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BackgroundThe single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.Patients and methodsForty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.ResultsORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.ConclusionNilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.Clinical trial registrationClinicalTrials.gov, NCT01028222.

Leslie A Fecher,1,3 William H Sharfman2 1Department of Internal Medicine and Dermatology, Indiana University Health Simon Cancer Center, Indianapolis, IN, USA; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 3Department of Internal Medicine and Dermatology, University of Michigan, MI, USA Abstract: Cutaneous basal cell carcinoma (BCC) is the most common human cancer and its incidence is rising worldwide. Ultraviolet radiation exposure, including tanning bed use, as well as host factors play a role in its development. The majority of cases are treated and cured with local therapies including surgery. Yet, the health care costs of diagnosis and treatment of BCCs in the US is substantial. In the United States, the cost of nonmelanoma skin cancer care in the Medicare population is estimated to be US$426 million per year. While rare, locally advanced BCCs that can no longer be controlled with surgery and/or radiation, and metastatic BCCs do occur and can be associated with significant morbidity and mortality. Vismodegib (GDC-0449), a smoothened inhibitor targeted at the hedgehog pathway, is the first US Food and Drug Association (FDA)-approved agent in the treatment of locally advanced, unresectable, and metastatic BCCs. This class of agents appears to be changing the survival rates in advanced BCC patients, but appropriate patient selection and monitoring are important. Multidisciplinary assessments are essential for the optimal care and management of these patients. For some patients with locally advanced BCC, treatment with a hedgehog inhibitor may eliminate the need for an excessively disfiguring or morbid surgery. Keywords: basal cell carcinoma, hedgehog, smoothened, vismodegib, Gorlin, basal cell nevus syndrome

Background With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. Materials and methods Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n  = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPRbx, ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n  = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). Results Specimens from responders in the discovery cohort had features of immune-activation (moderate–high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P  ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P  = 0.009) and MPRbx associated with increased overall survival (n  = 51; HR 0.13; 95%CI, 0.054–0.31, P  = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPRbx, indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. Conclusions Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available. [ABSTRACT FROM AUTHOR]

