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Purpose: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis., Methods: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations., Results: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low., Recommendations: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.

Objectives: The objective of this study is to explore the characteristics of the subset of patients with hematologic malignancies (HMs) who had little to no change in SARS-CoV-2 spike antibody index value levels after a third mRNA vaccine dose (3V) and to compare the cohort of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus., Study Design: This retrospective cohort study analyzed SARS-CoV-2 spike IgG antibody index values pre and post the 3V data on 625 patients diagnosed with HM across a large Midwestern United States healthcare system between 31 October 2019 and 31 January 2022., Methods: To assess the association between individual characteristics and seroconversion status, patients were placed into two groups based on IgG antibody status pre and post the 3V dose, (-/+) and (-/-). Odds ratios were used as measures of association for all categorical variables. Logistic regressions were used to measure the association between HM condition and seroconversion., Results: HM diagnosis was significantly associated with seroconversion status ( P = 0.0003) with patients non-Hodgkin lymphoma six times the odds of not seroconverting compared with multiple myeloma patients ( P = 0.0010). Among the participants who were seronegative prior to 3V, 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not., Conclusion: This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V. This gain in scientific knowledge is needed for clinicians to target and counsel these vulnerable patients., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma., Methods: Adult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy., Results: Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each)., Conclusions: Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies., Competing Interests: Competing interests: BDC: data safety monitoring board for Merck; institutional funding from Bristol Myers Squibb and Viralytics; honoraria from Cullinan Oncology, Nektar Therapeutics, and Clinigen. JR: none. JRH: institutional funding from Merck, BMS, Takara, and Amgen; advisory boards for BMS/Nektar Therapeutics. GAD: none. MF: advisory boards for Merck, Bristol Myers Squibb, Novartis, Nektar, Sanofi, and Array Biopharma. LF: none. KAM: consultant for ImaginAb, Oncosec, Werewolf, Xilio, Instil, IOvance, and Checkmate Pharmaceuticals; institutional funding from Merck, BMS, Roche, BioNTech, Checkmate Pharmaceuticals, IO Biotech, Regeneron, and Agenus. SH: none. MG: consultant/independent contractor (contracted directly by Viralytics). YZ and AL: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, USA and stockholders in Merck & Co, Inc, Rahway, New Jersey, USA. RHIA: institutional research funding from Viralytics; in the past 3 years, employee of Seven and Eight Biopharmaceuticals Inc., (© 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.)

Purpose: This study sought to describe the changes in immune response to a third dose of either Pfizer's or Moderna's COVID-19 mRNA vaccine (3V) among patients with hematologic malignancies, as well as associated characteristics., Methods: This retrospective cohort study analyzed pre-3V and post-3V data on 493 patients diagnosed with hematologic malignancies across a large Midwestern health system between August 28, 2021, and November 1, 2021. For antibody testing, S1 spike antigen of the SARS-CoV-2 virus titer was used to determine serostatus., Results: Among 493 participants, 274 (55.6%) were seropositive both pre- and post-3V (+/+) while 115 (23.3%) seroconverted to positive from prior negative following the third dose (-/+). The remaining 104 (21.1%) were seronegative both before and after 3V (-/-). No participant was seropositive pre-3V and seronegative post-3V (+/-). Results showed a statistically significant increase in the proportion of seropositivity after receiving a third COVID-19 vaccine (P<0.00001). Response to 3V was significantly associated with the 3V vaccine type (P=0.0006), previous COVID-19 infection (P=0.0453), and malignancy diagnosis (P<0.0001). Likelihood of seroconversion (-/+) after 3V was higher in the group of patients with multiple myeloma or related disorders compared to patients with lymphoid leukemias (odds ratio: 8.22, 95% CI: 2.12-31.79; P=0.0008)., Conclusions: A third COVID-19 vaccination is effective in producing measurable seroconversion in many patients with hematologic malignancies. Oncologists should actively encourage all their patients, especially those with multiple myeloma, to receive a 3V, given the high likelihood of seroconversion., Competing Interests: Conflicts of Interest None., (© 2022 Aurora Health Care, Inc.)

