Faculty Bibliography

BACKGROUND:The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared to the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared to AJCC7. METHODS:We analyzed a cohort of 1,315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve (AUC) of 5-year survival to predict RFS/OS. All statistical tests were two-sided. RESULTS:Stage IIC continued to have worse outcomes than those for stage IIIA patients, with 5-year RFS of 26.5% (95%CI=12.8-55.1%) vs. 56.0% (95%CI=37.0-84.7%) by AJCC8 (P = 0.002). For stage I, removing mitotic index as T classification factor decreased its prognostic value, although not statistically significantly (RFS C-index=0.63 [95%CI=0.56-0.69] to 0.56 [95%CI=0.49-0.63], P = 0.07; OS C-index=0.48 [95%CI=0.38-0.58] to 0.48 [95%CI=0.41-0.56], P = 0.90). For stage II, prognostication remained constant (RFS C-index=0.65 [95%CI=0.57-0.72]; OS C-index=0.61 [95%CI=0.50-0.72]), and. For stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index=0.65 [95%CI=0.60-0.70] to 0.70 [95%CI=0.66-0.75], P = 0.01). CONCLUSIONS:Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.

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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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.

PURPOSE/OBJECTIVE:We used a novel paramagnetic, nanoparticle-based artificial antigen presenting cell (nano-aAPC) that combines anti-CD28 co-stimulatory and human MHC class I molecules that are loaded with antigenic peptides to rapidly expand tumor antigen-specific T cells from melanoma patients. EXPERIMENTAL DESIGN/METHODS:Nano-aAPC expressing HLA-A*0201 molecules and costimulatory anti-CD28 antibody and loaded with MART-1 or gp100 class I restricted peptides were used to stimulate CD8 T cells purified from the peripheral blood of treatment-naïve or PD-1 antibody-treated patients with stage IV melanoma. Expanded cells were re-stimulated with fresh peptide-pulsed nano-aAPC at day 7. Phenotype analysis and functional assays including cytokine release, cytolysis, and measurement of avidity were conducted. RESULTS:, and expressed a highly diverse TCR V beta repertoire. CONCLUSIONS:Peptide-pulsed nanoparticle aAPC rapidly expanded polyfunctional antigen-specific CD8 T cells with high avidity, potent lytic function and a stem-memory phenotype from melanoma patients.

BACKGROUND:The reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well-described. METHODS:We used high-parameter flow cytometry and a novel computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO>IPI or IPI>NIVO (CheckMate-064). RESULTS:The two treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only two immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring post-NIVO were predominately associated with response to IPI>NIVO, but changes occurring post-IPI were predominately associated with progression after NIVO>IPI. Among these changes, CD4+CD38+CD39+CD127-GARP- T-cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO>IPI cohort. CONCLUSION/CONCLUSIONS:Collectively, these data suggest that the impact of IPI and NIVO on the immunophenotypic landscape of patients is distinct and that the impact of IPI may be associated with resistance to subsequent NIVO therapy, consistent with poor outcomes in the IPI>NIVO cohort of Checkmate-064.

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.

The impact on survival of steroids and TNF-alpha blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNF-alpha blocking antibodies such as infliximab.

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.

In the past 10 years, immune checkpoint inhibitors (ICIs) have become an additional pillar of cancer therapy by activating the immune system to treat a number of different malignancies. Many patients receiving ICIs develop immune-related adverse events (irAEs) that mimic some features of classical autoimmune diseases. Unfortunately, patients with underlying autoimmune conditions, many of whom have an increased risk for malignancy, have been excluded from clinical trials of ICIs due to a concern that they will have an increased risk of irAEs. Retrospective data from patients with autoimmune diseases and concomitant malignancy treated with ICIs are encouraging and suggest that ICIs may be tolerated safely in patients with specific autoimmune diseases, but there are no prospective data to guide management. In this manuscript, we review the relationship between pre-existing autoimmune disease and irAEs from checkpoint inhibitors. In addition, we assess the likelihood of autoimmune disease exacerbations in patients with pre-existing autoimmunity receiving ICI.