Background: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors., Methods: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m 2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments., Results: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab., Conclusions: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer., Trial Registration Numbers: NCT02110082; NCT02253992., Competing Interests: Competing interests: NIK reports consulting fees from Bristol Myers Squibb, Merck, Jounce, Novartis, Regeneron, Genzyme, Iovance, Castle Biosciences, Nektar, Replimune, and Instil Bio; research funding (to institute) from Bristol Myers Squibb, Merck, Celgene, Novartis, GSK, HUYA, Regeneron, Replimune, Modulation Therapeutics; participation on a data safety monitoring board with Incyte, AstraZeneca; participation in a study steering committee with Bristol Myers Squibb, Nektar, Regerenon, Replimune; and ownership of common stock in Bellicum, Amarin, and Asensus Surgical. PAO reports grants from Bristol Myers Squibb, Neon Therapeutics, Merck, Pfizer, Novartis, Celldex, Xencor, Roche/Genentech, Oncorus; consulting fees from Bristol Myers Squibb, Evaxion, Merck, Roche/Genentech, Novartis, Immunetune, LG Chem; leadership or fiduciary role with NCCN. RF reports grants or contracts from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck, Novasenta, Tesaro; consulting fees with Adagene, Aduro Biotech, Bicara Therapeutics, Brooklyn ImmunoTherapeutics, Catenion, EMD Serono, Everest Clinical Research Corporation, F. Hoffman-La Roche Ltd., Federation Bio, Genocea Biosciences, Kowa Research Institute, Mirati Therapeutics, Nanobiotix, Novartis, Novasenta, PPD Development, Sanofi, Zymeworks; participation on a data safety monitoring or advisory board with Coherus BioSciences, Eisai Europe Ltd., Genmab, Hookipa, Instil Bio, Lifescience Dynamics, MacroGenics, MeiraGtx, Merck, Mirror Biologics, Numab Therapeutics AG, OncoCyte, Pfizer, Rakuten Medical, Seagen, SIRPant Immunotherapeutics, Vir Biotechnology, stock or stock options with Novasenta. TC reports speaker fees/honoraria from AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; advisory role/consulting fees from Arrowhead Pharmaceuticals, Bristol Myers Squibb, Genentech, MedImmune/AstraZeneca, Merck, Pfizer, and Regeneron; institutional research funding from Bristol Myers Squibb, EMD Serono, and MedImmune/AstraZeneca; and travel, food and/or beverage expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, and Society for Immunotherapy of Cancer. DS reports research funding to the institution from Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Array; patient fees to the institution for clinical studies from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma; consulting fees/honoraria from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Philogen, Pfizer, Array, InflaRX, Nektar, Sun Pharma, OncoSec, Replimune, NeraCare, Sandoz, Ultimovacs; reimbursement from the Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape Oncology and PeerView Institute for travel; nonfinancial support from Bristol Myers Squibb, MSD, Novartis, Merck-EMD, Pierre-Fabre, Pfizer, InFlaRX, NeraCare, Nektar, Sun Pharma, Sandoz; consulting/advisory role fees from MedImmune, AstraZeneca, Bristol Myers Squibb, Merck& Co., Genentech, Arrowhead Pharmaceuticals, and EMD Serono; institutional clinical research funding from Boehringer Ingelheim, MedImmune, AstraZeneca, EMD Serono, and Bristol Myers Squibb. DTL reports serving on advisory boards for Merck, Bristol Myers Squibb, Nouscom, G1 Therapeutics, and Janssen; receiving research funding from Merck, Bristol Myers Squibb, Curegenix, Nouscom, and AbbVie; speaking honoraria from Merck; being an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. MRS reports support for present manuscript from Bristol Myers Squibb; participation on a data safety monitoring or advisory board with Pilant Therapeutics; stock or stock options with Bristol Myers Squibb. FB reports financial interest with AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Takeda. WS reports grants and personal fees from Bristol Myers Squibb, Merck, and Novartis; personal fees from Regeneron; and grants from Genentech. JJL reports grants or contracts from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, F-star, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, MacroGenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; consulting fees from 7 Hills, Bright Peak, Exo, F-star, Inzen, RefleXion, Xilio, Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, Stipe, Tempest, AbbVie, Alnylam, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, MacroGenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, Servier, Stingthera, Synlogic, Synthekine; provisional patents in cancer immunotherapy (serial no. 15/612,657) and microbiome biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic, and therapeutic uses thereof (PCT/US18/36052); participation on a data safety monitoring board or advisory board with AbbVie, Immutep, Evaxion; leadership or fiduciary role with Society for Immunotherapy of Cancer; stock or stock options with Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, Pyxis, Saros, STipe, Tempest. IM reports support for the current manuscript from Bristol Myers Squibb; grants or contracts from Bristol Myers Squibb, Roche, Genmab, Highlight Therapeutics, AstraZeneca; consulting fees from Bristol Myers Squibb, Roche, Genmab, Merus, Pieris, AstraZeneca, Numab, Highlight Therapeutics; payment or honoraria from Bristol Myers Squibb; support for attending meetings and/or travel from Bristol Myers Squibb and Roche. DL, JN and JH are employees and stock owners of Bristol Myers Squibb. AS is an employee of Boston Scientific. SS, AS, RS and SE report employment with Bristol Myers Squibb. NHS reports consulting fees from ABL Bio, Agenus, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Numab, Puretech, Regeneron, Revitope, and Roche/Genentech; and research funding from Agenus, AstraZeneca, Bristol Myers Squibb, Immunocore, Merck, Pfizer, Puretech, Regeneron, and Roche/Genentech., (© 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: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting., Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria., Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR., Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach., Trial Registration Number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759., Competing Interests: Competing interests: RLF reports consulting or advisory from Bristol Myers Squibb (BMS), MedImmune, Merck, Lilly, Pfizer, Amgen, EMD Serono, PPD, Bain Capital Life Sciences, GlaxoSmithKline, Iovance Biotherapeutics, Numab Therapeutics AG, Oncorus, Ono Pharmaceutical, Regeneron, Novasenta, Aduro Biotech, MacroGenics, Nanobiotix, Torque Therapeutics, Lifescience Dynamics, Sanofi, and Zymeworks, Inc; and research funding from BMS, MedImmune, Merck, Tesaro, Novasenta, VentiRx, and AstraZeneca/MedImmune. WCS reports consulting from BMS and Regeneron. RL reports personal and institutional research funding from BMS. AG has nothing to disclose. UMM reports consulting and advisory from MSD Oncology, Roche, BMS, and Celgene; and travel accommodations from BMS, Celgene, Amgen, and Pierre Fabre. CK has nothing to disclose. WS reports honoraria from BMS and Array BioPharma; consulting or advisory from BMS, Novartis, Regeneron, ION Pharma, and Merck; research funding from Novartis, Merck, and Genentech; and institutional research funding from BMS. CHC reports consulting or advisory fees from BMS, CUE Biopharma, Ignyta, Mirati Therapeutics, and Sanofi; research funding from BMS, Ignyta, Lilly, Regeneron, IRX Therapeutics, and Lion Biotechnologies; and travel accommodation expenses from Mirati Therapeutics. LAD reports institutional expert input forum payments from MSD BV Netherlands; and institutional speaker fee payment from BMS. HG has nothing to disclose. SIC has nothing to disclose. LV has nothing to disclose. JMT reports consulting and advisory from BMS, MedImmune, Merck, Compugen, and Akoya Biosciences, and stock options from Akoya Biosciences. JES has nothing to disclose. JL reports employment and stock ownership from BMS. BL reports employment and stock ownership from BMS. TC reports employment and stock ownership from BMS. AB reports employment and stock ownership from BMS. SLT reports consulting or advisory from Five Prime Therapeutics, Immunocore, and Merck; travel accommodations from Five Prime Therapeutics, Merck, and BMS; research funding from BMS; stock ownership by her spouse in Tizona Therapeutics, DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Trieza Therapeutics, and Dracen Pharmaceuticals; consulting or advisory by her spouse in DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Amgen, AstraZeneca, Immunomic Therapeutics, Janssen Oncology, and Dynavax Technologies; royalties by her spouse in WindMIL, Immunomic Therapeutics, Arbor Pharmaceuticals, BMS, and NexImmune; and research funding by her spouse from Compugen., (© 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.)