Purpose: To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline., Methods: An Expert Panel conducted a systematic review to identify new, potentially practice-changing data., Results: Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations., Recommendations: Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients' risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.Additional information can be found at www.asco.org/breast-cancer-guideline., Competing Interests: Andrea EisenOther Relationship: Cancer Care Ontario Melissa K. AccordinoHonoraria: Sermo (I), M3 (I), Charter Oak Research, ExpertConnect, Medscape, Deerfield Management, Incrowd, Massive BioOther Relationship: Onclive Mark J. ClemonsHonoraria: PfizerConsulting or Advisory Role: Cornerstone Research Group, ApotexTravel, Accommodations, Expenses: Pfizer Sukhbinder Dhesy-ThindHonoraria: PfizerConsulting or Advisory Role: Novartis Canada Pharmaceuticals Inc, Seattle Genetics Melissa S. DillmonStock and Other Ownership Interests: Johnson & Johnson (I), Bristol Myers Squibb (I)Consulting or Advisory Role: Puma Biotechnology Elizabeth S. FrankHonoraria: AstraZenecaTravel, Accommodations, Expenses: Roche Sigrun HallmeyerLeadership: Association of Community Cancer Centers (ACCC)Honoraria: Cardinal HealthConsulting or Advisory Role: Bristol Myers Squibb, Cardinal Health, Array PharamceuticalSpeakers' Bureau: Bristol Myers SquibbTravel, Accommodations, Expenses: Cardinal Health, Bristol Mers SquibbUncompensated Relationships: Society for Immunotherapy of Cancer Beverly MoyConsulting or Advisory Role: MOTUS (I)Research Funding: Puma Biotechnology (Inst) Alia ThawerHonoraria: Knight Pharmaceuticals, Novartis Canada Pharmaceuticals Inc, Pfizer, GlaxoSmithKline Canada, AbbVie, AstraZeneca CanadaConsulting or Advisory Role: Ipsen, Amgen, Novartis, Lilly, Sandoz-Novartis, Pfizer, EisaiResearch Funding: Novartis, AstraZeneca Joy Y. WuResearch Funding: Radius Health Catherine H. Van PoznakResearch Funding: Bayer (Inst)Patents, Royalties, Other Intellectual Property: UpToDateNo other potential conflicts of interest were reported.

Introduction: Healthcare workers experience a significant risk of exposure to and infection from SARS-CoV-2, COVID-19. Nonetheless, little research has focused on physicians' use of personal protective equipment (PPE), their concerns about becoming infected and their social distancing maneuvers., Methods: All staff physicians at Advocate Lutheran General Hospital were invited to participate. Their COVID-19 IgG antibody level was measured and an online questionnaire was completed. The questionnaire assessed the risk of COVID-19 exposure, PPE usage, concern for contracting COVID-19, the performance of high-risk procedures, work in high-risk settings, and social distancing practices. Testing was performed in September (T0), and December 2020 (T1) at the height of the global pandemic., Results: A total of 481 (26.7%) of 1800 AGLH physicians were enrolled at T0 and 458 (95% of the original group) at T1. A total of 21 (4.3%) and 39 (8.5%) participants had antibodies at T0 and T1. A total of 63 (13.8%) worked in high-risk settings and 111 (24.2%) performed high-risk procedures. Participants working in high-risk settings had increased exposure to COVID-19 infected patients (OR = 4.464 CI = 2.522-8.459, p < 0.001). Participants were highly adherent to the use of PPE and social distancing practices including mask-wearing in public (86%, 82.1%), avoiding crowds (85.1%, 85.6%), six feet distancing (83.8%, 83.4%), and avoiding public transportation (78%, 83.8%). A total of 251 (55.4%) participants expressed moderate to extreme concern about becoming infected with COVID-19., Conclusions and Relevance: Among a group of community physicians, consistent PPE use and social distancing practices were common. These practices were associated with a low level of initial acquisition of COVID-19 infections and a relatively low longitudinal risk of infection.

