Faculty Bibliography

Introduction: Le NIVO a demontre une amelioration de la survie sans recidive (SSR) vs l'IPI chez les patients (pts) atteints d'un melanome de stade III/IV operes dans l'etude de phase 3, CheckMate 238. Les donnees mises a jour de SSR, de survie sans metastases a distance (SSMD) et de SG a 48 mois sont presentees. Materiel et methodes: Des pts ages de >= 15 ans avec un melanome de stade IIIB/C ou IV entierement reseque ont ete stratifies selon le stade et le statut PDL-1, et randomises selon un rapport 1 : 1 pour recevoir NIVO (3 mg/kg toutes les 2 semaines [sem]; n = 453) ou IPI (10 mg/kg toutes les 3 sem pour 4 doses, puis toutes les 12 sem; n = 453) pendant une duree maximale d'1 an ou jusqu'a recidive de la maladie/toxicite inacceptable. Le critere d'evaluation principal etait la SSR. Les criteres d'evaluation secondaires comprenaient la SG et la tolerance; la SSMD pour le stade III de la maladie etait exploratoire. Resultats: A 4 ans de suivi, NIVO a continue de demontrer une SSR superieure a l'IPI (HR : 0,71; IC95 % : 0,60-0,86; p = 0,0003). La SSMD chez les pts atteints d'une maladie de stade III etait en faveur du NIVO (HR : 0,79; IC95 % : 0,63-0,99). A 48 mois, le nombre d'evenements en SG (n = 211) etait plus faible que prevu (n = 302) et les taux de SG etaient comparables : 78 % (IC95 % : 73,7-81,5) avec NIVO et 77 % (IC95 % : 72,2-80,3) avec IPI (HR : 0,87; IC95 % : 0,66-1,14; p = 0,3148). Un traitement systemique ulterieur etait recu par 150 (33 %) pts traites par NIVO et 189 (42 %) pts traites par IPI; plus de pts traites par IPI (34 % vs 23 %) ont recu une immunotherapie systemique ulterieure. Des evenements indesirables lies au traitement (EILT) d'apparition retardee (rapportes plus de 100 jours apres la derniere dose) et de tous grades confondus ont ete observes chez 18 (4 %) pts traites par NIVO et 25 (6 %) pts traites par IPI, avec un grade 3/4 dans 3 (1 %) et 7 (2 %) des cas, respectivement.
Discussion(s): Le NIVO a continue de demontrer une amelioration de la SSR et de la SSMD par rapport a l'IPI a 48 mois chez les pts avec un melanome de stade III/IV a haut risque de recidive. Les evenements de SG (n = 211) etaient inferieurs aux previsions (n = 302). Les taux de SG etaient similaires pour NIVO et IPI, bien que l'utilisation d'un traitement ulterieur par immunotherapie systemique ait ete plus elevee dans le bras IPI. Les EILT d'apparition tardive etaient conformes au profil de tolerance etabli pour NIVO et IPI, avec plus d'evenements rapportes avec IPI.
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Declaration de liens d'interets: W. Samlowski a recu une subvention de la part de Novartis, Regeneron, Sanofi-Genzyme, BMS, Merck, Pfizer, Novartis, est consultant pour Novartis, Regeneron, Sanofi-Genzyme, BMS, Merck, Pfizer, Novartis, N.J. Robert a un conflit d'interet avec McKesson Life Sciences, E. D. Nwokeji a un conflit d'interet avec BMS, B. Baidoo a un conflit d'interet avec BMS, B. Schenkel est actionnaire de BMS, est employe de BMS, A. Moshyk est actionnaire de BMS, est employe de BMS, S. Kotapati est employe de BMS, T. Poretta est consultant pour BMS, N. Ameur est employe de BMS, J. S. Weber est actionnaire de CytoMx, Biond et Altor, a recu une subvention de la part de Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Pfizer et EMD Serono, BMS, est consultant pour Merck, Genentech, Astra Zeneca, GSK, Novartis, Nektar, Celldex, Incyte, Pfizer and EMD Serono, BMS, Celldex, CytoMx, Incyte, Biond, Protean, CV6 et Sellas. Supplement en ligne Materiel complementaire: Le materiel complementaire accompagnant la version en ligne de cet article est disponible sur. Supplement en ligne Materiel complementaire: [Formula presented]
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BACKGROUND:Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results. METHODS:This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906. FINDINGS/RESULTS:Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported. INTERPRETATION/CONCLUSIONS:At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. FUNDING/BACKGROUND:Bristol Myers Squibb and Ono Pharmaceutical.