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged ≥18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82% [95% confidence interval (CI) 79-84] and 70% (95% CI 66-74), respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy., Competing Interests: Declaration of Interests C.S.G. reports a pending patent on the use of PAK4 inhibitors. J.T. is currently an employee of Tango Therapeutics. M.O. reports no conflicts of interest. G.A.R. reports a pending patent on the use of PAK4 inhibitors. P.R.-M. is an employee and stockholder for Bristol-Myers Squibb. M.W.-R. is an employee and stockholder for Bristol-Myers Squibb. A.C. reports no conflicts of interest. E.M. reports no conflicts of interest. D.Y.T. reports no conflicts of interest. D.S.S. received honoraria from Genentech (speakers bureau) and NovMetaPharma (consultant). P.T. reports no conflicts of interest. Y.J.K. reports no conflicts of interest. C.P.S. has received payment for licensing a patent on non-viral T cell gene editing to Arsenal. K.M.C. is a shareholder in Geneoscopy LLC. A.V-C. reports no conflicts of interest. M.Q. reports no conflicts of interest. C.M. reports no conflicts of interest. J.J.L. discloses Data and Safety Monitoring Board: TTC Oncology; Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Kanaph, Mavu (now part of AbbVie), Onc.AI, Pyxis, Springbank, Tempest, Consultancy: Abbvie, Akrevia, Algios, Array, Astellas, Bayer, Bristol-Myers Squibb, Eisai, EMD Serono, Ideaya, Incyte, Janssen, Merck, Mersana, Novartis, PTx, RefleXion, Silicon, Tesaro, Vividion; Research Support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, Xencor; Travel: Akrevia, Bayer, Bristol-Myers Squibb, EMD Serono, Incyte, Janssen, Merck, Mersana, Novartis, Pyxis, RefleXion; Patents: (both provisional) serial no. 15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). J.D.W. is consultant for: Adaptive Biotech; Amgen; Apricity; Ascentage Pharma; Astellas; AstraZeneca; Bayer; Beigene; Bristol-Myers Squibb; Celgene; Eli Lilly; F Star; Imvaq; Kyowa Hakko Kirin; Linneaus; AstraZeneca; Merck; Neon Therapuetics; Polynoma; Psioxus; Recepta; Takara Bio; Trieza; Truvax; Serametrix; Surface Oncology; Syndax; Syntalogic. J.D.W. receives research support from: Bristol-Myers Squibb; AstraZeneca; Sephora. J.D.W. has Equity in: Tizona Pharmaceuticals; Adaptive Biotechnologies; Imvaq; Beigene; Linneaus. D.B.J. serves on advisory boards for Array BioPharma, BMS, Jansen, Merck, and Novartis, receives research funding from BMS and Incyte, and has a patent pending on using MHC-II as a biomarker for immunotherapy response. B.C. is a member of the speakers bureau for Regeneron and Sanofi. F.S.H. reports funding from Bristol-Myers Squibb to institution, during the conduct of the study; grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis, personal fees from Takeda, personal fees from Surface, personal fees from Genentech/Roche, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Bayer, personal fees from Aduro, personal fees from Partners Therapeutics, personal fees from Sanofi, personal fees from Pfizer, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Verastem, personal fees from Torque, personal fees from Rheos, personal fees from Kairos, personal fees from Bicara, from Psioxus Therapeutics, personal fees from Amgen, other from Pieris Pharmaceutical, from Boston Pharmaceuticals, from Zumutor, outside the submitted work; In addition, Dr. Hodi has a patent for Methods for Treating MICA-Related Disorders (no. 20100111973) with royalties paid, a patent for Tumor Antigens and Uses Thereof (no. 7250291) issued, a patent for Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (no. 20170248603) pending, a patent for Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (no. 20160340407) pending, a patent for Therapeutic Peptides (no. 20160046716) pending, a patent for Therapeutic Peptides (no. 20140004112) pending, a patent for Therapeutic Peptides (no. 20170022275) pending, a patent for Therapeutic Peptides (no. 20170008962) pending, a patent for Therapeutic Peptides patent no. 9402905 issued, a patent for Methods of Using Pembrolizumab and Trebananib pending, a patent for vaccine compositions and methods for restoring NKG2D pathway function against cancers patent no. 10279021 issued, a patent for antibodies that bind to MHC class I polypeptide-related sequence A patent no. 10106611 issued, and a patent for Anti-Galectin Antibody Biomarkers Predictive of Anti-Immune Checkpoint and Anti-Angiogenesis Responses publication no. 20170343552 pending. S.B. reports advisory board participation (with honorarium) from Genentech, EMD Serono, BMS and Sanofi-Genzyme; and research funding to his institution (University of Washington) from BMS, Oncosec, EMD Serono, Merck, NantKwest, Novartis, Exicure, Incyte, and Immune Design. W.S. discloses consulting fees from BMS, Merck, Novartis, Regeneron and research grant support from BMS, Merck, Novartis. W.J.U. serves on a compensated data and safety monitoring committee for Astra Zeneca, and reports institutional grants from BMS and Merck. C.L.S. discloses research funding to his University from Merck, Celldex, and GlaxoSmithKline; research support in kind to his University from Theraclion and 3M; Scientific Advisory Board role with Immatics (prior), and Curvac (planned); PI role for Polynoma with compensation to his University; and patent royalties as co-inventor of peptides for use in cancer vaccines (patents held by the UVA Licensing and Ventures Group). A.D. reports receiving honoraria from Nektar, Idera, Novartis, and Array BioPharma. J.B.A.G.H. Advisory roles: Aimm, Amgen, AZ, Bayer, BMS, Celsius, Gadeta, GSK, Immunocore, MSD, Merck Serono, Neon, Neogene, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Vaximm. Grant support: Neon, BMS, MSD, Novartis. Stock options: Neogene Therapeutics. S.M.A. participated in advisory boards with Amgen, BMS, Merck Serono, MSD, Pierre-Fabre, Sanofi-Aventis and in educational events organized by BMS, MSD, Pierre-Fabre, Roche, Sanofi-Aventis. V.A. receives research funding from Bristol-Myers Squibb. D.M.P. and S.L.T. report stock and other ownership interests from Aduro Biotech, Compugen, DNAtrix, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, FLX Bio, Jounce Therapeutics, Potenza Therapeutics, Tizona Therapeutics, and WindMIL; consulting or advisory roles with AbbVie, Amgen, Bayer, Compugen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, FLX Bio, Immunocore, lmmunomic Therapeutics, Janssen Oncology, Medlmmune, Merck, Tizona Therapeutics, and Wind MIL; research funding from Bristol-Myers Squibb, Compugen, and Potenza Therapeutics; patents, royalties, and other intellectual property from Aduro Biotech, Bristol-Myers Squibb, and lmmunonomic Therapeutics; and travel, accommodations, and expenses from Bristol-Myers Squibb and Five Prime Therapeutics. V.E.V. is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. In addition, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. V.E.V. is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals. Within the last 5 years, V.E.V. has been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. D.E.S. reports no conflicts of interest. A.K. reports no conflicts of interest. A.R. has received honoraria from consulting with Amgen, Bristol-Myers Squibb, Chugai, Genentech, Merck, Novartis, Roche, and Sanofi, is or has been a member of the scientific advisory board and holds stock in Advaxis, Apricity, Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime, FLX Bio, ImaginAb, Isoplexis, Kite-Gilead, Lutris Pharma, Merus, PACT Pharma, Rgenix, and Tango Therapeutics, has a reports a pending patent on the use of PAK4 inhibitors, has received research funding from Agilent and from Bristol-Myers Squibb through Stand Up to Cancer (SU2C), and has received payment for licensing a patent on non-viral T cell gene editing to Arsenal., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available., Methods: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants., Results: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma., Conclusion: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