Purpose: We evaluated the activity of intratumoral Coxsackievirus A21 (V937) in 57 patients with unresectable stage IIIC or IV melanoma., Patients and Methods: In this multicenter, open-label, phase II study, patients received up to a total V937 dose of 3 × 10 8 TCID 50 (50% tissue culture infectious dose) in a maximum 4.0-mL volume by intratumoral injection. Ten sets of V937 injections were administered between days 1 and 127 (NCT01227551). Patients who had stable disease or were responding could continue treatment in an extension study (NCT01636882). Response and progression status were based on contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and were categorized using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Other evaluations included monitoring of adverse events and serum levels of V937 and anti-V937 antibody titers. The primary efficacy end point was 6-month progression-free survival (PFS) rate per irRECIST., Results: The primary efficacy end point, 6-month PFS rate per irRECIST, was 38.6% (95% CI, 26.0 to 52.4). Durable response rate (partial or complete response for ≥ 6 months) was 21.1% per irRECIST. Best overall response rate (complete plus partial response) was 38.6% (unconfirmed) and 28.1% (confirmed) per irRECIST. Regression of melanoma was observed in noninjected lesions. Based on Kaplan-Meier estimation, 12-month PFS was 32.9% (95% CI, 19.5 to 46.9) per irRECIST and 12-month overall survival was 75.4% (95% CI, 62.1 to 84.7). No treatment-related grade ≥ 3 adverse events occurred. Viral RNA was detected in serum within 30 minutes of administration. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, without effect on clinical or immunologic response., Conclusion: V937 was well tolerated and warrants further investigation for treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing., Competing Interests: Robert H. I. AndtbackaEmployment: Novartis, Merck Sharp & Dohme, Seven and Eight BiopharmaceuticalsStock and Other Ownership Interests: Novartis, Merck Sharp & Dohme Brendan CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Amgen, Viralytics, Nektar, Merck Sigrun HallmeyerLeadership: Association of Community Cancer Centers (ACCC)Honoraria: Cardinal HealthConsulting or Advisory Role: Bristol Myers Squibb, Cardinal Health, Array PharamceuticalSpeakers' Bureau: Bristol Myers SquibbTravel, Accommodations, Expenses: Cardinal Health, Bristol Myers SquibbUncompensated Relationships: Society for Immunotherapy of Cancer Eric D. WhitmanConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Castle Biosciences, Novartis, Eisai, PfizerSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Castle Biosciences, Genentech/Roche, Amgen, TRACON Pharma, AstraZeneca/MedImmune, Provectus, Oncolys BioPharma, Iovance Biotherapeutics, Dynavax Technologies, OncoSec, Toray Industries, Array BioPharmaPatents, Royalties, Other Intellectual Property: Nerve monitoring dissection device, Lighted Polyhedral surgical retractor Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Lynn E. SpitlerLeadership: Nuclear RNA Networks IncStock and Other Ownership Interests: Nuclear RNA Networks Inc Praveen K. BommareddyEmployment: ReplimuneStock and Other Ownership Interests: Replimune Mark GroseConsulting or Advisory Role: ImmVirX Meihua WangEmployment: MerckStock and Other Ownership Interests: Merck Cai WuEmployment: Merck (at the time the work was conducted)Stock and Other Ownership Interests: Merck Sharp & Dohme Howard L. KaufmanEmployment: ImmuneeringLeadership: ImmuneeringStock and Other Ownership Interests: ImmuneeringHonoraria: Society for Immunotherapy of CancerNo other potential conflicts of interest were reported.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies., Competing Interests: MH, DRM, RH, BT, LFl, LFe have no conflicts of interest to disclose. WHS reports grants and personal fees from Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from Merck, grants and personal fees from Novartis, personal fees from Regeneron, grants from Genentech, outside the submitted work. LDC’s institution (University of Arizona) received payments from Prometheus Laboratories to support the conduct of this study. LDC receives research funding, paid to the institution (University of Washington), from Eli Lilly, AADi, BluePrint Medicine, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma. LDC has received honoraria or has served on advisory boards for Daaichi Sankyo, BluePrint Medicines, and Regeneron. GAD reports position at the advisory board for Clinigen and institutional research support from Bristol-Myers Squibb and Clinigen. SH reports position at advisory board for Cardinal Health, Bristol-Myers Squibb, Immunomedics, Pfizer, and Speakers bureau at Bristol-Myers Squibb. MM reports other interests from Exicure, Blueprints Medicine, Immunocore, Amgen, Trieza, Array Biopharma, Biontech, and Novartis, outside the submitted work. GD reports fees from Novartis, Merck & Co, and Bristol-Myers Squibb. NG is employed by study sponsor