Background: Long-term safety of pembrolizumab in metastatic melanoma was analyzed using data from phase 1-3 studies: KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.
Method(s): Safety was assessed in randomized patients who received >=1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses with patients who were progression-free before day 147.
Result(s): Adverse events (AEs) were analyzed for 1567 patients. Median follow-up was 42.4 months (range, 24.6-47.8), which represents the largest analysis of the safety of pembrolizumab in advanced melanoma to date. Most treatment-related AEs (TRAEs) were mild/moderate; grade 3/4 TRAEs occurred in 17.7% of patients. Two deaths were considered pembrolizumab-related. Any-grade and grade 3/4 immune-mediated AEs (imAEs) occurred in 23.0% and 6.9% of patients, respectively; imAEs occurring in >=3.0% of patients were hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); median time to onset/resolution was 15.9/8.6, 36.0/8.1, and 7.3/6.1 weeks. Most imAEs occurred within 16 weeks of treatment initiation. In the week-21 landmark analysis (n = 291 still on study), patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% vs 63.0%); median time to response (TTR) was 5.6 months for both; median duration of response (DOR) was 20.0 versus 25.3 months; median progression-free survival (PFS) was 17.0 versus 17.7 months; median overall survival (OS) was not reached (NR) versus 43 months (P = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids at week 21 had similar ORRs (70.6% vs 62.9%) and median TTR (6.4 vs 5.6 months) but numerically shorter median PFS (9.9 vs 17.0 months); median DOR was 14.2 months versus NR; median OS was NR for both.
Conclusion(s): These results further support pembrolizumab use in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large patient population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAE occurrence or systemic corticosteroid use. Clinical trial identification: KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006: NCT01295827, NCT01704287, and NCT01866319, respectively. Editorial acknowledgement: Medical writing and/or editorial assistance was provided by Doyel Mitra, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding(s): Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: O. Hamid: Advisory/Consultancy: Merck; Research grant/Funding (institution): Arcus, Aduro, Akeso, Amgen, Array, BMS, Cytomx, Exelixis, Genentech, GSK, Immunocore, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Regeneron, Roche, Seattle Genetics, Torque, and Zelluna. A. Ribas: Honoraria (institution), Advisory/Consultancy: Amgen, Chugai, Genentech-Roche, Novartis, and Merck; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Arcus, Bioncotech, Compugen, Cytomx, Five Prime, FLX-Bio, Merus, Rgenix, PACT Pharma, and Tango Therapeutics. J. Weber: Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck, BMS, Genentech, Celldex, Pfizer, and AstraZeneca; Licensing/Royalties, Patent named on a PD-1 biomarker: Biodesix. A.S. Daud: Research grant/Funding (institution): Merck, BMS, Incyte, OncoSec, and Regeneron; Honoraria (self): Regeneron. F.S. Hodi: Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb, EMD Serono; Advisory/Consultancy: Takeda, Surface, Genentech/Roche, Compass Therapeutics, Verastem, 7 Hills Pharma, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Rheos, Kairos; Advisory/Consultancy, Licensing/Royalties: Apricity, Torque, Bicara; Advisory/Consultancy: Novartis; Advisory/Consultancy, Licensing/Royalties: Pionyr; Licensing/Royalties: Patent Methods for Treating MICA-Related Disorders (#20100111973); Licensing/Royalties: Patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending; Licensing/Royalties: Patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending; Licensing/Royalties: Patent Therapeutic peptides (#20160046716) pending; Licensing/Royalties: Patents pending for Therapeutic Peptides (#20140004112), Therapeutic Peptides (#20170022275), Therapeutic Peptides (#20170008962), Therapeutic Peptides (#9402905), and for methods of using pembrolizumab and trebanaib. J.D. Wolchok: Advisory/Consultancy: Adaptive Biotech; Amgen; Apricity; Ascentage Pharma; Astellas; AstraZeneca; Bayer; Beigene; Bristol-Myers Squibb; Celgene; Chugai; Eli Lilly; F Star; Imvaq; Kyowa Hakko Kirin; Linneaus; MedImmune; Merck; Neon Therapeutics; Ono; Polaris Pharma; Polynoma; P; Research grant/Funding (institution): Bristol-Myers Squibb; AstraZeneca; Shareholder/Stockholder/Stock options: Potenza Therapeutics; Tizona Pharmaceuticals; Adaptive Biotechnologies; Imvaq; Beigene; Trieza; Linneaus. T.C. Mitchell: Honoraria (self): BMS, Aduro, Merck, and Incyte. R.W. Joseph: Advisory/Consultancy: Merck. C. Boutros: Advisory/Consultancy: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Merck; Travel/Accommodation/Expenses: Amgen, Sandoz. L. Min: Research grant/Funding (institution): BMS. G.V. Long: Advisory/Consultancy: Aduro, Amgen, Array, Bristol-Myers Squibb, Merck Sharp Dohme, Novartis, Pierre-Fabre, Oncosec, and Roche. J. Lin: Full/Part-time employment: Merck. N. Ibrahim: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck; Shareholder/Stockholder/Stock options: GSK. M. Carlino: Advisory/Consultancy: Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Novartis, Roche, Pierre Fabre, Amgen, and Ideaya. C. Robert: Advisory/Consultancy: Roche, Pierre Fabre, Merck, Novartis, Amgen, BMS, Novartis, MSD, and Sanofi. All other authors have declared no conflicts of interest.
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Background: NIVO has shown improved recurrence-free survival (RFS) vs IPI in patients (pts) with resected stage III/IV melanoma in the phase III CheckMate 238 study. Updated 48-mo RFS and distant metastases-free survival (DMFS) and primary OS are presented.
Method(s): Pts aged >= 15 y with completely resected stage IIIB/C or IV melanoma were stratified by stage and tumor programmed death ligand 1 (PD-L1) status and randomized 1:1 to NIVO (3 mg/kg Q2W; n = 453) or IPI (10 mg/kg Q3W for 4 doses, Q12W thereafter; n = 453) for <= 1 y or until disease recurrence/unacceptable toxicity. The primary endpoint was RFS. Secondary endpoints included OS and safety; DMFS in stage III disease was exploratory.
Result(s): At 48 mo of follow-up, NIVO continued to demonstrate superior RFS vs IPI (HR 0.71; 95% CI 0.60-0.86; P = 0.0003; Table). DMFS in pts with stage III disease favored NIVO (HR 0.79; 95% CI 0.63-0.99). At 48 mo, the number of OS events (n = 211) was lower than anticipated (n = 302) and OS rates were comparable: 78% (95% CI 73.7-81.5) with NIVO and 77% (95% CI 72.2-80.3) with IPI (HR 0.87, 95.03% CI 0.66-1.14, P = 0.3148). Subsequent systemic next-line therapy was received by 150 (33%) NIVO-treated pts and 189 (42%) IPI-treated pts; more IPI-treated pts (34% vs 23%) received subsequent systemic immunotherapy (IO). Any-grade late-emergent treatment-related adverse events (TRAEs; reported > 100 d after last dose) were observed in 18 (4%) NIVO-treated pts and 25 (6%) IPI-treated pts, with grade 3/4 in 3 (1%) and 7 (2%), respectively.
Conclusion(s): NIVO continued to demonstrate improved RFS and DMFS vs IPI at 48 mo in pts with stage III/IV melanoma at high risk of recurrence. OS events (n = 211) were lower than anticipated (n = 302). OS rates were similar to NIVO and IPI, although use of subsequent IO therapy was higher in the IPI arm. Late-emergent TRAEs were consistent with the established safety profile of NIVO and IPI, with more events reported with IPI. [Formula presented] Clinical trial identification: NCT02388906. Editorial acknowledgement: Writing and editorial assistance were provided by Jessica Augello, PhD, and Michele Salernitano of Ashfield Healthcare Communications, funded by Bristol-Myers Squibb Company. Legal entity responsible for the study: Bristol-Myers Squibb Company.
