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Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. Methods: The primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival. Results: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed. Conclusions: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted. In a phase 1/2 trial of heavily pretreated patients who had recurrent gynecologic cancers, avelumab in combination with a 4‐1BB agonist, an OX40 agonist, and/or radiation was safe and had a similar rate of immune‐related adverse events compared with single‐agent immune checkpoint blockade. The combination of multiple immune‐modulating agents, however, did not result in increased efficacy. [ABSTRACT FROM AUTHOR]

Background: Selinexor (KPT‐330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple‐negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. Methods: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose‐escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose‐expansion cohort. Results: Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose‐escalation cohort (N = 10) and in the dose‐expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment‐related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose‐limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m2 eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose‐escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose‐expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). Conclusions: Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. Plain Language Summary: Effective therapies for advanced, triple‐negative breast cancer and sarcoma represent an unmet need.Exportin 1 is associated with the transport of cancer‐related proteins.Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin.In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple‐negative breast cancer or sarcoma.The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support.The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple‐negative breast cancer.This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple‐negative breast cancer. Combined selinexor and eribulin was safe, with a manageable toxicity profile and modest overall clinical efficacy. Durable responses and disease control were observed in patients who had metastatic, triple‐negative breast cancer. Further study is needed to examine the determinants of response to this combination. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings. Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study. [ABSTRACT FROM AUTHOR]

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043)., Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 mg as dose level 1 (L1) or 100 mg as dose level 2 (L2)), every 3 weeks (Q3W). Group 2 (G2, n=10) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (dose as determined in G1, Q3W) with SABR (50 Gy/4 fx or 60-70 Gy/10 fx to liver/lung lesions. Group 3 (G3, n=20) received four cycles of nivolumab (480 mg) plus BMS-986156 (30 mg), every 4 weeks with SABR. Maintenance nivolumab could be given up to 2 years. Tumor responses were assessed every 1-3 months until progression, using immune-related response criteria., Results: 50 patients were enrolled between 10/2019 and 12/2021. Patients received a median of 3 (IQR 2-4.25) initial treatment cycles. 100 mg BMS-986156 with ipilimumab was tolerated well. Five discontinued BMS-986156 with ipilimumab due to treatment-related adverse events (TRAEs), with three in G1/L1, one in G1/L2 and one in G2, respectively. 22 patients (44%) experienced Grade 1-3 TRAEs (6, 4, 5, 7 patients for G1/L1, G1/L2, G2, G3). Six (12%) had Grade 3 TRAEs (2, 2, 1, 1 for G1/L1, G1/L2, G2, G3), with elevated alanine aminotransferase (n=3, in G1/L2, G2 and G3) and aspartate aminotransferase (n=2, in G2 and G3) being the most common. There was no Grade 4-5 TRAEs. Overall, 19/39 (48.7%) patients eligible for efficacy analysis had stable disease and 3 (7.7%) achieved a partial response. Out-of-field (abscopal) disease control rate (ACR) and out-of-field (abscopal) response rate (ARR) were 38.5% and 7.7%, respectively, with the highest ACR (50%, 9/18) and ARR (11.1%, 2/18) in G3., Conclusions: BMS-986156 was well-tolerated with ipilimumab, nivolumab, with or without SABR. Outcomes were encouraging in this population, as more than half