD, Novartis, Roche–Genentech, GSK, Janssen, Eli Lilly, Netris Pharma, AstraZeneca, Celgene, Taiho, Toray, LOXO Oncology, and Innate Pharma, all outside the submitted work. GL reports consultant roles for Bayer, Blueprint Medicines, Cue Biopharma, Eisai, Exelixis, Roche–Genentech, Eli Lilly, LOXO Oncology, Merck, and Rakuten Medical, all outside the submitted work. DSWT reports personal fees from Novartis, Bayer, Boehringer Ingelheim, AstraZeneca, Eli Lilly, LOXO Oncology, Merck, Pfizer, Roche, Takeda, and Merrimack, and grants from Novartis, Bayer, AstraZeneca, Pfizer, and GSK, all outside the submitted work. EG reports personal fees from Roche–Genentech, Hoffman–La Roche, Ellipses Pharma, Neomed Therapeutics, Boehringer Ingelheim, Janssen, Seattle Genetics, TFS, Alkermes, Thermo Fisher, BMS, and MSD, grants from Menarini and Glycotope, and other support from Novartis, Roche, and Thermo Fisher, all outside the submitted work. LGP-A reports personal fees from Eli Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint Medicines, BMS, and Mirati, grants from MSD, AstraZeneca, Pfizer, and BMS, is a board member of Genomica, and is a board member and cofounder of Altum Sequencing, all outside the submitted work. BCC reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceuticals, Dizal Pharma, MSD, AbbVie, MedPacto, GI Innovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Center, personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono Pharmaceuticals, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, MedPacto, Blueprint Medicines, TheraCanVac, Gencurix, Bridgebio Therapeutics, KANAPH Therapeutics, Cyrus Therapeutics, Interpark Bio Convergence Center, Guardant Health, and Oscotec, other support from Champions Oncology, is a board member of Gencurix and Interpark Bio Convergence Center, and is a founder of DAAN Biotherapeutics, all outside the submitted work. SMG reports personal fees from Blueprint Medicines, Roche–Genentech, AstraZeneca, Janssen, Merck, BMS, Pfizer, Eli Lilly, Novartis, and Daiichi-Sankyo, grants from Merck, and is a compensated member of the independent data monitoring committee for a phase 3 trial sponsored by AstraZeneca, all outside the submitted work. MT reports grants from Blueprint Medicines during the conduct of the submitted work; personal fees and non-financial support from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Novartis, Pfizer, Roche, and Takeda, and grants from AstraZeneca, BMS, and Takeda, all outside the submitted work. SVL reports grants from Alkermes, Bayer, Blueprint Medicines, BMS, Roche–Genentech, Eli Lilly, Lycera, Merck/MSD, Molecular Partners, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics, Corvus, Debiopharm, Merus, and Elevation Oncology, and personal fees from AstraZeneca, Blueprint Medicines, BMS, G1 Therapeutics, Roche–Genentech, Guardant Health, Inivata, Janssen, Jazz, Eli Lilly, Merck–MSD, PharmaMar, Pfizer, Regeneron, Takeda, BeiGene, Catalyst, Amgen, and Daiichi-Sankyo, all outside the submitted work. MHT reports consulting or advisory roles for Bayer, Blueprint Medicines, Novartis, Sanofi–Genzyme, ArQule, BMS, Eisai, Merck, Array BioPharma, and LOXO Oncology, travel support from Bayer, Blueprint Medicines, Novartis, Sanofi–Genzyme, ArQule, BMS, Eisai, Array BioPharma, and LOXO Oncology, speaker bureau roles for BMS, Eisai, and Merck, and institutional research funding from Abreos Biosciences and Arch Oncology, all outside the submitted work. ASM reports honoraria to his institution for consulting or advisory roles from Janssen, Roche–Genentech, BMS, AbbVie, AstraZeneca, travel, accommodation, and expenses from AbbVie and Roche, research funding from Novartis, NIH, Verily, and Mark Foundation, and is a non-remunerated board member for the Mesothelioma Applied Research Foundation. VWZ reports personal fees from AstraZeneca, Blueprint Medicines, Roche-Foundation Medicine, Roche–Genentech, Takeda, Turning Point Therapeutics, and Xcovery, all outside the submitted work. CC and HZ are employees of and hold equity interest in Blueprint Medicines. MP is a former employee of and holds equity interest in Blueprint Medicines and reports other support from C4 Therapeutics outside the submitted work. JG reports consulting or advisory roles for Blueprint Medicines, Tesaro, Genocea, and Arvinas. CDT is a former