Publications by authors named "Jean-Jacques Grob"

174 Publications

Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for V600-Mutant Unresectable or Metastatic Melanoma.

J Clin Oncol 2022 Jan 14:JCO2101601. Epub 2022 Jan 14.

University Hospital Essen, Essen, and German Cancer Consortium, Heidelberg, Germany.

Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with V600-mutant unresectable or metastatic melanoma.

Methods: Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).

Results: At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.

Conclusion: The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
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http://dx.doi.org/10.1200/JCO.21.01601DOI Listing
January 2022

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.

N Engl J Med 2022 01;386(1):24-34

From the Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.); the Department of Dermatology, University Hospital Essen, and the German Cancer Consortium, Essen, Germany (D.S.); the Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore (E.J.L.); Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy (P.A.A.); the Department of Oncology, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago, Chile (L.M.); FAICIC Clinical Research, Veracruz, Mexico (E.C.G.); Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); the Department of Medicine, National and Kapodistrian University of Athens, Athens (H.J.G.); Michigan Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor (C.D.L.); Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil (J.J.D.M.); the Unit of Dermatology, Hospices Civils de Lyon, Cancer Research Center of Lyon, Pierre-Bénite (S.D.), and Aix-Marseille University, CHU Timone, Marseille (J.-J.G.) - both in France; the Department of Medical Oncology, Hospital Clinic Barcelona and IDIBAPS, Barcelona (A.A.); Bristol Myers Squibb, Princeton, NJ (S.S., M.A., M.H., S.K., K.L.S., A.M.S., B.L.); the Dana-Farber Cancer Institute, Boston (F.S.H.); and Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney (G.V.L.).

Background: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.

Methods: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.

Results: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.

Conclusions: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).
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http://dx.doi.org/10.1056/NEJMoa2109970DOI Listing
January 2022

Methotrexate for idiopathic chronic eczematous eruption of aging.

Eur J Dermatol 2021 Dec 17. Epub 2021 Dec 17.

Department of dermatology, Aix-Marseille University, La Timone university hospital, Marseille, France, CEReSS-EA 3279, health services and quality of life research centre, Aix Marseille University, dermatology department, La Timone university hospital APHM, 13385, Marseille, France.

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http://dx.doi.org/10.1684/ejd.2021.4177DOI Listing
December 2021

[BRAF mutation evolution in melanoma: Myth or reality?]

Ann Pathol 2021 Dec 2. Epub 2021 Dec 2.

Anatomie Pathologique, APHM Timone, Marseille, France; Aix Marseille Univ, INSERM, MMG, Marseille, France.

Knowledge of the BRAF mutational status has become essential for melanoma therapeutic management. B-Raf inhibitors are associated with significant overall survival in patients with BRAFV600-mutated metastatic melanoma. Although the BRAF mutation appears to be an early and driver mutation, some authors hypothesized that its expression was not stable during melanoma progression, suggesting a molecular heterogeneity. This argument is often used to explain discrepancy in molecular status among patients with melanoma, discrepancies that we occasionally met during our practice. We retrospectively compared BRAF mutational status on matched melanoma samples (primary & metastatic lesions), thus 150 samples from 56 patients were analysed through immunohistochemistry anti-BRAF, PCR-HRM and Sanger sequencing, Next Generation Sequencing (NGS) and digital PCR. Seven cases presented an apparent tumor heterogeneity. The analysis of these discrepancies by a technique of increasing sensitivity made it possible to identify 1 false-negative result for the immunohistochemistry, 1 false-negative result for the NGS sequencing and 5 (3%) false-negative results by PCR-HRM SANGER. Our results are consistent with the most recent data, demonstrating the stability of the BRAF mutation during the course of melanoma. Immunohistochemistry shows excellent sensitivity for detecting the main BRAF mutation. In our study, the mutational heterogeneity was actually misleading, a result of imperfect sensitivity of some older molecular approaches.
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http://dx.doi.org/10.1016/j.annpat.2021.11.001DOI Listing
December 2021

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma.

J Clin Oncol 2022 Jan 24;40(2):127-137. Epub 2021 Nov 24.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.