Funding(s): Bristol-Myers Squibb Company. Disclosure: J. Weber: Honoraria (self), Advisory/Consultancy: Celldex; Honoraria (self), Advisory/Consultancy: Ichor Medical Systems; Honoraria (self), Advisory/Consultancy: cCam Biotherapeutics; Honoraria (self), Advisory/Consultancy: Lion Biotechnologies; Honoraria (self), Advisory/Consultancy: Pieris Pharmaceuticals; Honoraria (self), Advisory/Consultancy, Shareholder/Stockholder/Stock options: Altor BioScience; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): GSK; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Shareholder/Stockholder/Stock options: CytomX Therapeutics; Honoraria (self), Advisory/Consultancy: Nektar; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Shareholder/Stockholder/Stock options: Biond; Honoraria (self): Medivation; Honoraria (self): Sellas Life Sciences; Honoraria (self): WindMIL; Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Incyte; Licensing/Royalties, Named on patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker issued: Moffitt Cancer Center; Licensing/Royalties, Named on a patent from Biodesix for a PD-1 antibody biomarker issued: Biodesix. M. Del Vecchio: Advisory/Consultancy: Novartis; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pierre Fabre. M. Mandala: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Honoraria (self), Advisory/Consultancy: MSD Oncology. H. Gogas: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self): Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy: Amgen; Travel/Accommodation/Expenses: Roche. A.M. Arance Fernandez: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen. S. Dalle: Advisory/Consultancy, Research grant/Funding (institution): MDS; Research grant/Funding (institution), Travel/Accommodation/Expenses: BMS; Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Spouse/Financial dependant, An immediate family member is employed by Sanofi Pasteur: Sanofi Pasteur. C.L. Cowey: Research grant/Funding (institution): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Regeneron; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Caudex; Research grant/Funding (institution): Array; Research grant/Funding (institution): Amgen. M. Schenker: Research grant/Funding (self), Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (self), Research grant/Funding (institution): MSD; Research grant/Funding (self), Research grant/Funding (institution): Roche; Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca; Research grant/Funding (self), Research grant/Funding (institution): Novartis; Research grant/Funding (self), Research grant/Funding (institution): Eli Lilly; Research grant/Funding (self), Research grant/Funding (institution): AbbVie; Research grant/Funding (self), Research grant/Funding (institution): Regeneron; Research grant/Funding (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (self), Research grant/Funding (institution): Merck Serono; Research grant/Funding (self), Research grant/Funding (institution): Mylan; Research grant/Funding (self), Research grant/Funding (institution): Samsung; Research grant/Funding (self), Research grant/Funding (institution): Gilead; Research grant/Funding (self), Research grant/Funding (institution): Amgen. J-J. Grob: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Merck; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Sanofi. V. Chiarion Sileni: Travel/Accommodation/Expenses: Bristol-Myers Squibb; Travel/Accommodation/Expenses: Pierre Fabre. I. Marquez-Rodas: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharpe & Dohme; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy: Sanofi; Advisory/Consultancy: INCYTE; Advisory/Consultancy: Merck SERONO; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Bioncotech. M.O. Butler: Advisory/Consultancy: Merck & Co., Inc.; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Leadership role, Safety Review Board Member: Adaptimmune; Advisory/Consultancy, Leadership role, Safety Review Board Member: GlaxoSmithKline. M. Maio: Honoraria (self), Advisory/Consultancy, Patient Fees to my institution: Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy: AstraZeneca; Honoraria (institution), Advisory/Consultancy: Roche; Honoraria (institution), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (institution), Advisory/Consultancy: Merck Serono; Honoraria (institution), Advisory/Consultancy: GlaxoSmithKline; Honoraria (institution), Advisory/Consultancy: Incyte. M. Middleton: Advisory/Consultancy: Amgen; Honoraria (self), Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Millennium; Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunocore; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, IDSMC: Merck/Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (institution): Rigontec (acquired by MSD); Research grant/Funding (institution): Regeneron; Advisory/Consultancy, Research grant/Funding (institution): BioLineRx; Advisory/Consultancy, Research grant/Funding (institution): Array Biopharma (now Pfizer)); Advisory/Consultancy: Kineta; Advisory/Consultancy: Silicon Therapeutics; Research grant/Funding (self), Travel/Accommodation/Expenses: Replimune. M. Lobo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb; Shareholder/Stockholder/Stock options: Advaxis Immunotherapies. V. de Pril: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol-Myers Squibb. J. Larkin: Advisory/Consultancy, Research grant/Funding (institution): Achilles Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Boston Biomedical; Advisory/Consultancy: Eisai; Advisory/Consultancy: EUSA Pharma; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Imugene; Advisory/Consultancy: Incyte; Advisory/Consultancy: iOnctura; Advisory/Consultancy: Kymab; Advisory/Consultancy: Merck Serono; Advisory/Consultancy, Research grant/Funding (self): Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (self): Nektar; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy: Secarma; Advisory/Consultancy: Vitaccess; Advisory/Consultancy: Covance; Advisory/Consultancy, Research grant/Funding (self): Immunocore; Advisory/Consultancy: Aveo; Advisory/Consultancy: Pharmacyclics. P.A. Ascierto: Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): Roche/Genentech; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy, Research grant/Funding (self): Array BioPharma; Advisory/Consultancy, Leadership role: Merck Serono; Advisory/Consultancy: Newlink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Incyte; Advisory/Consultancy: MedImmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco; Advisory/Consultancy: Nektar; Advisory/Consultancy: Boehringer-Ingelheim; Travel/Accommodation/Expenses: Merck Sharp & Dohme. All other authors have declared no conflicts of interest.