Prometheus Labs, Clinigen, Inc. SPP reports institutional clinical trial support from Bristol Myers Squibb, InxMed, Novartis, Provectus, and Reata; advisory board participation for Cardinal Health and Castle Biosciences; data safety monitoring board activities for Immunocore, and personal fees from Merck outside the submitted work., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy., Methods: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR., Results: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes., Conclusion: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability., Competing Interests: Zeynep ErogluConsulting or Advisory Role: Regeneron, Sun Pharma, Genentech/Roche, Novartis, OncoSec, Natera, ElsevierResearch Funding: Novartis, Pfizer Bruce BrocksteinConsulting or Advisory Role: Exelixis/IpsenResearch Funding: AstraZenecaPatents, Royalties, Other Intellectual Property: UpToDate. Author and Editorial duties Andrew S. PoklepovicConsulting or Advisory Role: NovartisSpeakers' Bureau: Bristol Myers Squibb Sunil BabuEmployment: Fort Wayne Medical Oncology & HematologyStock and Other Ownership Interests: Fort Wayne Medical Oncology & Hematology, Lutheran HospitalHonoraria: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Bayer, AstraZenecaConsulting or Advisory Role: Bristol Myers Squibb, Alexion Pharmaceuticals, AstraZeneca, argenx, Boehringer Ingelheim, Bayer, Kite, a Gilead company, Janssen Oncology, AmgenSpeakers' Bureau: Alexion PharmaceuticalsResearch Funding: Bristol Myers Squibb, Novartis, Genentech/Roche, AstraZeneca/MedImmune, Janssen Oncology, Amgen, TG Therapeutics, Abbvie, Lilly, Alexion Pharmaceuticals, Merck, Novartis, Syndax, Nektar, Sanofi, argenxTravel, Accommodations, Expenses: Bristol Myers Squibb, Alexion Pharmaceuticals, Lilly, Janssen Oncology, Genentech/Roche Sigrun HallmeyerLeadership: Association of Community Cancer Centers (ACCC)Honoraria: Cardinal HealthConsulting or Advisory Role: Bristol Myers Squibb, Cardinal Health, Array PharamceuticalSpeakers' Bureau: Bristol Myers SquibbTravel, Accommodations, Expenses: Cardinal Health, Bristol Myers SquibbUncompensated Relationships: Society for Immunotherapy of Cancer Mario VelascoEmployment: Cancer Care Specialists of IL Jose LutzkyConsulting or Advisory Role: Castle Biosciences, Iovance Biotherapeutics, Replimune, RegeneronResearch Funding: Bristol Myers Squibb, Novartis, Iovance Biotherapeutics, Immunocore, Regeneron, Replimune, Vyriad Emily HiggsEmployment: LillyStock and Other Ownership Interests: LillyResearch Funding: LillyPatents, Royalties, Other Intellectual Property: Jeffrey D. Helterbrand, Richard E. Higgs, Phillip W. Iversen, Automatic Contextual Segmentation for Imaging Bones for Osteoporosis Therapies (Granted February 1, 2000, US Patent 6,021,213). Raymond E. Kaiser, Richard E. Higgs, Randall K. Julian Jr, System and Methods for Quantitatively Comparing Complex Mixtures Using Single Ion Chromatograms Derived From Spectroscopic Analysis of Such Admixtures (Granted March 23, 1999, US Patent 5,885,841)Travel, Accommodations, Expenses: Lilly Vernon K. SondakConsulting or Advisory Role: Merck/Schering Plough, Novartis, Bristol Myers Squibb, Regeneron, Replimune, EisaiTravel, Accommodations, Expenses: Polynoma, Merck, Bristol Myers Squibb, Replimune Thomas F. GajewskiStock and Other Ownership Interests: Jounce Therapeutics, Evelo Therapeutics, Five Prime Therapeutics, PyxisConsulting or Advisory Role: Merck, Jounce Therapeutics, Adaptimmune, FOGPharma, Allogene Therapeutics, Pyxis, Trillium Therapeutics, Janssen Oncology, Gilead SciencesResearch Funding: Bristol Myers Squibb, Merck, Roche/Genentech, Incyte, Seattle Genetics, Ono Pharmaceutical, Aduro Biotech, Pyxis, BayerPatents, Royalties, Other Intellectual Property: Licensing to Evelo, Licensing to Aduro, Licensing to BMS, Licensing to Pyxis Nikhil I. KhushalaniStock and Other Ownership Interests: Bellicum Pharmaceuticals, Mazor Robotics, Amarin Corporation, Asensus SurgicalHonoraria: SanofiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/PfizerResearch Funding: Bristol Myers Squibb, Merck, Novartis, GlaxoSmithKline, HUYA Bioscience International, Amgen, Regeneron, Celgene, Replimune Jason J. LukeStock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch OncologyConsulting or Advisory Role: Array BioPharma, Bristol Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, TTC Oncology, Alphamab, Compugen, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf Therapeutics, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius Therapeutics, Tesaro, Xilio Therapeutics, XencorResearch Funding: Merck, Bristol Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Checkmate Pharmaceuticals, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring Bank, Trishula TherapeuticsPatents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)Travel, Accommodations, Expenses: Bristol Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio TherapeuticsNo other potential conflicts of interest were reported.