Patients And Methods: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.

Results: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with -mutant tumors and 46%, 42%, and 22% in those with -wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.

Conclusion: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
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http://dx.doi.org/10.1200/JCO.21.02229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718224PMC
January 2022

Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006.

Eur J Cancer 2021 11 25;157:391-402. Epub 2021 Sep 25.

Department of Medicine, Jonsson Comprehensive Cancer Center and David Geffen School of Medicine, University of California Los Angeles, 100 Medical Plaza Driveway #550, Los Angeles, CA 90095, USA. Electronic address:

Objective: Patients with melanoma and early stable disease (SD) with pembrolizumab have unclear prognosis. We present post hoc analyses of long-term outcomes for patients with early SD, partial response (PR) or complete response (CR) with pembrolizumab.

Patients And Methods: Patients who received pembrolizumab in the KEYNOTE-001 and KEYNOTE-006 studies and had SD, PR or CR at weeks 12 or 24 were included.

Results: Of 294 patients in the week 12 analysis, 107 (36.4%) had SD at week 12, of whom 7 (6.5%) had a best overall response of CR, 43 (40.2%) had PR and 57 (53.3%) had SD. Forty-eight-month overall survival (OS) rates were 95.2%, 73.0% and 47.7%, respectively, for patients with CR, PR and SD at week 12. Similar results were observed in the 241 patients in the week 24 analysis. Forty-eight-month OS rates were 72.1% for patients with SD at week 12 followed by subsequent response and 75.0% for patients with PR at week 12 followed by no change in response or progression. Thirty-six-month and 48-month OS rates were 11.6% and not reached, respectively, for patients with SD at week 12 followed by progression before week 24.

Conclusions: A substantial proportion of patients (46.7%) with early (week 12) SD with pembrolizumab achieved subsequent PR or CR. Patients with SD at week 12 and subsequent CR/PR had similar survival to those who maintained PR. In contrast, patients with SD at week 12 and subsequent progression had poor survival outcomes. These findings may guide treatment decisions for patients achieving early SD.

Trial Registration: Clinicaltrials.gov: NCT01295827 (KEYNOTE-001); NCT01866319 (KEYNOTE-006).
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http://dx.doi.org/10.1016/j.ejca.2021.08.013DOI Listing
November 2021

Health-Related Quality of Life of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma Treated with Pembrolizumab in KEYNOTE-629.

Dermatol Ther (Heidelb) 2021 Oct 23;11(5):1777-1790. Epub 2021 Sep 23.

Aix-Marseille University, Marseille, France.

Introduction: Pembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629.

Methods: Patients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method.

Results: Analyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, -1.00 to 10.90) and physical functioning (-3.38 points; 95% confidence interval, -8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%).

Conclusions: In elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment.

Trial Registration: ClinicalTrials.gov identifier: NCT03284424.
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http://dx.doi.org/10.1007/s13555-021-00598-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484388PMC
October 2021

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival.

J Immunother Cancer 2021 08;9(8)

Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.

Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.

Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.

Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.

Trial Registration Number: NCT02388906.
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http://dx.doi.org/10.1136/jitc-2021-003188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404438PMC
August 2021

First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study.

J Immunother Cancer 2021 07;9(7)

Division of Dermatology, University of Washington Medical Center at South Lake Union, Seattle, Washington, USA.

Background: Avelumab (anti-programmed death ligand 1 (PD-L1)) is approved in multiple countries for the treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. We report efficacy and safety data and exploratory biomarker analyses from a cohort of patients with mMCC treated with first-line avelumab in a phase II trial.

Methods: Patients with treatment-naive mMCC received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was durable response, defined as objective response (complete or partial response; assessed by independent review) lasting ≥6 months. Additional assessments included progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses.