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OBJECTIVES/OBJECTIVE:Melanoma is one of the most common malignancies diagnosed during pregnancy. This study examined the impact of pregnancy on management decisions of melanoma patients treated at NYU Langone Health (NYULH). METHODS:We analyzed data for patients who were pregnant at initial or recurrent melanoma diagnosis at NYULH from 2012 to 2019 with prospective protocol-driven follow-up. RESULTS:Of the 900 female patients accrued during this period, 11 women in the childbearing range were pregnant at melanoma diagnosis. Six patients presented with early (stage 0 or I) disease and five with advanced (stage III or IV) melanoma. Women with early stage disease had normal deliveries and minimal changes to their treatment timeline and regimen. However, patients with more advanced stage disease opted for either termination of the pregnancy or early delivery and altered treatment timelines because of pregnancy. CONCLUSION/CONCLUSIONS:Both melanoma stage and gestational age at diagnosis contribute to the differences in the therapeutic management of melanoma in pregnant women. Given the complexity and variety of each case of melanoma during pregnancy, informed discussion between patients and physicians allows for individualized treatment plans that address each patient's unique situation.

Melanoma disseminates to the skeletal system where it is then difficult to treat. Yet, there remains limited research investigating metastatic bone disease (MBD) in melanoma. Here, we evaluate whether there are distinct clinicopathologic variables at the time of primary melanoma diagnosis that predispose metastases to engraft bone, and we test the hypothesis that patients with MBD have different responses to treatment. Cutaneous melanoma patients enrolled in a prospective database were studied. Individuals with metastatic melanoma and bone metastases (M-Bone) were compared to those with metastatic disease but no M-Bone. Of the 463 (42.7%) patients, 198 with unresectable metastatic melanoma had M-Bone and 98 developed bone metastasis (bone mets) as first site. Progression-free survival and overall survival were significantly worse in patients with M-Bone compared to those without M-Bone (P < 0.001) independent of treatment modalities, and in patients whose melanoma spread to bone first, compared to those who developed first mets elsewhere (P < 0.001). Interestingly, patients with bone mets presented with primary tumors that had more tumor infiltrating lymphocytes (P < 0.001) and less often a nodular histologic subtype compared to patients without M-Bone (P < 0.001). Our data suggest that melanoma bone metastasis is a distinct clinical and biological entity that cannot be explained by generalized metastatic phenotype in all patients. The observed dichotomy between more favorable primary histopathologic characteristics and a grave overall prognosis requires more studies to elucidate the molecular processes by which melanomas infiltrate bone and to build a mechanistic understanding of how melanoma bone metastases yield such detrimental outcomes.

INTRODUCTION/BACKGROUND:Recent changes in the adjuvant treatment of melanoma have raised interest in confirming relapse-free survival (RFS) as a surrogate for overall survival (OS). METHODS:We explore this issue with the meta-analytic framework, using individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial of ipilimumab and published results from other adjuvant trials. RESULTS: = 0.59; 95% CI: 0.08-1.00). CONCLUSIONS:The trial-level association previously observed in interferon-based trials appeared to be maintained when the EORTC 18071 results were added to a regression analysis using published results from other trials. More data from adjuvant trials are required to confirm the strength of association between RFS and OS in this setting.