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Purpose The adaptation of the Cancer Care Ontario (CCO) guideline Interventions to Address Sexual Problems in People With Cancer provides recommendations to manage sexual function adverse effects that occur as a result of cancer diagnosis and/or treatment. Methods ASCO staff reviewed the guideline for developmental rigor and updated the literature search. An ASCO Expert Panel ( Table A1 ) was assembled to review the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the 2016 CCO guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO statements and modifications were added to adapt the CCO guideline for a broader audience. Recommendations It is recommended that there be a discussion with the patient, initiated by a member of the health care team, regarding sexual health and dysfunction resulting from cancer or its treatment. Psychosocial and/or psychosexual counseling should be offered to all patients with cancer, aiming to improve sexual response, body image, intimacy and relationship issues, and overall sexual functioning and satisfaction. Medical and treatable contributing factors should be identified and addressed first. In women with symptoms of vaginal and/or vulvar atrophy, lubricants in addition to vaginal moisturizers may be tried as a first option. Low-dose vaginal estrogen, lidocaine, and dehydroepiandrosterone may also be considered in some cases. In men, medication such as phosphodiesterase type 5 inhibitors may be beneficial, and surgery remains an option for those with symptoms or treatment complications refractory to medical management. Both women and men experiencing vasomotor symptoms should be offered interventions for symptomatic improvement, including behavioral options such as cognitive behavioral therapy, slow breathing and hypnosis, and medications such as venlafaxine and gabapentin.Additional information is available at: www.asco.org/survivorship-guidelines and www.asco.org/guidelineswiki .

