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The objective of this study was to describe the outcome of allogeneic stem cell transplantation (alloSCT) in a series of patients with B cell chronic lymphocytic leukemia (B-CLL). Twenty-three B-CLL patients were transplanted between 1988 and 1997 using stem cells from a related (n = 20) or an unrelated donor (n = 3). The median age of the patients was 46 years, and the median number of prior chemotherapy regimens received was two. At transplantation, 14 patients had chemorefractory disease and 12 of these were refractory to fludarabine. The preparative regimens included total body irradiation (TBI) in 22 of the 23 cases. All patients received graft-versus-host disease (GVHD) prophylaxis with cyclosporine and methotrexate. Twenty patients (87%) achieved a complete remission (CR). The incidence of grade II–IV acute GVHD was 54%. Fourteen (61%) patients are alive and disease-free, including two with unrelated donors, at a median of 26 months (range, 9–115 months). Nine patients (39%) have died, one of whom had progressive B-CLL. The only favorable prognostic factor for failure-free survival (FFS) and overall survival (OS) after alloSCT was the use of a cyclophosphamide/TBI rather than an etoposide/ cyclophosphamide/TBI regimen (P = 0.03). The projected 5-year FFS, OS, and relapse rates after alloSCT were 65% (95% CI, 48–88%), 62% (95% CI, 43–88%), and 5% (95%, CI 0–13%), respectively. These findings demonstrate the potential of high-dose therapy and alloSCT for inducing and maintaining a remission in patients with advanced or chemorefractory B-CLL. The low relapse rate may be due to an allogeneic graft-versus-leukemia effect. Bone Marrow Transplantation (2000) 25, 717–722. [ABSTRACT FROM AUTHOR]

Background: Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial., Methods: LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing., Findings: Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57-72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24·3 months (IQR 13·9-32·0). 35 (70%, 95% CI 55-82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3-4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred., Interpretation: Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2α inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted., Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and the National Cancer Institute., Competing Interests: Declaration of interests TKC reports institutional or personal and paid or unpaid support for research, advisory boards, consultancy, or honoraria in the past 5 years, ongoing or not, from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GSK, Gilead, HiberCell, IQVIA, Infinity Pharmaceuticals, Ipsen, Janssen, Kanaph, Eli Lilly and Company, Merck, NiKang, Nuscan, Novartis, OncoHost, Pfizer, Roche, Sanofi-Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest Therapeutics, and UpToDate and continuing medical education events (PeerView, OncLive, MJH Life Sciences, CCO, and Mashup Media) outside the submitted work; institutional patents filed on molecular alterations and immunotherapy response and toxicity and circulating tumour DNA; equity in Curesponse, InnDura Therapeutics, Osel, Pionyr, Precede Biosciences, Primium, and Tempest; service on committees for the National Comprehensive Cancer Network, Genitourinary Steering Committee, American Society of Clinical Oncology-European Society for Medical Oncology, Academic & Community Cancer Research United, and KidneyCAN; and mentorship of several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. TKC's institution (Dana-Farber Cancer Institute) might have received additional independent funding from drug companies or royalties potentially involved in research around the subject matter. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney Specialised Programs of Research Excellence (2P50CA101942-16) and Program 5P30CA006516-56, Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute. JRM has received research funding (to their institution) from Merck & Co, Inc, Rahway, NJ, USA, Arcus, Eisai, Genentech, Imugene, Trishula, Seagen, Exelixis, Dynamicure, Sillajen, Vyriad, Rubius Therapeutics, Peloton Therapeutics, and Corvus Pharmaceuticals; has received authorship royalties from UpToDate; and is a member of the University of Miami-Sylvester Cancer Center data safety monitoring board (institutional role). RF is a member of the Aveo Oncology phase 3 trial data safety monitoring board. DFM has received honoraria from Bristol Myers Squibb, Pfizer, Merck & Co, Inc, Rahway, NJ, USA, Eisai, Xilio, Aveo, Genentech, Cullinan, and Exelixis; and has received cancer research support from Bristol Myers Squibb, Pfizer, Merck & Co, Inc, Rahway, NJ, USA, Genentech, Exelixis, X4 Pharma, and Alkermes. EA has received research funding (to their institution) from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cephalon, Chorus, Cougar Biotechnology, Eisai, EMD Serono, Evelo Biosciences, Exelixis, Genentech, Gilead Sciences, Incyte, Merck & Co, Inc, Rahway, NJ, USA, Millennium, Modra Pharmaceuticals, Novartis, Oncogenex, Onyx, Peloton Therapeutics, Pfizer, Sarah Cannon Research Institute, Takeda, Colvis Oncology, Lilly, Infinity Pharmaceuticals, Janssen Research & Development, Leap Therapeutics, F Hoffman-La Roche, Loxo, Tolmar, Dana-Farber Cancer Institute, AbbVie, and GI Therapeutics. SST has received research funding (to their institution) from Merck & Co, Inc, Rahway, NJ, USA, Xencor, AVEO Oncology, Bristol Myers Squibb, Exelixis, Pfizer, Nektar Therapeutics, and Iovance Biotherapeutics; consulting fees from FirstWord, Bristol Myers Squibb, AVEO Oncology, and Exelixis; honoraria from OncLive-MJH Life Sciences, Targeted Oncology, and CancerNetwork; support for attending meetings or travel from DAVA Oncology; and has a patent pending (for binding proteins specific for 5T4 and uses thereof). EIH has received research funding from Astellas Pharma, Arvinas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Calibr, Calithera Biosciences, Caris Life Sciences, Corcept Therapeutics, Corvis Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Five Prime Therapeutics, Fortis, GSK, Gilead Sciences, Harpoon Therapeutics, F Hoffman-La Roche, Infinity Pharmaceuticals, iTeos Therapeutics, Janssen Research & Development, Merck & Co, Inc, Rahway, NJ, USA, Mirati Therapeutics, Modra Pharmaceuticals, Oncolys BioPharma, Peloton Therapeutics, Pfizer, Pharmacyclics, POINT Biopharma, and Seagen; has had consulting or advisory role with Astellas Pharma, AstraZeneca, Bayer, Dendreon, Caris Life Sciences, Janssen Research & Development, and Sanofi; has received honoraria from AstraZeneca, Bayer, Dendreon, Sanofi, Janssen Research & Development, and Seagen; received funding for travel from Sanofi and Caris Life Science; and has participated on advisory boards for AstraZeneca, Janssen Research & Development, and Sanofi. DRS has had a consulting or advisory role with Genentech-Roche, Novartis, Bristol Myers Squibb, AstraZeneca, GSK, Molecular Templates, Jazz Pharmaceuticals, Sanofi-Aventis, Regeneron, Lilly, BeiGene, Ipsen, Monte Rosa Therapeutics, AbbVie, Lyell Immunopharma, and Novocure; has received research funding (paid to their institution) from Genentech-Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, University of Texas Southwestern Medical Center—Simmons Cancer Center, Merck & Co, Inc, Rahway, NJ, USA, G1 Therapeutics, Neon Therapeutics, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, Janssen Oncology, MedImmune, Agios, GSK, Tesaro, Cyteir, Novocure, Elevation Oncology, Calithera Biosciences, Arcus Biosciences, Arrys Therapeutics, Bayer, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Hutchison MediPharma, Incyte, Kronos Bio, Loxo, Macrogenics, Molecular Templates, PureTech, Razor Genomics, Repare Therapeutics, Rgenix, Tizona Therapeutics, Verastem, BioNTech, AbbVie, Amgen, Anheart Therapeutics, Ascendis Pharma, Endeavor BioMedicines, Erasca, Faeth Therapeutics, Fujifilm, Gilead Sciences, Jazz Pharmaceuticals, Lyell Immunopharma, Millennium, Moderna Therapeutics, Monte Rosa Therapeutics, Peloton Therapeutics, Shenzhen Chipscreen Biosciences, Stemline Therapeutics, Synthekine, Taiho Oncology, Tango Therapeutics, Tarveda Therapeutics, Zai Lab, Apollomics, Strata Oncology, and Asher Biotherapeutics; and has received travel and accommodation support from AstraZeneca, Genentech, and Novartis. LK is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. RFP and DV are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA and have stock ownership in Merck & Co, Inc, Rahway, NJ, USA. TMB has received research funding (to their institution) from Lilly and has received consulting fees from Pfizer and Bayer. AD’S declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: A recent real-world study observed that 24% of patients with advanced non-small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADOs) initiated nontargeted therapies before biomarker test results became available. This study assessed the clinical impact of the timing of first-line (1L) targeted therapies (TTs) in aNSCLC., Materials and Methods: This retrospective analysis of a nationwide electronic health record-derived deidentified database included patients aged ≥18 years diagnosed with aNSCLC with ADOs (ALK, BRAF, EGFR, RET, MET, ROS-1, and NTRK) from January 1, 2015, to October 18, 2022, by biomarker testing within 90 