employee of and holds equity interest in Blueprint Medicines. VS reports grants from Blueprint Medicines and LOXO Oncology–Eli Lilly during the conduct of the study; research funding or grant support for clinical trials from Roche–Genentech, Novartis, Bayer, GSK, Nanocarrier, Vegenics, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfasiga, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, MedImmune, Altum, Dragonfly Therapeutics, Takeda, Immunogen, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals, travel support from Novartis, PharmaMar, ASCO, ESMO, Helsinn, and Incyte, consultancy or advisory board participation for Helsinn, LOXO Oncology–Eli Lilly, R-Pharma US, Incyte, QED Pharma, MedImmune, and Novartis, and other support from Medscape. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Colony-stimulating factor 1 receptor (CSF1R) blockade abates tumor-associated macrophage (TAM) infiltrates and provides marked clinical benefits in diffuse-type tenosynovial giant cell tumors. However, facial edema is a common adverse event associated with TAM elimination in patients. In this study, we examined molecular and cellular events associated with edema formation in mice and human patients with cancer treated with a CSF1R blocking antibody. Extended antibody treatment of mice caused marked body weight gain, an indicator of enhanced body fluid retention. This was associated with an increase of extracellular matrix-remodeling metalloproteinases (MMPs), namely MMP2 and MMP3, and enhanced deposition of hyaluronan (HA) and proteoglycans, leading to skin thickening. Discontinuation of anti-CSF1R treatment or blockade of MMP activity restored unaltered body weight and normal skin morphology in the mice. In patients, edema developed at doses well below the established optimal biological dose for emactuzumab, a CSF1R dimerization inhibitor. Patients who developed edema in response to emactuzumab had elevated HA in peripheral blood. Our findings indicate that an early increase of peripheral HA can serve as a pharmacodynamic marker for edema development and suggest potential interventions based on MMP inhibition for relieving periorbital edema in patients treated with CSF1R inhibitors., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST., Materials and Methods: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy., Results: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6)., Conclusion: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations., Implications for Practice: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: PDGFRA D842V mutations occur in 5-10% of gastrointestinal stromal tumours (GISTs), and previously approved tyrosine kinase inhibitors (TKIs) are inactive against this mutation. Consequently, patients have a poor prognosis. We present an updated analysis of avapritinib efficacy and long-term safety in this patient population., Methods: NAVIGATOR (NCT02508532), a two-part, open-label, dose-escalation/dose-expansion phase I study, enrolled adult patients with unresectable GISTs. Patients with PDGFRA D842V-mutant GIST were a prespecified subgroup within the overall safety population, which included patients who received ≥1 avapritinib dose. Primary end-points were overall response rate (ORR) and avapritinib safety profile. Secondary end-points were clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS). Overall survival (OS) was an exploratory end-point., Results: Between 7 October 2015 and 9 March 2020, 250 patients enrolled in the safety population; 56 patients were included in the PDGFRA D842V population, 11 were TKI-naïve. At data cut-off, median follow-up was 27.5 months. Safety profile was comparable between the overall safety and PDGFRA D842V populations. In the PDGFRA D842V population, the most frequent adverse events were nausea (38 [68%] patients) and diarrhoea (37 [66%]), and cognitive effects occurred in 32 (57%) patients. The ORR was 91% (51/56 patients). The CBR was 98% (55/56 patients). The median DOR was 27.6 months (95% confidence interval [CI]: 17.6-not reached [NR]); median PFS was 34.0 months (95% CI: 22.9-NR). Median OS was not reached., Conclusion: Targeting PDGFRA D842V-mutant GIST with avapritinib resulted in an unprecedented, durable clinical benefit, with a manageable safety profile. Avapritinib should be considered as