Purpose: To characterize the effect of concurrent stereotactic radiosurgery-stereotactic radiation therapy (SRS-SRT) and immune checkpoint inhibitors on patient outcomes and safety in patients with brain metastases (BMs)., Methods and Materials: We retrospectively identified metastatic non-small cell lung cancer, melanoma, and renal cell carcinoma patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy. We included SRS-SRT patients who were treated with anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) and anti-programmed cell death protein 1 receptor (nivolumab, pembrolizumab). Patients who were given immune checkpoint inhibitors on active or unreported clinical trials were excluded, and concurrent immune checkpoint inhibition (ICI) was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with nonconcurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events, and new BMs., Results: A total of 260 patients were treated with SRS-SRT to 623 BMs. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35% of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related adverse events or acute neurologic toxicity and predicted for a decreased likelihood of the development of ≥3 new BMs after SRS-SRT (P=.045; odds ratio, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with nonconcurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (P=.002; hazard ratio [HR], 2.69) and compared with nonconcurrent SRS-SRT and ICI (P=.006; HR, 2.40) on multivariate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (P=.002; HR, 3.82) or after ICI (P=.021; HR, 2.64)., Conclusions: Delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BMs and favorable survival outcomes without increased rates of adverse events., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

We report the acute onset of aseptic sinusitis in 2 patients receiving the immune checkpoint inhibitors, ipilimumab and nivolumab, for treatment of metastatic melanoma. Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4, and nivolumab, targeting programmed cell death-1, have been associated with numerous immune-related adverse events. To the authors' knowledge, this is the first report of aseptic sinusitis as a consequence of immune checkpoint inhibition therapy.