Results: In 116 patients treated with avelumab, median follow-up was 21.2 months (range: 14.9-36.6). Thirty-five patients had a response lasting ≥6 months, giving a durable response rate of 30.2% (95% CI: 22.0% to 39.4%). The objective response rate was 39.7% (95% CI: 30.7% to 49.2%). Median PFS was 4.1 months (95% CI: 1.4 to 6.1) and median OS was 20.3 months (95% CI: 12.4 to not estimable). Response rates were numerically higher in patients with PD-L1+ tumors, Merkel cell polyomavirus (MCPyV)-negative tumors, and tumors with increased intratumoral CD8 T-cell density. Exploratory analyses did not identify a biomarker that could reliably predict a response to first-line treatment with avelumab; however, a novel gene expression signature to identify the presence of MCPyV+ tumors was derived. Treatment-related adverse events (any grade) occurred in 94 (81.0%) patients, including grade 3/4 events in 21 (18.1%) patients; no treatment-related deaths occurred.

Conclusion: In patients with mMCC, first-line treatment with avelumab led to responses in 40% and durable responses in 30%, and was associated with a low rate of grade 3/4 treatment-related adverse events.
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http://dx.doi.org/10.1136/jitc-2021-002646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311489PMC
July 2021

Molecular characterization of fast-growing melanomas.

J Am Acad Dermatol 2021 Jul 16. Epub 2021 Jul 16.

Skin Cancer and Ageing Lab, Cancer Research United Kingdom Manchester Institute, The University of Manchester, Manchester, United Kingdom. Electronic address:

Background: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied.

Objective: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth.

Methods: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month).

Results: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth.

Limitations: Single-center study, cohort size, potential memory bias, number of investigated genes.

Conclusion: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.
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http://dx.doi.org/10.1016/j.jaad.2021.07.011DOI Listing
July 2021

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib.

Eur J Cancer 2021 09 6;154:57-65. Epub 2021 Jul 6.

Department of Dermatology, CHU Bordeaux Hôpital St. André, Bordeaux, France.

Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.

Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis.

Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively.

Conclusions: This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.
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http://dx.doi.org/10.1016/j.ejca.2021.05.031DOI Listing
September 2021

Surgery of small bowel melanoma metastases in the era of efficient medical therapies: a retrospective cohort study.

Melanoma Res 2021 08;31(4):358-365

Department of Digestive Surgery, INSERM, CRCM, APHM, CHU Nord, Hôpital Nord.

Surgery of small bowel melanoma metastases has to be reconsidered in the era of targeted treatments and immunotherapy. To retrospectively assess context and outcomes of small bowel melanoma metastases resections. All consecutive melanoma patients who underwent resection of small bowel metastases between 2011 and 2017, in a single referral center, were retrospectively analyzed through melanoma-specific survival (MSS). A total of 20 patients were included with a 47.8 months median follow-up. Before small bowel surgery, eight patients (40%) were asymptomatic while seven had anemia and five patients had abdominal pain. All resections were decided on tumor boards except for three surgeries performed in the emergency setting. In the whole cohort, MSS was 89.5 months with 50% of patients alive at the study endpoint. We classified surgical indications in three groups: (1) surgery as a pivotal treatment for mono- or oligo-metastases limited to the small bowel (n = 6); (2) salvage surgery for symptomatic patients in order to preserve their chances to switch to an active line of medical treatment (n = 8); and (3) surgery of small bowel dissociated metastatic progression for patients otherwise controlled (n = 6), aiming at keeping patients with the same treatment or active follow-up. In these three situations, the objective of surgery was usually met, and most patients had a long median MSS after surgery: 70.3 months, 89.5 months and 72.4 months, respectively. Although medical treatments have dramatically improved survival in metastatic melanoma, surgical control of life-threatening localization like small bowel metastases is often a condition for long survival.
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http://dx.doi.org/10.1097/CMR.0000000000000737DOI Listing
August 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):655-664. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00081-4DOI Listing
May 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):643-654. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00065-6DOI Listing
May 2021

The "Great Debate" at Melanoma Bridge 2020: December, 5th, 2020.

J Transl Med 2021 04 7;19(1):142. Epub 2021 Apr 7.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.
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http://dx.doi.org/10.1186/s12967-021-02808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028182PMC
April 2021

Identification of an Immature Subset of PMN-MDSC Correlated to Response to Checkpoint Inhibitor Therapy in Patients with Metastatic Melanoma.