BRAF mutations are found in ~50% of metastatic melanomas, most commonly in codon V600. Vemurafenib improves progression-free survival and overall survival in patients with advanced BRAF-mutated melanoma. The results of a descriptive study evaluating vemurafenib in patients with advanced melanoma harbouring BRAF mutations other than V600E are reported. Eligible patients with stage IIIC or IV melanoma and non-V600E BRAF mutations received vemurafenib (960 mg, twice daily). End points included investigator-assessed best overall response rate (primary), time to response, duration of response, progression-free survival, overall survival and safety. Planned (V600K vs. non-V600K mutations) subgroup analyses were carried out. Thirty-one patients were enrolled; 13 (42%) had V600K mutations and 18 (58%) had other mutations. Investigator-assessed confirmed that the best overall response rate was 23% (95% confidence interval=10-41%) in the overall population, and was similar between patients with V600K mutations (23%; 95% confidence interval=5-54%) versus other mutations (22%; 95% confidence interval=6-48%). Responses were observed in patients with V600K (n=3), V600E2 (n=1), V600R (n=1), L597S (n=1) and D594G (n=1) mutations. No new safety signals were reported. Vemurafenib showed activity in patients with advanced melanoma with rarer BRAF mutations.

Background: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2)., Patients and Methods: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin R Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM SM ) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015., Results: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2., Conclusions: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus talimogene laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF)., Methods: Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given talimogene laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between talimogene laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma., Results: DRR was higher for talimogene laherparepvec-treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with talimogene laherparepvec versus 0% with GM-CSF. Among talimogene laherparepvec-treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with talimogene laherparepvec., Conclusion: Treatment with talimogene laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1752-1758, 2016., (© 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc.)

Opinion Statement: Identification of BRAF driver mutations and agents that block their activity combined with development of immune checkpoint inhibitor therapies have dramatically changed survival and quality of life for patients with metastatic melanoma. Approximately half of patients with metastatic melanoma do not harbor mutations in the BRAF gene and therefore cannot benefit from currently available agents that target this mutation. Additionally, few patients with metastatic melanoma achieve durable disease control with these targeted therapies alone. Conversely, immune-based therapies have the potential to treat melanomas with or without mutations and produce durable responses following discontinuation of therapy, but responses can be delayed. Defining the goals of therapy (rapid response vs durable disease control), establishing the presence of targetable mutations, and considering the toxicities associated with each therapy can inform a treatment strategy. Incorporating both recent therapeutic modalities and older treatment options can provide the greatest potential for durable response. Overall, we recommend using immunotherapies (anti-CTLA4, anti-PD-1, combined anti-CTLA4/anti-PD-1, or interleukin-2) as the backbone of treatment for metastatic melanoma due to their potential for durable response. The targeted therapies and cytotoxic therapies can then be used intermittently to rescue patients from symptomatic disease progression. Of course, available clinical trials should always be considered, whenever possible.

Background: High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored., Methods: The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed., Results: A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death., Conclusion: In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment (index therapy) for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), dacarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued index treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months (95% confidence interval [CI], 2.1-2.9) and median overall survival was 8.8 months (95% CI, 6.5-9.7). During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: This open-label, multicenter study was designed to allow access to vemurafenib for patients with metastatic melanoma, bridging the time between end of enrollment in the phase III registration trial (December 2010) and commercial availability following US Food and Drug Administration approval of vemurafenib for the treatment of unresectable or metastatic BRAF-mutated melanoma (August 2011)., Patients and Methods: Eligible patients had metastatic melanoma with a BRAF mutation (detected by the cobas 4800 BRAF V600 Mutation Test). Unlike previous vemurafenib trials, patients with poor performance status (PS) and treated brain metastases were permitted. Enrolled patients received oral vemurafenib 960 mg twice daily., Results: Of 374 patients enrolled at 29 US sites (December 2010 to October 2011), 371 patients received vemurafenib and were followed up for a median of 2.8 months (the study had a prespecified end upon vemurafenib approval and commercial availability). At baseline, most patients (75%) had stage M1c disease, and 19% had an Eastern Cooperative Oncology Group PS of 2 or 3; 72% of patients had received prior systemic therapy for metastatic melanoma, 27% received prior ipilimumab, and 29% radiotherapy for prior brain metastases. Because reassessment data to confirm response were not available for most patients, point estimates of objective response rate (ORR) are reported. Among 241 efficacy-evaluable patients, the ORR was 54% (median time to response, 1.9 months). The ORR in non-central nervous system sites in patients with previously treated brain metastases (n = 68) was 53%. The ORR in prior ipilimumab-treated patients (n = 68) was 52%. For patients with PS of 0 or 1 (n = 210) and 2 or 3 (n = 31), the ORRs were 55%, and 42%, respectively. The safety profile observed was consistent with that reported in previous studies. The number of patients with grade 3 or 4 treatment-related adverse events was higher in patients with PS 2 or 3 than in those with PS 0 or 1 (10% vs. 5%, respectively). Adverse events requiring a dose reduction (at least 1 level) occurred in 11% of patients, and 9 patients (2%) experienced events leading to vemurafenib withdrawal, including 2 with repeated QT interval prolongation., Discussion: This study confirmed the established rapid and high tumor response rate achievable with vemurafenib in BRAF mutation-positive metastatic melanoma. Several groups not included in previous studies, including patients with previously treated brain metastases, Eastern Cooperative Oncology Group PS 2 to 3, or previous ipilimumab treatment had benefitted from vemurafenib similar to the overall population. No new safety signals were detected.