first-line therapy for these patients., Competing Interests: Conflict of interest statement Dr Jones reported receiving grants from MSD; and personal fees from Adaptimmune, Athenex, Blueprint Medicines Corporation, Clinigen, Eisai, Eli Lilly, Epizyme, Daichii Sankyo, Deciphera Pharmaceuticals, Helsinn, Immunedesign, Merck, PharmaMar, Tracon and UptoDate outside the submitted work. Dr Serrano reported receiving other support from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Eli Lilly, Novartis, Pfizer and PharmaMar; and grants from Bayer, Deciphera Pharmaceuticals and Pfizer outside the submitted work. Dr von Mehren reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; and other support from Arog Pharmaceuticals, Deciphera Pharmaceuticals, Exelixis and Novartis outside the submitted work. Dr George reported receiving research support to her institution from Ariad, Bayer, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Novartis and Pfizer; and advisory board/consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals and Eli Lilly. Dr Heinrich reported receiving grants and personal fees from Blueprint Medicines Corporation; and personal fees and other support from Molecular MD during the conduct of the study; personal fees and other from Novartis; and grants and personal fees from Deciphera Pharmaceuticals outside the submitted work. Dr Heinrich also has a patent “Treatment of Gastrointestinal Stromal Tumors” licenced to Novartis, and a patent “Activating Mutations of PDGFRA” issued. Dr Kang reported receiving personal fees from ALX Oncology, Amgen, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Novartis, Surface Oncology and Zymeworks outside the submitted work. Dr Schöffski reported receiving personal fees from Deciphera Pharmaceuticals; other support from Adaptimmune, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis, Eisai, Eli Lilly, Ellipses Pharma, Genmab, Intellisphere, Loxo Oncology, Merck, Plexxikon, Servier and Transgene; and grants from Ipsen and MSD outside the submitted work. Dr Cassier reported receiving personal fees from Blueprint Medicines Corporation during the conduct of the study; other support from AbbVie, Bayer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis and Roche/Genentech; personal fees from Amgen, Bristol Myers Squibb, MSD, Novartis and Roche/Genentech; non-financial support from MSD and Novartis; and grants from Novartis outside the submitted work. Dr Mir reported receiving consulting fees from Eli Lilly, Janssen, Lundbeck, Pfizer, Roche, Servier and Vifor Pharma; and owns stock options from Amplitude Surgical, Transgene and Ipsen. Dr Chawla reported receiving funding from ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC and Tracon outside the submitted work. Dr Eskens has nothing to disclose. Dr Rutkowski reported receiving personal fees from Blueprint Medicines Corporation, Bristol Myers Squibb, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Roche and Sanofi outside the submitted work. Dr Tap reported receiving other support from Blueprint Medicines Corporation during the conduct of the study; receiving personal fees from Agios Pharmaceuticals, Blueprint Medicines Corporation, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, GlaxoSmithKline, Janssen, Immune Design, Loxo Oncology and NanoCarrier outside the submitted work; having a patent Companion Diagnostic for CDK4 inhibitors – 14/854,329 pending to MSKCC/SKI; attending scientific advisory boards for Atropos Therapeutics and Certis Oncology Solutions; being a consultant for Daiichi Sankyo; having stock ownership in Atropos Therapeutics and Daiichi Sankyo; and having involvement in an FDA ODAC meeting for pexidartinib. Dr Zhou is a former employee of Blueprint Medicines Corporation. Dr Roche reported receiving other support from Epizyme outside the submitted work; and being a current employee and shareholder of Blueprint Medicines Corporation. Dr Bauer reported receiving grants from Blueprint Medicines Corporation, Incyte and Novartis; personal fees from Bayer, Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Exelixis and Novartis during the conduct of the study; and personal fees from ADC Therapeutics, Daiichi Sankyo, Eli Lilly, Exelixis, Janssen-Cilag, Nanobiotix, PharmaMar and Plexxikon outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)