Background Treatment options are limited for patients with advanced melanoma who have progressed on checkpoint inhibitors and targeted therapies such as BRAF/MEK inhibitors (if BRAF-V600E mutated). Adoptive cell therapy utilizing tumor-infiltrating lymphocytes (TIL) has shown antitumor efficacy with durable responses in heavily pretreated melanoma patients. Safety and efficacy of lifileucel, a centrally manufactured cryopreserved autologous TIL therapy assessed by both investigator and an independent review committee (IRC), are presented. Methods C-144-01 is a global Phase 2 open-label, multicenter study of the safety and efficacy of lifileucel in patients with unresectable metastatic melanoma. We report on Cohort 2 (N = 66) patients with Stage IIIC/IV unresectable melanoma who received lifileucel. Tumors resected at local institutions were processed in central GMP facilities for TIL production in a 22-day process. Final TIL infusion product was cryopreserved and shipped to sites. Patients received one week of cyclophosphamide/ fludarabine preconditioning lymphodepletion, a single lifileucel infusion, followed by up to 6 doses of IL-2. All responses were assessed by RECIST 1.1. Results 66 patients had the following baseline characteristics: 3.3 mean prior therapies (anti-PD1 100%; anti-CTLA-4 80%; BRAF/MEK inhibitor 23%), relatively high tumor burden (106 mm mean target lesion sum of diameters), 44% with liver and/or brain lesions, median LDH 244 U/L. Objective Response Rate (ORR) by investigator was 36.4% (2 CR, 22 PR, 1 previously confirmed PR is now changed to SD) and Disease Control Rate (DCR) of 80.3%. At a median follow up of 9.7 months, median Duration of Response (DOR) has not been reached. The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens. The ORR per IRC was 34.8% (2 CR, 21 PR) and DCR was 72.7%. At a median follow up of 6.9 months, the median IRC DOR has not been reached. Overall concordance rate of investigator and IRC read of response was 89.4%. The concordance compares favorably with literature reports in a metastatic disease.1 Conclusions Lifileucel treatment resulted in a 36.4% ORR in heavily pretreated metastatic melanoma patients with high baseline disease burden who had received prior anti-PD1 and BRAF/MEK inhibitors, if tumor BRAF mutated. The high concordance of 89.4% between investigator and IRC confirms the original assessment of lifileucel efficacy in metastatic melanoma.2

BACKGROUND:Inflammatory mediators, including acute phase reactants and cytokines, have been reported to be associated with clinical efficacy in patients with melanoma and other cancers receiving immune checkpoint inhibitors (ICI). Analyses of patient sera from three large phase II/III randomized ICI trials, one of which included a chemotherapy arm, were performed to assess whether baseline levels of C-reactive protein (CRP), interleukin-6 (IL-6) or neutrophil/lymphocyte (N/L) ratios were prognostic or predictive. PATIENTS AND METHODS/METHODS:Baseline and on-treatment sera were analyzed by multiplex protein assays from immunotherapy-naïve patients with metastatic melanoma randomized 1:1 on the Checkmate-064 phase II trial of sequential administration of nivolumab followed by ipilimumab or the reverse sequence. Baseline sera, and peripheral blood mononuclear cells using automated cell counting, were analyzed from treatment-naïve patients who were BRAF wild-type and randomly allocated 1:1 to receive nivolumab or dacarbazine on the phase III Checkmate-066 trial, and from treatment-naïve patients allocated 1:1:1 to receive nivolumab, ipilimumab or both ipilimumab and nivolumab on the phase III Checkmate-067 trial. RESULTS:Higher baseline levels of IL-6 and the N/L ratio, and to a lesser degree, CRP were associated with shorter survival in patients receiving ICI or chemotherapy. Increased on-treatment levels of IL-6 in patients on the Checkmate-064 study were also associated with shorter survival. IL-6 levels from patients on Checkmate-064, Checkmate-066 and Checkmate-067 were highly correlated with levels of CRP and the N/L ratio. CONCLUSION/CONCLUSIONS:IL-6, CRP and the N/L ratio are prognostic factors with higher levels associated with shorter overall survival in patients with metastatic melanoma receiving ICI or chemotherapy in large randomized trials. In a multi-variable analysis of the randomized phase III Checkmate-067 study, IL-6 was a significant prognostic factor for survival.