of patients had stable disease/partial response., Competing Interests: Competing interests: JYC has received research grants from BMS-MDACC Research Alliance, Siemens, AstraZeneca and NCI NIH SORT study; honoraria for scientific meetings from Varian Medical System and IBA; and has served as Scientific Program Co-chair for PTCOG: Particle Therapy Co-Operative Group; also a member in Board of Directors of IASLC: International Association for the Study of Lung Cancer. DSH has received research grants from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astelles, AstraZeneca, Bayer, Biomea, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Eli Lilly, Endeavor, Erasca, F. Hoffmann-LaRoche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Incyte Inc, Infinity, Kyowa Kirin, Merck, Mirati, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Quanta, Revolution Medicine, SeaGen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology; honoraria for travel, accommodations and expenses from AACR, ASCO, CLCC, Bayer, Genmab, Northwestern, SITC, Telperian, UNC; has consulting, speaker, or advisory role in 280Bio- YingLing Pharma, AbbVie, Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Affini-T, Astellas, Aumbiosciences, Axiom, Baxter, Bayer, BeiGene USA, Boxer Capital, BridgeBio, CARSgen, CLCC, COG, COR2ed, Cowen, Ecor1, EDDC, Erasca, Exelixis, Fate Therapeutics, F.Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, Incyte Inc, Inhibrix Inc, InduPro, Innovent, Janssen, Jounce Therapeutics Inc, Lan-Bio, Liberium, MedaCorp, Medscape, Novartis, Northwestern, Numab, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Projects in Knowledge, Quanta, RAIN, Ridgeline, Revolution Medicine, Sanofi and Genzyme Inc, SeaGen, Stanford, STCube, Takeda, Tavistock, Trieza Therapeutics, T-Knife, Turning Point Therapeutics, UNC, WebMD, Ziopharm; and has been advisor for CrossBridge Bio, Molecular Match; and is founder and advisor for OncoResponse, Telperian. JW has received research grants from Alkermes, Nanobiotix, Varian, Artidis, Takeda, HotSpot Therapeutics, Gilead, Kiromic, Bayer Health, BMS, AstraZeneca, Merck, Sciclone, Novocure, Pebble Life Science; and has received consulting fees from Accuray, Alkermes, Checkmate Pharmaceuticals, Kezar Life Sciences, Legion Healthcare Partners, Novocure, Taiwan Lung Cancer Society, Radiosurgery Society, Life Science Dynamics Limited, Nanorobotics, Nanobiotix, Oncoresponse, Artidis, Boehringer Ingleheim, Alpine Immune Science, Lifescience Dynamics Limited, McKesson Corporation, Reflexion; and has support for travel from Nanobiotix, Varian, Reflexion; has been in the Advisory Boards of Nanobiotix, Reflexion, Novocure, Oncoresponse, McKesson, Life Science Dynamics Limited, Kezar Life Sciences, Boehringer Ingelheim, Alpine Immune Sciences; and has stock options from Reflexion, Oncoresponse; is the founder of Oligo Immune; has business ownership of DV8; and has equity of Molecular Match, Alpine Immune Science, Checkmate Pharmaceuticals, Legion Healthcare Partners, Nanorobotics, Reflexion, Oncoresponse. EED has received research grants from Bayer HealthCare Pharmaceuticals Inc, Immunocore LTD, Amgen, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc, Unum Therapeutics, Gilead Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira Immunologics, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Poseida, Mersana Therapeutics, Genentech, Boehringer Ingelheim, Dragonfly Therapeutics, A2A Pharma, Volastra, AstraZeneca; is a member in Advisory Boards of BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics, PMV Pharma, Fate Therapeutics; is a speaker of PMV Pharma; and has received honoraria for travel, accommodations and expenses from ASCO, LFSA Association, Rain Oncology, Banner MD Anderson Cancer Center, Triumvira Immunologics. The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer., Methods: Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo . Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor., Results: GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors., Conclusion: Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors., Competing Interests: Competing interests: JRA reports non-financial support and reasonable reimbursement for travel from European Society for Medical Oncology and Loxo Oncology; receiving consulting and travel fees from Ellipses Pharma, Molecular Partners, IONCTURA, Sardona, Mekanistic, Amgen, Merus, MonteRosa, Aadi and Bridgebio (including serving on the scientific advisory board); consulting fees from Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC and Guidepoint, receiving research funding from Blueprint Medicines, Merck Sharp and serving as investigator in clinical trials with Cancer Core Europe, Symphogen, BioAlta, Pfizer, Kelun-Biotech, GlaxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, Merus, Aadi Bioscience, ForeBio, Loxo Oncology, Hutchison MediPharma, Ideaya, Amgen, Tango Therapeutics, Mirati Therapeutics, Linnaeus Therapeutics, MonteRosa, Kinnate, Yingli, Debio, BioTheryX, Storm Therapeutics, Beigene, MapKure, Relay, Novartis, FusionPharma, C4 Therapeutics, Scorpion Therapeutics, Incyte, Fog Pharmaceuticals, Tyra, Nuvectis Pharma. MTB is a co-founder of EpiCypher. No potential conflicts of interest were disclosed by other authors., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: One of the most common sporadic homozygous deletions in cancers is 9p21 loss, which includes the genes methylthioadenosine phosphorylase (MTAP), CDKN2A, and CDKN2B, and has been correlated with worsened outcomes and immunotherapy resistance. MTAP-loss is a developing drug target through synthetic lethality with MAT2A and PMRT5 inhibitors. The purpose of this study is to investigate the prevalence and genomic landscape of MTAP-loss in advanced gastrointestinal (GI) tumors and investigate its role as a prognostic biomarker., Materials and Methods: We performed next-generation sequencing and comparative genomic and clinical analysis on an extensive cohort of 64 860 tumors comprising 5 GI cancers. We compared the clinical outcomes of patients with GI cancer harboring MTAP-loss and MTAP-intact tumors in a retrospective study., Results: The prevalence of MTAP-loss in GI cancers is 8.30%. MTAP-loss was most prevalent in pancreatic ductal adenocarcinoma (PDAC) at 21.7% and least in colorectal carcinoma (CRC) at 1.1%. MTAP-loss tumors were more prevalent in East Asian patients with PDAC (4.4% vs 3.2%, P = .005) or intrahepatic cholangiocarcinoma (IHCC; 6.4% vs 4.3%, P = .036). Significant differences in the prevalence of potentially targetable genomic alterations (ATM, BRAF, BRCA2, ERBB2, IDH1, PIK3CA, and PTEN) were observed in MTAP-loss tumors and varied according to tumor type. MTAP-loss PDAC, IHCC, and CRC had a lower prevalence of microsatellite instability or elevated tumor mutational burden. Positive PD-L1 tumor cell expression was less frequent among MTAP-loss versus MTAP-intact IHCC tumors (23.2% vs 31.2%, P = .017)., Conclusion: In GI cancers, MTAP-loss occurs as part of 9p21 loss and has an overall prevalence of 8%. MTAP-loss occurs in 22% of PDAC, 15% of IHCC, 8.7% of gastroesophageal adenocarcinoma, 2.4% of hepatocellular carcinoma, and 1.1% of CRC and is not mutually exclusive with other targetable mutations., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC., Experimental Design: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT)., Results: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS., Conclusions: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations., (©2023 American Association for Cancer Research.)

Purpose: Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes., Experimental Design: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas., Results: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising in the extremities, associated with higher age at diagnosis, and more common in dedifferentiated chondrosarcomas compared with grades 1-3 conventional chondrosarcoma. There was no difference in survival based on IDH mutation in univariate and multivariate analyses. TP53 mutation was the next most prevalent (41.9%) and is associated with worse overall survival and metastasis-free survival in both univariate and multivariate analyses. TP53 mutation was also associated with higher risk of recurrence following curative-intent surgery and worse survival among patients that presented with de novo metastatic disease., Conclusions: IDH mutations are prevalent in chondrosarcoma though were not associated with survival outcomes in this cohort. TP53 mutations were the next most common alteration and were associated with worse outcomes., (©2023 American Association for Cancer Research.)