Cancers (Basel) 2021 Mar 17;13(6). Epub 2021 Mar 17.

Immunity and Cancer Team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS, UMR7258, Institut Paoli-Calmettes, Aix Marseille University, UM105, 13009 Marseille, France.

PMN-MDSCs support tumor progression and resistance to ICI therapy through their suppressive functions but their heterogeneity limits their use as biomarkers in cancer. Our aim was to investigate the phenotypic and functional subsets of PMN-MDSCs to identify biomarkers of response to ICI therapy. We isolated low-density CD15 PMNs from patients with metastatic melanoma and assessed their immune-suppressive capacities. Expression of CD10 and CD16 was used to identify mature and immature subsets and correlate them to inhibition of T cell proliferation or direct cytotoxicity. Frequencies of the PMN-MDSCs subsets were next correlated to the radiological response of 36 patients receiving ICI therapy. Mature activated cells constituted the major population of PMN-MDSCs. They were found in a higher proportion in the pre-treatment blood of patients non responders to ICI. A subset of immature cells characterized by intermediate levels of CD10 and CD16, the absence of expression of SIRPα and a strong direct cytotoxicity to T cells was increased in patients responding to ICI. The paradoxical expansion of such cells during ICI therapy suggests a role of PMNs in the inflammatory events associated to efficient ICI therapy and the usefulness of their monitoring in patients care.
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http://dx.doi.org/10.3390/cancers13061362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002694PMC
March 2021

Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma.

J Immunother Cancer 2021 03;9(3)

First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.

Methods: In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.

Results: Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions.

Conclusions: This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy.

Trial Registration Number: NCT02366195.
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http://dx.doi.org/10.1136/jitc-2020-001621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011715PMC
March 2021

Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.

Lancet Oncol 2021 03 12;22(3):370-380. Epub 2021 Feb 12.

NYU Langone Health, New York, NY, USA. Electronic address:

Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes.

Methods: In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAF-mutant ctDNA in pretreatment and on-treatment plasma samples from patients aged 18 years or older enrolled in two clinical trials. COMBI-d (NCT01584648) was a double-blind, randomised phase 3 study of dabrafenib plus trametinib versus dabrafenib plus placebo in previously untreated patients with BRAF mutation-positive unresectable or metastatic melanoma. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. COMBI-MB (NCT02039947) was an open-label, non-randomised, phase 2 study evaluating dabrafenib plus trametinib in patients with BRAF mutation-positive metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG performance status of 0 or 1. Biomarker analysis was a prespecified exploratory endpoint in both trials and performed in the intention-to-treat populations in COMBI-d and COMBI-MB. We investigated the association between mutant copy number (baseline or week 4 or zero conversion status) and efficacy endpoints (progression-free survival, overall survival, and best overall response). We used Cox models, Kaplan-Meier plots, and log-rank tests to explore the association of pretreatment ctDNA concentrations with progression-free survival and overall survival. The effect of additional prognostic variables such as lactate dehydrogenase was also investigated in addition to the mutant copy number.

Findings: In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF mutation-positive ctDNA concentration was associated with worse overall survival outcome (hazard ratio [HR] 1·13 [95% CI 1·09-1·18], p<0·0001 by univariate analysis), independent of treatment group and baseline lactate dehydrogenase concentrations (1·08 [1·03-1·13], p=0·0020), in COMBI-d. A ctDNA cutoff point of 64 copies per mL of plasma stratified patients enrolled in COMBI-d as high risk or low risk with respect to survival outcomes (HR 1·74 [95% CI 1·37-2·21], p<0·0001 for progression-free survival; 2·23 [1·73-2·87], p<0·0001 for overall survival) and was validated in the COMBI-MB cohort (3·20 [1·39-7·34], p=0·0047 for progression-free survival; 2·94 [1·18-7·32], p=0·016 for overall survival). In COMBI-d, undetectable ctDNA at week 4 was significantly associated with extended progression-free and overall survival, particularly in patients with elevated lactate dehydrogenase concentrations (HR 1·99 [95% CI 1·08-3·64], p=0·027 for progression-free survival; 2·38 [1·24-4·54], p=0·0089 for overall survival).