days after advanced diagnosis and received 1L treatment. Cohorts were defined by treatment patterns ≤42 days after test results: "Upfront TT" received 1L TT ≤42 days; "Switchers" initiated 1L non-TT before or after testing but switched to TT ≤42 days; and "Non-switchers" initiated non-TT before or after testing and did not switch at any time. Adjusted multivariate Cox regression evaluated real-world progression-free survival, real-world time to next treatment or death, and real-world overall survival., Results: A total of 3540 patients met the study criteria; 78% were treated in a community setting, and 50% underwent next-generation sequencing (NGS). There was no significant difference in outcomes between Switchers and Upfront TT; inferior outcomes were observed in Non-switchers versus Upfront TT., Conclusion: Our findings demonstrated improved outcomes with upfront 1L TT versus non-TT in patients with aNSCLC with ADOs and observed timely switching to TT after biomarker test result had similar outcomes to Upfront TT. Opportunities remain to improve the use of NGS for early ADO identification and determination of 1L TT., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Inhibition of the adenosine 2A receptor (A 2A R) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A 2A R antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer., Methods: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics., Results: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 -3.8) and 1.5 (1.3- 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature., Conclusion: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile., Clinical Trial: gov identifier: NCT04089553., (© 2024. The Author(s).)

Background: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy., Methods: This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing., Findings: Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure)., Interpretation: Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor., Funding: Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute., Competing Interests: Declaration of interests TKC reports institutional and personal, paid or unpaid support, or both, for research, advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, NuScan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and Continuing Medical Education events (Peerview, OncLive, and MJH). TKC has institutional patents filed on molecular alterations and immunotherapy response or toxicity, and ctDNA. TKC has stock or stock options in Tempest, Pionyr, Osel, Precede Bio, and CureResponse, and serves on committees for the National Comprehensive Cancer Network, Genitourinary Cancer Steering Committee, American Society of Clinical Oncology, European Society for Medical Oncology, Academic and Community Cancer Research United, and KidneyCan. TKC mentored several non-US citizens on research projects with potential funding (in part) from non-US sources or foreign components. TKC's institution (Dana-Farber Cancer Institute) might have received additional independent funding of drug companies or royalties potentially involved in research around the subject matter. DFM has received honoraria from BMS, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly, Werewolf Therapeutics, Calithera Biosciences, Synthekine, Johnson & Johnson, and Aveo and research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes, Checkmate Pharmaceuticals, and CRISPR Therapeutics. JM has received research grants from Merck, Eisai, Exelixis, Rubius Therapeutics, Corvus, Trishula, Genentech, Peloton, Vyriad, SillaJen, Seattle Genetics, Tocagen, and Replimune; royalties from UpToDate; and participated on an advisory board for Merck. TMB has received study support from Merck; and speaking or consulting fees from Pfizer, Bayer, Eli Lilly, and Bristol Myers Squibb. RF has received research grants from Merck. MDM has participated in advisory boards for Merck, Eisai, Janssen, and Exelixis. SZ has participated on an advisory board for Exelixis. AR, RP, and DV are employees of Merck & Co. SST has received research funding from Genentech, BMS, Merck Sharp & Dohme, Pfizer, Nektar, Exelixis, Clinigen Group, and Aveo Oncology; honoraria for FirstWord Pharma, Targeted Oncology, and Natera; and participated on an advisory board for Merck, BMS, and Exelixis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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