Background: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past., Patients and Methods: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3)., Results: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs., Conclusion: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs., Competing Interests: Competing interests: TL was employed as a research scientist by Thermo Fisher Scientific during the time of study. JH declares research funding from The Texas Medical Center Digestive Diseases Center, Jeffery Modell Foundation, Immune Deficiency Foundation, Baxalta US Inc, Chao Physician-Scientist Foundation, is Consultant/Advisory board: Takeda, Pharming Healthcare Inc, and Horizon Therapeutics USA, Inc. and Ad hoc consultancy speaker: Alfaisal University. SS is a full-time employee of Thermo Fisher Scientific, Inc. DYD received honorarium from Chrysalis Biomedical. JMC is an employee of OmniSeq and shareholder of Labcorp. SPP declares institutional funding for clinical trial from NCI, Bristol Myers Squibb, Novartis, Consulting fees: Immunocore; Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events: Delcath (non-promotional), Merck & Co (non-promotional), Support for attending meetings and/or travel: Merck & Co, Cardinal Health, TriSalus LifeSciences, Participation on a Data Safety Monitoring Board or Advisory Board: Reata, Immunocore, Immatics, Bristol Myers Squibb, Cardinal Health, Castle Biosciences, Delcath, Novartis, Stock or stock options: Pfizer, Amgen. YY reports personal fees from AbbVie, personal fees from Amgen, personal fees from Bexion Pharmaceuticals, personal fees from BeyondSpring Pharmaceuticals, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Bristol Myers Squibb, personal fees from Century Therapeutics, personal fees from Enliven Therapeutics, personal fees from Repare Therapeutics, personal fees from Servier Pharmaceuticals, personal fees from Starpax Pharmaceuticals, personal fees from Vertex Pharmaceuticals, during the conduct of the study. JRA is on the advisory board of Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA, declares research funding (to institution): Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d'Hebron Institute of Oncology/Cancer Core Europe, clinical research (to institution): Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati Linnaeus Therapeutics, travel reimbursement: European Society for Medical Oncology and Other: Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC. SF receives Clinical Trial Research Support/Grant Funding through the institution from the following sources: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; CUE Biopharma, Inc.; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; Virogin Biotech, Ltd. FM-B (36 months) declares: consulting <5,000/year: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, advisory committee <5,000/year: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, sponsored research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., honoraria <5,000/year: Chugai Biopharmaceuticals, and other (travel related): none. GML is an employee/shareholder of Thermo Fisher Scientific. AN declares research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, and SOTIO Biotech AG, on advisory board/Consulting fees from Deka Biosciences, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Corp, OncoNano, Servier, Lynx Health, AbbVie, PsiOxus, received travel and accommodation expense from ARMO BioSciences, NeoImmuneTech and honoraria for speaking engagements from AKH Inc, The Lynx Group, Society for Immunotherapy of Cancer (SITC), Korean Society of Medical Oncology (KSMO), Scripps Cancer Care Symposium, ASCO Direct Oncology Highlights, European Society for Medical Oncology (ESMO), CME Outfitters. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers., Methods: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance., Findings: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively., Conclusion: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Interpretation: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Competing Interests: Competing interests: CN reports grant support and personal fees from General Electric Healthcare, outside the submitted work. SB reports grant support from National Institutes of Health, outside the submitted work. JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, Ipsen, from null, outside the submitted work. VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work. JH reports grants from Immune Deficiency Foundation, Jeffery Modell Foundatoin and Chao Physician-Scientist, and Baxalta, and has served as an advisory board member for Takeda, CSL Behring, and Horizn Pharma outside the submitted work. AN reports research support and non-financial support from Merck Sharp & Dohme Corp., grants from NCI/NIH, research support from The University of Texas MD Anderson Cancer Center, during the conduct of the study; grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, and has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab outside the submitted work. RRC, CR, MAk, MAyoub, SA, NE, PM, POZ, RV, CP, BS, DDK declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer., Methods: To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing., Results: Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration., Conclusions: Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations., Competing