Interpretation: Pretreatment and on-treatment BRAF-mutant ctDNA measurements could serve as independent, predictive biomarkers of clinical outcome with targeted therapy.

Funding: Novartis.
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http://dx.doi.org/10.1016/S1470-2045(20)30726-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034833PMC
March 2021

Reply to E. Hindié.

J Clin Oncol 2021 03 25;39(8):944-946. Epub 2021 Jan 25.

Alexander M. M. Eggermont, MD, PhD, Princess Máxima Center, Utrecht, the Netherlands; Christian U. Blank, MD, PhD, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Mario Mandala, MD, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Georgina V. Long, BSc, MBBS, Melanoma Institute Australia, The University of Sydney, and Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia; Victoria G. Atkinson, MBBS, Princess Alexandra Hospital, Brisbane, Queensland, Australia; St 00B4ephane Dalle, MD, PhD, Hospices Civils de Lyon Cancer Institute, Lyon, France; Andrew M. Haydon, MBBS, PhD, Alfred Hospital, Melbourne, Victoria, Australia; Andrey Meshcheryakov, MD, PhD, N.N. Blokhin Cancer Research Center, Moscow, Russian Federation; Adnan Khattak, MD, Fiona Stanley Hospital and Edith Cowan University, Perth, Western Australia, Australia; Matteo S. Carlino, BMedSc, MBBS, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, New South Wales, Australia; Shahneen Sandhu, MD, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; James Larkin, PhD, Royal Marsden Hospital, London, United Kingdom; Susana Puig, MD, PhD, Hospital Clinic Universitari de Barcelona, Barcelona, Spain; Paolo A. Ascierto, MD, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale," Naples, Italy; Piotr Rutkowski, MD, PhD, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Dirk Schadendorf, MD, PhD, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany; Rutger Koornstra, MD, PhD, Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands; Leonel Hernandez-Aya, MD, Washington University School of Medicine, St Louis, MO; Anna Maria Di Giacomo, MD, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy; Alfonsus J. M. van den Eertwegh, MD, PhD, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Jean-Jacques Grob, MD, Aix Marseille University, Hôpital de la Timone, Marseille, France; Ralf Gutzmer, MD, Skin Cancer Center, Hannover Medical School, Hanover, Germany; Rahima Jamal, MD, BSc, Centre Hospitalier de l'Université de Montreal (CHUM), Centre de recherche du CHUM, Montreal, Quebec, Canada; Paul C. Lorigan, MD, Christie NHS Foundation Trust, Manchester, United Kingdom; Alexander C. J. van Akkooi, MD, PhD, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Clemens Krepler, MD, Merck & Co, Inc, Kenilworth, NJ; Nageatte Ibrahim, MD, Merck & Co, Inc, Kenilworth, NJ; Sandrine Marreaud, MD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Michal Kicinski, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; Stefan Suciu, PhD, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; and Caroline Robert, MD, PhD, Gustave Roussy and Paris-Saclay University, Villejuif, France.

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http://dx.doi.org/10.1200/JCO.20.03463DOI Listing
March 2021

Cross-cultural adaptation into French and validation of the SCAR-Q questionnaire.

Qual Life Res 2021 Apr 3;30(4):1225-1231. Epub 2021 Jan 3.

Aix Marseille Univ, APHM, IUSTI, Department of Oto-Rhino-Laryngology and Head and Neck Surgery, La Conception University Hospital, Marseille, France.

Purpose: Most questionnaires designed to evaluate patient-reported outcomes regarding scarring are available in English. The objective was to generate a validated French version of the SCAR-Q questionnaire.

Methods: The SCAR-Q questionnaire (including Appearance, Symptom and Psychological impact scales) was translated into French using a translation-back-translation process in accordance with international guidelines (ISPOR and WHO). For validation, two hundred patients consulting in our tertiary center completed the questionnaire. We tested scale reliability (Cronbach's α), floor/ceiling effects and item redundancy (inter-item correlations). Structural validity was tested using confirmatory factor analysis (CFA) with the robust weighted least squares (WLSMV) estimator and Delta parameterization. Model fit was examined using the root mean square error of approximation (RMSEA), the comparative fit index (CFI) and the Tucker-Lewis index (TLI). Correlations between scales and scale repeatability were tested (Spearman coefficient, Intra-class-coefficient).