To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis. RAF265 has a serum half-life of approximately 200 h. The MTD was 48 mg once daily given continuously. Among 77 patients, most common treatment-related adverse effects were fatigue (52%), diarrhea (34%), weight loss (31%) and vitreous floaters (27%). Eight of 66 evaluable patients (12.1%) had an objective response, including seven partial and one complete response. Responses occurred in BRAF-mutant and BRAF wild-type (WT) patients. Twelve of 58 (20.7%) evaluable patients had a partial metabolic response. On-treatment versus pretreatment IHC staining in 23 patients showed dose-dependent p-ERK inhibition. We observed a significant temporal increase in placental growth factor levels and decrease in soluble vascular endothelial growth factor receptor 2 (sVEGFR-2) levels in all dose levels. RAF265 is an oral RAF/VEGFR-2 inhibitor that produced antitumor responses, metabolic responses, and modulated angiogenic growth factor levels. Antitumor activity occurred in patients with BRAF-mutant and BRAF-WT disease. Despite low activity at tolerable doses, this study provides a framework for the development of pan-RAF inhibitors and modulators of angiogenesis for the treatment of melanoma., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management., Methods: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned., Results: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy ( n  = 22), noninfective meningitis ( n  = 5), encephalitis ( n  = 6), neuromuscular disorders ( n  = 3), and nonspecific adverse events ( n  = 7). Study drug was discontinued ( n  = 20), interrupted ( n  = 8), or unchanged ( n  = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal., Conclusion: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs., Implications for Practice: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non-small cell lung cancer after initial response to immune checkpoint blockade with anti-PD-1 or anti-PD-1/anti-CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264-76. ©2017 AACR. See related commentary by Yang, p. 250 This article is highlighted in the In This Issue feature, p. 235 ., (©2017 American Association for Cancer Research.)

Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

Background: Bortezomib is a proteasome inhibitor with manageable clinical toxicity and laboratory evidence of anti-melanoma activity. Therefore, it was considered for clinical testing in patients with metastatic melanoma., Methods: Patients with metastatic melanoma and adequate hematologic, renal, and hepatic function were treated with bortezomib (a 1.5-mg/m2 intravenous bolus twice weekly for 2 of every 3 weeks). Eligible patients were age > or = 18 years with an Eastern Cooperative Oncology Group performance status of 0-1. The primary goal of the current study was to evaluate the 18-week disease progression-free survival rate and tolerability of bortezomib in these patients., Results: The current study was intended to treat 45 patients. It was closed at the planned interim analysis due to early evidence of insufficient clinical efficacy. Twenty-seven patients with a median age of 56 years (range, 32-77 years)were accrued. There were no major clinical responses to treatment. Only 6 patients (22%) achieved stable disease. Of these 6 patients, 4 were still stable after 4 cycles of treatment, but were removed from the study due to toxicity. The median time to disease progression was 1.5 months (95% confidence interval [95% CI], 1.4-1.6) with a median overall survival of 14.5 months (95% CI, 9-22). Having failed bortezomib, most patients proceeded to other clinical trials. Twenty-six patients were evaluable for toxicity. One patient was removed from the study for other reasons and could not return for the cycle evaluation and thus was never evaluated. Of the 26 patients, no Grade 4/5 treatment-related toxicities (using the National Cancer Institute Common Toxicity Criteria [version 2.0]) were reported. Eleven patients (42%) had Grade 3 toxicities (believed to be at least possibly related to treatment), including sensory neuropathy, thrombocytopenia, constipation, fatigue, ileus, abdominal pain, and infection without neutropenia. The median number of treatment cycles patients received was two (range, one to six treatment cycles). Two patients (7%) had 1 dose delay and 6 patients (22%) had dose reductions during 1 treatment cycle due to adverse events., Conclusions: Single-agent bortezomib, administered twice weekly x 2 weeks, every 3 weeks at a dose of 1.5 mg/m2, was not found to be effective in the treatment of patients with metastatic melanoma., (Copyright 2005 American Cancer Society.)

We conducted a phase II randomized trial of recombinant granculocyte-macrophage colony-stimulating factor (GM-CSF) administered before topotecan chemotherapy to determine whether it could prevent myelosuppression and to determine the antitumor activity of this topoisomerase I inhibitor in 53 patients with metastatic malignant melanoma and renal cell cancer. All patients received GM-CSF after topotecan at a dose of 250 microg/m(2) daily for at least 8 days. Patients randomly assigned to receive GM-CSF priming were treated with GM-CSF at 250 microg/m(2) twice daily for 5 days before treatment. Twenty-five patients were randomly assigned to receive GM-CSF priming and 28 to receive topotecan without priming. The primary analysis was restricted to the protective effects seen during the first cycle of therapy. Grade 4 neutropenia occurred in 8 of 23 patients (35%) and grade 3 neutropenia in 5 of 23 patients (22%) randomized to GM-CSF priming, whereas 18 of 26 (69%) and 5 of 26 (19%) patients experienced grade 4 or 3 neutropenia, respectively, without GM-CSF priming (P =.0074). The mean duration of neutropenia was reduced by GM-CSF priming: grade 3 neutropenia from 5.2 +/- 0.7 to 2.8 +/- 0.7 days (P =.0232) and grade 4 neutropenia from 2.7 +/- 0.6 to 1.1 +/- 0.4 days (P = 0.0332). The protective effects of GM-CSF extended to the second cycle of treatment. The incidence of febrile neutropenia was also reduced. Chemotherapy-induced anemia and thrombocytopenia were similar in both groups. One partial response was seen in a patient with melanoma, and one patient with renal cell cancer had complete regression of pulmonary metastases and was rendered disease-free by nephrectomy. (Blood. 2001;97:1942-1946)