Interests: Competing interests: WP received honoraria and travel support from Bristol-Myers Squibb (BMS). PH is on the scientific advisory boards for Immatics, Dragonfly, Sanofi and GlaxoSmithKline (GSK). JR received consulting and/or travel fees from European Journal of Cancer, Vall d'Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GSK, Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners (including serving on the scientific advisory board from 2015 to present), received research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and served as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium and GSK. No potential conflicts of interest were disclosed by other authors., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Immunotherapies have revolutionized the treatment of various cancers, but little is known about their symptomatic toxicity. Assessing these symptoms is best accomplished by asking the patients themselves. However, such reports are subjective and may face challenges as bonafide scientific data. Demonstrating the validity of symptom assessment tools, mainly through the reduction of measurement errors, has the potential to improve patient care if these tools are widely adopted. To that end, we present herein the psychometric properties of the Immunotherapy for Early-Phase Trials module of the MD Anderson Symptom Inventory (MDASI-Immunotherapy EPT) in patients receiving various immunotherapies in early phase trials at a major cancer center., Methods: One hundred forty-five patients completed the inventory at baseline, with 85 of them also doing so after 9 weeks of treatment. The mean (±SD) age of the patients was 57.0±12.9 years. Also, 56% of the patients were women, 79% identified as white, and 49% had at least some college education., Results: The internal consistency reliability of the MDASI-Immunotherapy EPT was excellent, as the Cronbach's alphas for all of its subscales were at least 0.88 (range 0.88-0.95). Known-group validity based on Eastern Cooperative Oncology Group performance status groupings was excellent at 9 weeks after the start of an immunotherapy trial for the MDASI-Immunotherapy EPT severity (effect size, 0.96) and interference (effect size, 0.82) subscales. We found substantial changes in the symptom items difficulty remembering (effect size, -0.85), fever and/or chills (effect size, -0.63), disturbed sleep (effect size, -0.52), diarrhea (effect size, -0.42), and swelling of hands, legs, or feet (effect size, -0.39)., Conclusions: In conclusion, the MDASI-Immunotherapy EPT is a valid, reliable, and sensitive tool for measuring symptomatic toxicity., Competing Interests: Competing interests: The MD Anderson Symptom Inventory and its derivative versions are copyrighted and licensed by The University of Texas MD Anderson Cancer Center and CC. CC has a financial interest in the MDASI and its derivative versions., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers., Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR)., Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug., Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: AN reports research support and non-financial support from Merck Sharpe grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, Armo BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, and PsiOxus, non-financial support for travel and accommodation from Armo BioSciences, and has served as an advisory board member for Novartis and CytomX Therapeutics outside the submitted work; FM-B reports grants from Novartis/Aduro, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, PUMA Biotechnology, Curis, Millennium, GlaxoSmithkline, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and Aileron, personal fees for advisory from Inflection Biosciences, Darwin Health and Spectrum, personal fees for consulting from GRAIL, Clearlight Diagnostics, Dialectica, Samsung Bioepis, Aduro, Xencor, Jackson Laboratory, personal fees from OrigiMed, Kolon Life Science and Parexel International, personal fees for consulting/travel related from Pieris, Sumitomo Dainippon, and OrigMed, personal fees for advisory/travel related from Mersana, grants and personal fees for travel related from Taiho, grants and personal fees for Consulting/travel related from Genentech, Debio, and Pfizer, grants and personal fees for consulting from Zymeworks, grants and personal fees for advisory from Seattle Genetics, grants from AstraZeneca outside the submitted work; JH reports grant from Immune Deficiency Foundation, outside the submitted work; JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GlaxoSmithkline, Ipsen, from null, outside the submitted work. SAP-P reports grants from AbbVie, Inc., Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Five Prime Therapeutics, Flex Bio, Inc., Genmab A/S, GlaxoSmithkline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd, Medimmune, LLC, Medivation, Inc., Merck Sharpe & Dome Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., Transthera Bio, and XuanZhu Biopharma, outside the submitted work; RF reports personal fees for serving on advisory board from Ayala and Regeron-Sanofi, personal fees for consultation from Cellestia, and other from Merck, outside the submitted work; MC reports personal fees