Results: Four steps were required to obtain a translation consistent with the original version. Two hundred patients completed the questionnaire for validation. Internal consistency analysis found Cronbach's alphas > 0.7 for all scales (0.90 < α < 0.97). No floor or ceiling effect was found for all items (max = 85%). A ceiling effect was observed for all scales. Appearance and psychosocial impact scale items showed redundancy, with many inter-item correlations above 0.7. The CFA of the original structure displayed a reasonable fit, with RMSEA = 0.065, CFI = 0.974 and TLI = 0.972. Scales were positively correlated (0.45 <  ρ < 0.65; p < 0.001). Test-retest intra-class correlation coefficients ranged from 0.94 to 0.99 for all scales.

Conclusion: A French version of the SCAR-Q questionnaire is validated, ready for use.
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http://dx.doi.org/10.1007/s11136-020-02719-8DOI Listing
April 2021

ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells.

Blood Adv 2020 10;4(20):5203-5214

Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique U7258, Aix Marseille Université, Institut Paoli-Calmettes, Marseille, France.

The treatment of advanced-stage cutaneous T-cell lymphoma (CTCL) remains an unmet medical need. Mogamulizumab, anti-KIR3DL2, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) coupled with monomethyl-auristatin-E (MMAE), provided encouraging results, but new targeted therapies are needed. Inducible T-cell costimulator (ICOS), a T-cell costimulatory receptor, is a promising therapeutic target, not only because it is expressed by malignant T cells in CTCL but also because of its connection with the suppressive activity of regulatory T (Treg) cells. Immunohistochemical analysis revealed that ICOS was widely expressed by malignant cells in skin biopsy specimens from 52 patients with mycosis fungoides and Sézary syndrome (SS), as well as in involved node biopsy specimens from patients with SS. Furthermore, flow cytometry demonstrated its strong expression by circulating tumor cells in all our patients with SS. Percentages of ICOS+ Treg cells were significantly higher in patients with SS than in healthy donors. We then investigated the preclinical efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE and pyrrolobenzodiazepine. In 3 CTCL cell lines (Myla, MJ, and HUT78), we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In addition, anti-ICOS-MMAE ADCs had an in vitro and in vivo efficacy superior to BV in a mouse xenograft model (MyLa). Finally, we assessed the efficacy of anti-ICOS ADCs in ICOS+ patient-derived xenografts from patients with SS and angioimmunoblastic T-cell lymphoma. Collectively, our findings provide the preliminary basis for a therapeutic trial.
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http://dx.doi.org/10.1182/bloodadvances.2020002395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594390PMC
October 2020

Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 11 19;21(11):1465-1477. Epub 2020 Sep 19.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

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: 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: 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: Bristol Myers Squibb and Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30494-0DOI Listing
November 2020

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.

J Clin Oncol 2020 11 18;38(33):3925-3936. Epub 2020 Sep 18.

European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients And Methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% 44.1% for pembrolizumab placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] 0.66 [99% CI, 0.46 to 0.95] for V600 wild type).

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.
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http://dx.doi.org/10.1200/JCO.20.02110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676886PMC
November 2020

Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort.

Nephrol Dial Transplant 2021 08;36(9):1664-1674

Assistance Publique-Hôpitaux de Marseille, Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Marseille, France.

Background: Immune checkpoints inhibitors have transformed the prognosis of advanced melanoma but are associated with immune-related adverse events (irAEs). We evaluated the incidence, risk factors and causes of acute kidney injury (AKI) in a monocentric real-life cohort of patients treated with anti-programmed death receptor-1 (anti-PD1) antibodies for advanced melanoma.