Background: CheckMate 920 (NCT02982954) is a multicohort, phase 3b/4 clinical trial of nivolumab plus ipilimumab treatment in predominantly US community-based patients with previously untreated advanced renal cell carcinoma (RCC) and clinical features mostly excluded from phase 3 trials. We report safety and efficacy results from the advanced non-clear cell RCC (nccRCC) cohort of CheckMate 920., Methods: Patients with previously untreated advanced/metastatic nccRCC, Karnofsky performance status ≥70%, and any International Metastatic Renal Cell Carcinoma Database Consortium risk received up to four doses of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks followed by nivolumab 480 mg every 4 weeks for ≤2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥3 immune-mediated adverse events (AEs) within 100 days of last dose of study drug. Key secondary endpoints included objective response rate (ORR), progression-free survival (PFS; both investigator-assessed), time to response (TTR), and duration of response (DOR), all using RECIST V.1.1. Overall survival (OS) was exploratory., Results: Fifty-two patients with nccRCC (unclassified histology, 42.3%; papillary, 34.6%; chromophobe, 13.5%; translocation-associated, 3.8%; collecting duct, 3.8%; renal medullary, 1.9%) received treatment. With 24.1 months minimum study follow-up, median duration of therapy (range) was 3.5 (0.0-25.8) months for nivolumab and 2.1 (0.0-3.9) months for ipilimumab. Median (range) number of doses received was 4.5 (1-28) for nivolumab and 4.0 (1-4) for ipilimumab. Grade 3-4 immune-mediated AEs were diarrhea/colitis (7.7%), rash (5.8%), nephritis and renal dysfunction (3.8%), hepatitis (1.9%), adrenal insufficiency (1.9%), and hypophysitis (1.9%). No grade 5 immune-mediated AEs occurred. ORR (n=46) was 19.6% (95% CI 9.4 to 33.9). Two patients achieved complete response (papillary, n=1; unclassified, n=1), seven achieved partial response (papillary, n=4; unclassified, n=3), and 17 had stable disease. Median TTR was 2.8 (range 2.1-14.8) months. Median DOR was not reached (range 0.0+-27.8+); eight of nine responders remain without reported progression. Median PFS (n=52) was 3.7 (95% CI 2.7 to 4.6) months. Median OS (n=52) was 21.2 (95% CI 16.6 to not estimable) months., Conclusions: Nivolumab plus ipilimumab for previously untreated advanced nccRCC showed no new safety signals and encouraging antitumor activity., Trial Registration Number: NCT02982954., Competing Interests: Competing interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. Relationships may not relate to the subject matter of this manuscript. SST reports consulting or advisory role from Merck, Intellisphere, Natera, Bristol Myers Squibb (BMS) and Exelixis; patent pending (institution); and research funding (all institution) from Genentech, BMS, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, and Clinigen Group. LNG reports employment from Florida Medical Clinic; leadership from Florida Cancer Specialists; honoraria from Ameris Pharma; consulting or advisory role from Janssen Oncology; and speakers bureau from Myriad Genetics. RSA reports consulting or advisory role from Eisai, Bayer, Janssen Biotech, EMD Serono; and speakers bureau from Astellas Pharma, Janssen Oncology, Bayer, and Pfizer. EA reports employment from Tennessee Oncology; travel accommodation, expenses from Flatiron Health, OneOncology, Sarah Cannon Research Institute; other relationship from Sarah Cannon Research Institute; stock or other ownership interests from OneOncology; and research funding (all institution) from AstraZeneca, Boehringer Ingelheim, BMS, Calistoga Pharmaceuticals, Celgene, Cephalon, Chorus, Cougar Biotechnology, Eisai, EMD Serono, Evelo Biosciences, Exelixis, Genentech, Gilead Sciences, Incyte, Merck, Millennium, Modra Pharmaceuticals, Novartis, OncoGenex, Onyx, Pelton Therapeutics, Pfizer, Sarah Cannon Research Institute, Takeda, Clovis Oncology, Lilly, Infinity Pharmaceuticals, and Janssen Research & Development. MRH reports consulting or advisory role from Bayer, Exelixis, Genentech, Fujifilm, Janssen Oncology, AstraZeneca, Pfizer, and BMS; speakers bureau from Genentech and Exelixis; and research funding (all institution) from BMS, Genentech, Pfizer, Merck, Clovis Oncology, Acerta Pharma, AstraZeneca, Astellas Pharma, Bayer, Exelixis, and Seattle Genetics. IP has nothing to disclose. RS reports consulting or advisory role from Aveo Pharmaceuticals, Janssen Scientific Affairs, and Dendreon. PVV reports honoraria from Sanofi. DJG reports consulting or advisory role from Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, BMS, Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J Hennessy Associates, Propella Therapeutics (formerly Vizuri), Constellation Pharmaceuticals, Flatiron, Modra Pharmaceuticals, Physician Education Resource, and RevHealth; leadership from Capio Biosciences; speakers bureau from Sanofi, Bayer, and Exelixis; travel, accommodations, expenses from Bayer, Exelixis, Sanofi, UroToday; honoraria from Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, American Association for Cancer Research, Axess Oncology, Janssen Oncology, Millennium Medical Publication, Ipsen, and UroGPO; and research funding (all institution) from Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, BMS, Calithera Biosciences, AstraZeneca, and Sanofi/Aventis. TH reports employment from Texas Oncology; consulting or advisory role from Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, BMS, Eisai, and Exelixis; speakers bureau from Pfizer, Johnson & Johnson, Eisai, Exelixis, Astella Pharma, and BMS; honoraria from Pfizer, Astellas Pharma, BMS, Exelixis, Eisai, Novartis, Johnson & Johnson, and Bayer/Onyx; and research funding (all institution) from Pfizer, Johnson & Johnson, Exelixis, Eisai, and BMS. JZh reports employment and stock ownership from BMS. JZo reports employment and consulting or advisory role from Syneos Health. JLJ reports employment and stock ownership from BMS. ARK reports remuneration for a consulting or advisory role from Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, BMS, and EMD Serono; speakers bureau from Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, BMS, Amgen, Exelixis, EMD Serono, Merck, Seattle Genetics/Astellas, Gilead, and Myovant; travel, accommodations and expenses from Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis, and AstraZeneca; stock ownership from ECOM Medical; and research funding (all institution) from Genentech, Exelixis, Janssen, AstraZeneca, Bayer, BMS, Eisai, MacroGenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics, and Epizyme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324)., Methods: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T cells) and CD274 gene expression., Results: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry., Conclusions: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The open-label phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma. Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the advanced non-clear cell RCC (nccRCC) cohort of CheckMate 374., Methods: Eligible patients received 0 to 3 prior systemic therapies. Patients received nivolumab 240 mg Q2W for ≤24 months or until confirmed progression or unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: Forty-four patients had advanced nccRCC (papillary [n = 24], chromophobe [n = 7], unclassified [n = 8], other [n = 5]); 34.1% received ≥1 prior systemic regimen in the advanced/metastatic setting. With median follow-up of 11 (range, 0.4-27) months, no all-cause grade 3-5 IMAEs or treatment-related grade 5 adverse events were reported. ORR was 13.6% (95% confidence interval [CI], 5.2-27.4), with 1 complete response (chromophobe) and 5 partial responses (papillary [n = 2], chromophobe [n = 1], collecting duct [n = 1], and unclassified [n = 1] histology). Median PFS was 2.2 months (95% CI, 1.8-5.4). Median OS was 16.3 months (95% CI, 9.2-not estimable)., Conclusions: Safety of flat-dose nivolumab 240 mg Q2W was consistent with previous results. Clinically meaningful efficacy was observed with responses in several histologies, supporting nivolumab as a treatment option for patients with advanced nccRCC, a patient population with high unmet need., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort., Patients and Methods: Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival., Results: Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable)., Conclusions: This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for multiple myeloma. The original treatment regimen of bendamustine 80 mg/m 2 , days 1, 4; bortezomib 1·3 mg/m 2 , days 1, 4, 8, 11; dexamethasone 40 mg, days 1, 2, 3, 4 on a 28-day cycle (up to 8 cycles) was efficacious but determined relatively toxic in an interim analysis. The regimen was amended to bendamustine 80 mg/m 2 , days 1, 2; bortezomib 1·3 mg/m 2 , days 1, 8, 15; dexamethasone 20 mg, days 1, 2, 8, 9, 15, 16 every 28 days (up to 8 cycles), then maintenance 1·3 mg/m 2 IV bortezomib every 2 weeks. Fifty-nine patients were enrolled. Primary endpoint was complete response (CR) rate. The original schema was given for a median of 7 cycles (range 1-8); modified schema was given for a median of 8 cycles (range 1-8) plus maintenance. Overall response was 91%, CR was 9%. Median follow-up was 19·1 months; median progression-free survival was 11·1 months and 18·9 months on the original and modified regimens, respectively. The most common Grade 3/4 adverse events were fatigue and neuropathy. The combination of BBD is tolerable and efficacious in this patient population. Modifications to decrease intensity but increase duration translated to better outcomes., (© 2017 John Wiley & Sons Ltd.)