for consulting from Pfizer Inc., Genentech, Inc., and Apricity Health LLC, personal fees for serving as scientific/advisory committee member from EMD Serono, Inc., and Genentech, Inc., outside the submitted work; SHS reports personal fees from Angiodynamics, non-financial support from Neuwave Medical, Medtronic, and Merit Medical, outside the submitted work; CT reports salary support from Merck, during the conduct of the study; salary support from Merck, and for contract work to perform correlatives from Armo Bioscience, outside the submitted work; MF reports personal fees and non-financial support for speaking engagements and research funding from Stryker, personal fees for serving on advisory board from Biom’Up, Genetech, and Ipsen, outside the submitted work; VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithkline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work; DSH reports research/grant funding from Abbvie, Adaptimmune, Amgen, Astra-Zeneca, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genmab, Ignyta, Kite, Kyowa, Lilly, Medimmune, Merck, Merrimack, Mirati, MIRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer; personal fees from Axiom, Baxter, GLG, Group H, Guidepoint Global, Jannsen, Medscape, Numab, Trieza Therapeutics; research/grant funding and personal fees from Bayer, Genentech, Infinity, LOXO, Seattle Genetics, Takeda; and other from Molecular Match, OncoResponse, Presagia Inc, during the conduct of the study; SP reports personal fees and other for financial relationship/speakers bureau consultant from Tyme, Inc., and 4-D Pharma, outside the submitted work; TAY reports personal fees and other for research support, consulting, speakers bureau from AstraZeneca and Pfizer, personal fees and other for research support, consulting from Bayer, Seattle Genetics, and Vertex Pharmaceuticals, personal fees and other for research support, speakers bureau from Tesaro, personal fees for consultant, speakers bureau from Merck, research support from Jounce, Eli Lilly and Kyowa, personal fees for consultant services from Aduro, Almac, Atrin, Bristol-Meyers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, and Roche, outside the submitted work; AMT reports grants from NIH/NCI, during the conduct of the study; grants from EMD Serono, Boston Biomedical, Inc., Verastem Oncology, Karus Therapeutics, Ltd., Immatics Biotechnologies, CPRIT, Tvardi Therapeutics, OBI Pharma, Parker Institute, Tempus, Foundation Medicine, and Placon Therapeutics, for consulting/advisory role from Genentech, Roche Europe, and Covance, outside the submitted work; FJ reports grants from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Piqur, Symphogen, Bayer, and Fujifilm Corporation and Upsher-Smith Laboratories, research funding & SAB from Deciphera, SAB from IFM Therapeutics, Synlogic, Gaurdant Health, services as paid consultant & ownership interests in Trovagene, and paid consultant in Immunomet, outside the submitted work; SF reports clinical trial research support from Polaris Pharmaceuticals, Inc., Takeda., Lilly, Astra Zeneca, Endocyte, Novartis NIH/NCI, Aprea Therapeutics, Aneropharma Science, OncoMed Pharmaceuticals, Huya Bioscience International, Parexel International, LLC, Medivir AB, New Pharma, Inc, BioAtla LLC, MacroGenics, BeiGene, IMV, Inc, and Tolero Pharmaceuticals, outside the submitted work; RMS reports fees for consulting services from Amgen, Bristol-Myers Squibb, Jansen, Abbvie, Pfizer, Innocrin Therapeutics, Tessa Therapeutics during the conduct of the study; MAH reports grants from Exelixis Inc, grants and personal fees from Eisai Inc, and HRA Pharma, outside the submitted work. BS, DDK, RRC, CJ, KPR, S-MT, LW, CB, NT, VR, SK, JMP, AA (Abonofal), JG, AA (Alshawa), LMM, MX, SA, EEID, KRH, and GRV declare no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS - and BRAF -mutated cell lines including BRAF -mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively ( N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue ( n = 15), nausea ( n = 12), dermatitis acneiform ( n = 10), decreased appetite ( n = 7), and maculopapular rash ( n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed., (©2019 American Association for Cancer Research.)

Since the first generation of small molecules was included in the armamentarium of treatment of solid tumors (imatinib, erlotinib, etc.), there has been an expansion of anticancer small molecules, mostly kinase inhibitors, in development. Some of these drugs may not be a real breakthrough but may be similar in pharmacologic properties and marginal benefit over previously existing agents for the same indication (i.e., me-too drugs). Other drugs, however, have been specifically designed to solve an unmet medical need. Overcoming the problems of the blood-brain barrier and brain metastasis, emerging resistance mutations (such as gatekeeper mutations), or increasing selectivity/potency can be addressed with modern drug design. In this article, we discuss the advancements in the field of drug discovery, drug development, and clinical development that have enabled solving some of these issues. The evolution of the different generations of EGFR and anaplastic lymphoma kinase inhibitors exemplifies recent advancements in pharmacology that are driving the field of anticancer small molecules as a whole.