T cell immunotherapy of prostate cancer (CaP) offers the potential for less toxic, more effective outcomes. A clinical trial was conducted in 28 patients with locally advanced or metastatic CaP to determine whether an HLA-A2 binding epitope of prostate-specific antigen, PSA146-154 (PSA-peptide), can induce specific T cell immunity. Patients were vaccinated either by intradermal injection of PSA-peptide and GM-CSF or by intravenous administration of autologous dendritic cells pulsed with PSA-peptide at weeks 1, 4 and 10. Delayed-type hypersensitivity (DTH) skin testing was performed at weeks 4, 14, 26 and 52. Fifty percent of the patients developed positive DTH responses to PSA-peptide. The size of the DTH induration progressively increased over time in the majority of responding patients. Skin biopsies from seven DTH-positive patients were available and T cells that developed in situ were also characterized. The phenotype of recovered T cells demonstrated variable proportions of CD4+CD8-, CD4-CD8+ and CD4+CD8+ T cell populations. Cytokine analysis of PSA-peptide stimulated T cells per bead array assay exhibited specific IFN-gamma and TNF-alpha response in six of seven patients. Specific IL-4 response was observed in five patients, while IL-10 response was detected in one patient. Purified CD4-CD8+ T cells isolated from four patients demonstrated specific cytolytic activity per chromium release assay. In conclusion, immunization with PSA-peptide induced specific T cell immunity in one-half of the patients with locally advanced and hormone-sensitive, metastatic CaP. DTH-derived T cells exhibited PSA-peptide-specific cytolytic activity and predominantly expressed a type-1 cytokine profile.

Background and Purpose: Thickening of the temporal bone in stroke-age patients may obviate sonographic evaluation of the circle of Willis in 20% to 30% of patients. We assessed the diagnostic efficacy of contrast-enhanced transcranial color-coded duplexsonography (TCCD) for noninvasive evaluation of the circle of Willis in stroke patients with limited bone windows., Methods: Of 171 consecutive patients who presented with ischemic symptoms in the middle cerebral artery (MCA) territory, 49 patients (32 female, 17 male; age range, 70.5+/-10.6 years) had no detectable colorflow signals from the circle of Willis by TCCD because of limited acoustic windows. These 49 patients received an IV injection of a sonographic contrast-enhancing agent, Levovist (Schering; Berlin, Germany), and were re-examined. Correlative imaging studies of the circle of Willis were obtained in 42 of 49 of these patients., Results: In 38 of 49 patients, contrast-enhanced TCCD enabled full visualization of the circle of Willis bilaterally; in an additional five patients, contrast-enhanced TCCD revealed only the portion of the circle of Willis ipsilateral to the probe through one temporal bone. In six of these 43 patients, contrast-enhanced TCCD showed MCA stenosis and MCA occlusion in three; three of the six cases of MCA stenosis and all three cases of the MCA occlusion were found on the symptomatic side. In six of 49 patients, no colorflow signals were obtained after contrast enhancement. All contrast-enhanced TCCD findings were confirmed by CT angiography, transfemoral digital subtraction angiography, MR angiography, or a combination of all three correlative studies. Levovist produced no serious adverse events., Conclusion: In stroke-age patients with limited acoustic windows, contrast-enhancement with Levovist can markedly increase the sensitivity of TCCD and increase the detection of clinically relevant intracranial arterial disease.

The selection of patients with severe vertebrobasilar artery stenosis for angioplasty is based mainly on clinical experience rather than on controlled data. We present a patient with severe vertebral artery stenosis in whom we could document the positive effect of angioplasty on posterior circulation hemodynamics by using transcranial Doppler sonography.