Methods: Retrospective collection of medical charts and comprehensive analysis of lab results from patients treated with nivolumab or pembrolizumab for advanced melanoma between 2014 and 2018 was carried out. AKI was defined by Kidney Disease Improving Global Outcomes criteria, and causes were determined by chart review. Overall survival, survival without AKI and impact of AKI on survival were analysed. Risk factors for death and for AKI were identified.

Results: Two hundred and thirty-nine patients were included. Forty-one (17%) had at least one episode of AKI. Independent risk factors for AKI were treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), pre-existing chronic kidney disease (CKD) and cumulated doses of anti-PD1. The main cause of AKI was prerenal, and only eight patients (3.3%) developed acute interstitial nephritis; 8% of patients developed CKD. The median overall survival was 13.4 months and was not affected by AKI. In multivariate analysis, the overall mortality was lower in overweight and obese patients and higher in patients treated with proton-pump inhibitors (PPI) or corticosteroids.

Conclusions: AKI is common in patients treated with anti-PD1 for advanced melanoma but is mostly prerenal and favoured by the use of RAASi; renal irAE is rare. PPI and corticosteroids were associated with poor survival in this population, while overweight/obesity was protective.
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http://dx.doi.org/10.1093/ndt/gfaa137DOI Listing
August 2021

Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas.

J Clin Oncol 2020 09 30;38(26):3051-3061. Epub 2020 Jul 30.

Assistance Publique-Hôpitaux de Paris, Agence Générale des Equipements et Produits de Santé, Paris, France.

Purpose: To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs).

Patients And Methods: Patients, predominantly men, with their CSSCs' immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort's objective response rate at week 15 (ORR). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR difference between PD-L1+ and PD-L1- patients, was assessed for ORR, disease control rate, and safety, but not survival.

Results: Median age of all patients was 79 years. The primary cohort's ORR was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%; = .02). Responders' W15 total FACT-G score had improved ( = .025) compared with nonresponders.

Conclusion: First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.
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http://dx.doi.org/10.1200/JCO.19.03357DOI Listing
September 2020

Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629).

J Clin Oncol 2020 09 16;38(25):2916-2925. Epub 2020 Jul 16.

Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Purpose: Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study.

Patients And Methods: Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety.

Results: At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy.

Conclusion: Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
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http://dx.doi.org/10.1200/JCO.19.03054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460151PMC
September 2020

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma.

JAMA Dermatol 2020 09;156(9):982-986

Department of Oncology, Comprehensive Cancer Center Eugène Marquis, Rennes, France.

Importance: Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies.

Objectives: To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs.

Design, Settings, And Participants: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017.

Exposures: Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy.

Main Outcomes And Measures: The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy.

Results: Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing).

Conclusions And Relevance: The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.
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http://dx.doi.org/10.1001/jamadermatol.2020.2149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364335PMC
September 2020

Early Phase of Primary Melanoma Growth from the Patient Point of view: A Prospective Cross Sectional Study on Melanoma over 1 mm in Thickness.

Acta Derm Venereol 2020 Jul 28;100(14):adv00222. Epub 2020 Jul 28.

Department of Dermatology and Skin Cancer, CHU Timone, APHM, Aix Marseille University, INSERM, CRCM, FR-13885 Marseille, France.

A Nodular Pink Lesion with an Uncommon Diagnosis: A QuizMost melanomas are diagnosed by the patients themselves or by their partners or relatives; they alone can describe its history. We designed a prospective cross-sectional study to describe patients' perception of morphology, growth pattern and kinetics of their primary melanoma over 1 mm in thickness before resection. Patients were interviewed with a questionnaire, a grid representing 9 possible scenarios of melanoma growth, and a set of 87 photographs of potential aspects of melanomas and precursors. Most patients were able to describe the growth of their melanoma and select pictures representative of its successive aspects before resection. Among 453 patients, 60% reported a preexisting lesion present for years. Growth pattern scenarios concurred with tumor kinetics but with no statistical difference between nodular and superficial spreading subtypes. These subjective patient-reported indicators about melanoma growth over time could dynamically complement its objective pathological analysis otherwise static at a single time point.
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http://dx.doi.org/10.2340/00015555-3591DOI Listing
July 2020
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