We determined whether a classical conditioning paradigm may be used to condition immunologic responses in normal human subjects receiving an optimal immunostimulating dose of recombinant human interferon-gamma (rhIFN-gamma). We conducted a placebo-controlled, double-blind study of 31 normal volunteers in order to determine whether an initially immune-neutral stimulus, oral propylene glycol (PG), could eventually elicit an immune response as a consequence of its being paired with a known immunostimulatory dose and schedule of rhIFN-gamma. Subjects were randomly assigned to one of three groups: (A) rhIFN-gamma injections paired with PG; (B) normal saline injections paired with PG; (C) rhIFN-gamma injections alone. During the 4-week study, subjects received progressively fewer injections so that, by the final week of the study, no injections were given and groups A and B received only PG. The principal outcome measures were serum concentrations of quinolinic acid (QUIN) and neopterin, two nonspecific but sensitive markers of immune activation, and expression of Fc receptors (CD64) on peripheral blood mononuclear cells. RhIFN-gamma injections produced significant and predictable alterations in each of the measured immune parameters. No group B subject made an immune response. Mean serum QUIN levels were significantly higher at the end of week three for subjects in the experimental condition (group A) than for subjects receiving rhIFN-gamma alone (group C) despite receiving identical doses of rhIFN-gamma. Similarly, the predicted decay in mean serum neopterin levels from the end of week 1 to the end of week 2 was seen in group C but not in group A. The exposure of group A to PG blunted the decline of CD64 expression in week four. The data suggest that the pairing of an unconditioned stimulus (rhIFN-gamma) and a conditioned stimulus (PG) permits the conditioned stimulus alone to prolong a cytokine-induced response in normal humans.

The purpose of this trial was to determine the toxicity and antineoplastic activity of cisplatin, carboplatin, tamoxifen, and interferon-alpha (IFN-alpha) in patients with advanced melanoma. Eleven patients with metastatic melanoma were enrolled. The patients received carboplatin 400 mg/m2 i.v. on day 0; cisplatin 25 mg/m2 i.v. on days 7, 14, and 21; tamoxifen 20 mg p.o. b.i.d. on days 0-27; and interferon-alpha 5 million units/m2 subcutaneously 3 times per week. Cycles were repeated every 28 days. Patients were assessed for tumor response at the end of 2 cycles. Toxicity was severe, with 14 of 24 cycles given requiring some form of dose reduction. Carboplatin dose reductions were related to bone-marrow toxicity, whereas IFN-alpha caused fatigue, arthralgias, myalgias, and fever. The overall response rate was 18% (2 partial responses [PRs]). The combination of cisplatin, carboplatin, tamoxifen, and IFN-alpha is active in advanced melanoma; however, the toxicity is unacceptable.

Purpose: To determine the pathologic complete response rate, toxicity, and survival of patients with resectable squamous cell or adenocarcinoma of the esophagus treated with a 30-day preoperative chemoradiation regimen and surgical resection., Patients and Methods: Fifty patients (16 squamous, 33 adeno, one undifferentiated) who had carcinoma of the esophagus (limited to the primary tumor and regional or celiac nodes) were treated with cisplatin 26 mg/m2/day continuous infusion days 1 through 5 and 26 through 30, 5-fluorouracil (5-FU) 300 mg/m2/day continuous infusion days 1 through 30, and radiation 44 Gy, 2 Gy/fx in 22 daily fractions, days 1 through 30, followed by esophagectomy., Results: Forty-seven patients underwent esophagectomy (94% operability rate), and 45 had total gross removal of disease and negative margins of resection (90% resectability rate). Nineteen patients (40%) had a pathologic complete response (CR). Forty (80%) received 100% of the planned cisplatin dose, 29 (58%) received 100% of the planned 5-FU dose, and 40 (80%) received > or = 80% of the planned 5-FU dose. Forty-five (90%) received the planned 44-Gy radiation dose. Grade 3 or 4 neutropenia occurred in 60% of patients. The incidence of febrile neutropenia was 34%. There was one septic death during chemoradiation and no operative deaths. Weight loss requiring nutritional support occurred in 50% of patients, secondary to anorexia, dysphagia, and/or esophagitis. The survival of all registered patients at a median follow-up of 43 months was 2-year survival 58%, median 31.3 months. Survival analysis by histology showed no difference between the two histologic types (squamous vs adenocarcinoma). However, survival by pathologic response was significantly different: pathologic CR, 19 patients, 2-year survival 78%, median survival 58 months; and pathology positive, 28 patients, 2-year survival 46%, median survival 22.4 months. A Cox proportional hazards model and logistic regression analysis demonstrated a significant survival advantage for pathologic CRs and stage I disease versus higher-stage disease and a correlation between chemotherapy dose received and pathologic staging., Discussion: This 30-day chemoradiation regimen followed by surgery resulted in a high pathologic complete response rate, 40%, and apparent survival advantage for this group. The median survival rate of 31.3 months and 2-year survival rate of 58% suggest that this regimen may improve survival over surgical treatment alone. Randomized trials with large accrual and statistical power are necessary to confirm our results and to determine optimal treatment.