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Preclinical models suggest that addition of anti-vascular endothelial growth factor therapy may improve the efficacy of anti-estrogens in hormone-sensitive breast cancer. This phase II trial evaluated the feasibility and efficacy of bevacizumab added to either anastrozole or fulvestrant in the first-line treatment of patients who have hormone receptor-positive metastatic breast cancer., Methods: Women who had newly diagnosed metastatic hormone receptor-positive breast cancer were eligible. Patients who had relapsed while receiving, or ≤ 12 months after receiving, adjuvant aromatase inhibitor therapy were treated with bevacizumab (10 mg/kg intravenously every 2 weeks) and fulvestrant (loading dose 500 mg intramuscularly [IM], then 250 mg IM 2 weeks later, then 250 mg IM every 4 weeks). All other patients received fulvestrant/bevacizumab or anastrozole (1 mg orally daily)/bevacizumab. Patients who were HER2-positive could also receive trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Patients were reevaluated after 8 weeks of therapy; responding or stable patients continued treatment until disease progression or unacceptable toxicity., Results: Seventy-nine patients were enrolled (38 were administered anastrozole 41 fulvestrant). Median treatment duration was 8 months in the anastrozole group and 5.5 months in the fulvestrant group. Both regimens were efficacious: overall response rate and median progression-free survival for the entire group were 28% and 13.5 months, respectively. Both regimens were well-tolerated; toxicity was consistent with the known toxicity profiles of each single agent., Conclusion: Bevacizumab combined with either anastrozole or fulvestrant was feasible and active in the first-line treatment of patients who have hormone receptor-positive metastatic breast cancer. Phase III trials evaluating the efficacy of bevacizumab added to endocrine therapy are in progress., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Between 1991 and 1999, 67 patients with acute non-lymphocytic leukemia (ANLL) in complete remission received high dose cytarabine (HiDAC) 3 gm/m2 q12h x 12 doses followed by daunorubicin 45 mg/m2/day x 3 days as consolidation therapy. Five year actuarial event free survival (EFS) was 34% +/- 6%. Age was significantly associated with EFS. EFS was 60% +/- 15% in patients age 20 to 29, 48% +/- 16% in patients age 30 to 39, 23% +/- 10% in patients age 40 to 49, 31% +/- 11% in patients age 50 to 59, and 0% in patients age > or = 60. Contrary to other reports which have used different HiDAC regimens, we found no relationship between cytogenetics and EFS. Cytogenetics were defined as favorable risk: t(8;21), inv (16), and del (16); neutral risk: normal or t(15;17); and unfavorable risk: any abnormality not included in favorable risk or neutral risk. EFS was 29% +/- 17% in patients with favorable cytogenetics, 37% +/- 14% in patients with neutral cytogenetics, and 31% +/- 12% in patients with unfavorable cytogenetics. These differences were not statistically significant. Because of the successful use of allogeneic transplantation at relapse in patients with matched related donors, five year actuarial survival (S) in this series was 40% +/- 6%. Five year actuarial survival was 57% +/- 9% for patients age < or = 44 and 25% +/- 8% for patients age > or = 45. This difference is statistically significant, p < .025. Clinicians should be cautious about making clinical decisions regarding consolidation therapy of ANLL on the basis of the presence or absence of cytogenetic abnormalities as the importance of cytogenetics may depend on the specific therapy which is employed.

A comparison was made between a macrotechnique in tubes and a microtechnique in plastic plates for complement-fixation tests, using strains of three subtypes of the Asia 1 type of foot-and-mouth disease (FMD) virus. The results obtained with these techniques were found to be comparable and delineated the antigenic relationships of the three strains employed. The microtechnique was considered to be both economical with reagents and capable of similar accuracy and reproducibility to that of the standard method in tubes. It was concluded that the antigenic analysis of subtype strains of FMD virus can be conveniently carried out by the use of the microtechnique as described.