We performed a prospective, randomized study to determine whether subcutaneous administration of interleukin-2 (IL-2) in combination with an autologous renal cell vaccine is feasible and can potentiate antitumor immunity. Seventeen patients with metastatic renal cell carcinoma underwent surgical resection with preparation of an autologous tumor cell vaccine. Patients were vaccinated intradermally twice at weakly intervals with 10(7) irradiated tumor cells plus bacillus Calmette-Guérin, and once with 10(7) tumor cells alone. Patients were randomized to one of three groups: no adjuvant IL-2, low-dose IL-2 (1.2 x 10(6) IU/m2), or high-dose IL-2 (1.2 x 10(7) IU/m2). IL-2 was administered subcutaneously on the day of vaccination and the subsequent 4 days. Immune response was monitored by delayed-type hypersensitivity (DTH) response to tumor cells as compared with normal autologous renal cells. Sixteen of 17 patients received vaccine therapy. Four patients developed cellular immunity specific for autologous tumor cells as measured by DTH responses; two had received no IL-2 and two had received high-dose IL-2. There were two partial responses (PR) noted, both in patients who received high-dose IL-2. One responding patient was DTH(+) and one was negative. A third patient who was DTH(+) after vaccination with no IL-2 had a dramatic PR after receiving IL-2 subcutaneously in a subsequent protocol. Prospective testing of response to recall antigens indicated that only 5 of 12 tested patients were positive, including both clinical responders. These data suggest that subcutaneously administered adjuvant IL-2 does not dramatically augment the immunologic response to autologous renal cell vaccines as determined by the development of tumor-specific DTH response.

The adoptive transfer of anti-CD3-stimulated T killer (T-AK) cells was tested with different bolus and infusional interleukin-2 (IL-2) regimens, and anti-CD3 stimulation procedures to determine immunologic and antitumor effects in patients with a variety of advanced cancers. Indium-111 labeling was used to observe traffic patterns of the infused T-AK. Autologous peripheral blood mononuclear cells were obtained by leukapheresis. Cyclophosphamide (300 mg/m2) was given to most patients immediately after leukapheresis. The harvested cells were activated ex vivo with anti-CD3 overnight or for 4 days, at which time cells were reinfused and an IL-2 regimen was begun. Treatment was repeated 28 days later. This treatment regimen induced significant increases in leukocytes, lymphocytes, and eosinophils in patients in most treatment cohorts. Circulating lymphocytes were predominantly CD3+ T cells with preferential expansion of the CD8+ subset. Patients receiving cells stimulated in vitro for 4 days had significant T-cell lymphocytosis with either infusional or bolus plus infusional IL-2 regimens. T-cell viability was decreased in culture after a second 4-day stimulation with anti-CD3 at day 28; this decrease could be prevented by adding IL-2 to the culture media. Cells stimulated overnight required both bolus and infusional IL-2 to show an atypical lymphocytosis in vivo. Overnight-stimulated T-AK did not show decreases in in vitro viability at the day 28 restimulation. Indium-III-labeled cells trafficked to the liver, spleen, and bone marrow. No increase in uptake was observed in tumor deposits. There were 2 patients with partial responses, 5 with minor responses, 19 with stable disease, and 88 with progressive disease. The length of in vitro anti-CD3 stimulation, and the dose and timing of IL-2 administration in vivo results in different circulating leukocyte populations after adoptive T-AK infusion. Generally, the CD8+ T-cell subset was preferentially expanded by this treatment approach. Repeated ex vivo stimulation with anti-CD3 may cause cell death.

Previous primate and rodent studies suggested that interleukin-1 alpha (IL-1 alpha) caused changes in the secretion of pituitary, adrenal, thyroid, and gonadal hormones, as well as acute-phase reactants. Plasma samples were obtained after IL-1 alpha and beta treatment in cancer patients to document the changes in endocrine function suggested by the animal models. Successive groups of patients were treated at IL-1 alpha doses of 0.01, 0.03, 0.1, 0.3, and 1.0 microgram/kg, given daily as a 15-min intravenous bolus. IL-1 beta was given at 0.1 microgram/kg by the same route and time course. After the first dose of IL-1, statistically significant elevations of a.m. and p.m. cortisol, growth hormone (GH), and prolactin (PRL) occurred. Thyroid-stimulating hormone (TSH) and C-reactive protein (CRP) were elevated by the sixth treatment day. Testosterone decreased significantly in male patients. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were more variable but decreased in most patients. The changes in cortisol, GH, PRL, TSH, CRP, FSH, LH, and testosterone resolved after treatment and did not result in clinically apparent endocrinopathies. Bolus doses of IL-1 alpha and beta cause significant changes in many endocrine laboratory parameters and influence the in vivo activities of multiple homeostatic endocrine functions in human beings.

Background: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed., Purpose: Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination., Methods: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1 alpha (O.1 micrograms/kg per day by intravenous bolus) infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests., Results: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with non-visceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1 alpha-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011)., Conclusions: The combination of IL-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response., Implications: Administration of higher doses of IL-1 alpha alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1 alpha doses alone may be a strategy for attaining better response rates.

We conducted a phase I/II trial of 5-fluorouracil (5-FU), calcium leucovorin (LV), zidovudine (AZT) and dipyridamole (DP), (FLAP) in patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. AZT and DP were given to enhance the biochemical modulation and antitumor activity of 5-FU and LV. All patients received 5-FU (370 mg/m(2) i.v. bolus day 0-4), LV (50 mg/m(2) p.o. every 4 h day 0-4) and DP (50 mg/m(2) p.o. every 6 h days 0-27). In the phase I portion of the study, AZT was dose escalated in cohorts of 5 patients each, from 50 mg p.o. every 6 h days 0-27 to the MTD of 200 mg p.o. every 6 h days 0-27. Thirty-three patients received 200 mg of AZT in the phase II portion of the trial. Eleven patients developed grade III and 5 patients developed grade IV leukopenia. Four patients developed grade III and 21 patients developed grade IV neutropenia, with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. Fifty-eight percent (19 of 33) of patients required dose reductions of AZT for hematologic toxicity (13 of 19 in the first treatment cycle). At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%), no objective responses in 14 patients with renal cell carcinoma or in 14 patients with melanoma. FLAP does not have significant activity in melanoma, renal cell carcinoma or 5-FU-treated colorectal cancer patients, although it may have activity in untreated colon cancer.

Background: Thrombocytopenia is a frequent side effect of cancer chemotherapy and commonly limits attempts to escalate drug doses. To determine whether interleukin-1 alpha could ameliorate carboplatin-induced thrombocytopenia, we combined it with high-dose carboplatin in 43 patients with advanced neoplasms., Methods: High-dose carboplatin (800 mg per square meter of body-surface area) was administered alone to a control group. Subsequent patients were randomly assigned to receive the same dose of carboplatin with interleukin-1 alpha, administered either before or after carboplatin. Interleukin-1 alpha was given intravenously at a dose of 0.03, 0.1, or 0.3 microgram per kilogram of body weight per day for five days., Results: Carboplatin alone consistently produced thrombocytopenia with a median nadir of 19,000 platelets per cubic millimeter and a median of 10 days with less than 100,000 platelets per cubic millimeter. All 15 patients receiving interleukin-1 alpha before carboplatin had similar findings. In contrast, 5 of the 15 patients given one of the two higher doses of interleukin-1 alpha after carboplatin had minimal thrombocytopenia (nadir, 91,000 to 332,000 platelets per cubic millimeter). In the 10 patients given 0.3 microgram of interleukin-1 alpha per kilogram after carboplatin treatment, the platelet count recovered to 100,000 per cubic millimeter significantly earlier than in either the control group (P = 0.002) or the patients who received interleukin-1 alpha before carboplatin (P = 0.003), with the median times to recovery in the three groups being 16, 21, and 23 days, respectively. At the highest dose of interleukin-1 alpha, toxicity was substantial (but reversible), requiring inpatient support for hypotension, supraventricular arrhythmias, and pulmonary-capillary leak., Conclusions: Interleukin-1 alpha can accelerate the recovery of platelets after high-dose carboplatin therapy and may be clinically useful in preventing or treating thrombocytopenia induced by chemotherapy.

Objective: Based upon their individual clinical activity and combined effects in animal models or in vitro, we wished to evaluate a regimen of cisplatin, interferon-alpha, and IL-2 in patients with metastatic melanoma., Design: Phase II pilot study., Setting: Referral-based US Government clinical research unit., Patients: Nine patients with metastatic malignant melanoma., Intervention: Cisplatin 75-100 mg/m2 was administered intravenously over 30 minutes on days 1 and 8. Interferon-alpha 2a 5 Mu/m2 body surface area (BSA) was given subcutaneously for 4 days beginning 1 day before each dose of cisplatin. Beginning on day 15 and day 22, IL-2 was administered by intravenous continuous infusion at 3 Mu/m2 BSA/d for 96 hours and by daily intravenous bolus concurrent with daily subcutaneous doses of interferon-alpha 2a., Main Outcome Measures: Antitumor response and toxicities., Results: The study was stopped due to renal and hematopoietic toxicity and severe, delayed nausea and vomiting associated with the cisplatin-interferon treatment. Three of 9 patients achieved a partial response (duration 2.5, 4, 14+ months), and an additional patient had a 50% reduction in measurable tumor volume before undergoing resection of residual disease. Overall response rate was 45%., Conclusion: This regimen was associated with excessive toxicity, and the lack of complete responses in a patient cohort with favorable characteristics for response (good performance status, predominance of skin and lymph node metastatic sites) suggests that it had no advantage over less toxic treatment regimens., Registration: National Cancer Institute/Cancer Therapy Evaluation Program T89-0137.

Background: Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclophosphamide or doxorubicin or by the biologic agent interferon alpha., Purpose: We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN alpha-2a) in patients with metastatic melanoma and renal cell carcinoma., Methods: IL-2 (3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN alpha-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study., Results: For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths., Conclusions: This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN alpha-2a as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.