Nature and management of melanoma recurrences following adjuvant anti-PD-1 based therapy.

INTRODUCTION: Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. METHODS: This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. RESULTS: 711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. CONCLUSION: Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

PROM2 overexpression induces metastatic potential through epithelial-to-mesenchymal transition and ferroptosis resistance in human cancers.

INTRODUCTION: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. METHODS AND RESULTS: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient-derived xenograft models. Using an oligonucleotide anti-sense anti-PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. CONCLUSION: Our results open the way for further studies using PROM2 as a bio-target in resort situations in human metastatic melanoma and also in other cancer types.

Efficacy and safety of 'Second Adjuvant' therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy.

BACKGROUND: Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi. PATIENTS AND METHODS: Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group). RESULTS: 73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). CONCLUSION: This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.

BACKGROUND: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown. METHODS: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated. RESULTS: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001). CONCLUSIONS: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.

Combined PDE4+MEK inhibition shows antiproliferative effects in NRASQ61 mutated melanoma preclinical models.

Upregulation of phosphodiesterase type 4 (PDE4) has been associated with worse prognosis in several cancers. In melanomas harboring NRAS mutations, PDE4 upregulation has been shown to trigger a switch in signaling from BRAF to RAF1 which leads to mitogen-activated protein kinase pathway activation. Previous in vitro evidence showed that PDE4 inhibition induced death in NRASQ61mut melanoma cells and such a strategy may thus be a relevant therapeutic option in those cases with no molecular targeted therapies approved to date. In this study, we generated patient-derived xenografts (PDX) from two NRASQ61mut melanoma lesions. We performed ex vivo histoculture drug response assays and in vivo experiments. A significant ex vivo inhibition of proliferation with the combination of roflumilast+cobimetinib was observed compared to dimethyl sulfoxide control in both models (51 and 67%). This antiproliferative effect was confirmed in vivo for PDX-1 with a 56% inhibition of tumor growth. To decipher molecular mechanisms underlying this effect, we performed transcriptomic analyses and revealed a decrease in MKI67, RAF1 and CCND1 expression under bitherapy. Our findings strengthen the therapeutic interest of PDE4 inhibitors and support further experiments to evaluate this approach in metastatic melanoma.

Differential gradients of immunotherapy vs targeted therapy efficacy according to the sun-exposure pattern of the site of occurrence of primary melanoma: a multicenter prospective cohort study (MelBase).

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment. Patients and methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS). Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively). Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research.

Efficacy of ipilimumab 3 mg/kg following progression on low-dose ipilimumab in metastatic melanoma.

BACKGROUND: Differing doses of ipilimumab (IPI) are used in combination with an anti-PD1 antibody in advanced melanoma. There is no data on the outcomes of patients who progress following low-dose IPI (< 3 mg/kg) and are subsequently treated with IPI 3 mg/kg (IPI3). We conducted a multicentre retrospective survey to assess the efficacy of this strategy. METHODS: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (< 3 mg/kg) with an anti-PD1 antibody with recurrence (neo/adjuvant) or progressive disease (metastatic), who then received IPI3± anti-PD1 antibody were eligible. Best investigator-determined Response Evaluation Criteria in Solid Tumours response, progression-free survival (PFS) and overall survival (OS) were analysed. RESULTS: Total 36 patients received low-dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting. Of which, 20 (56%) had primary resistance and 16 (44%) had acquired resistance. All patients received IPI3 for unresectable stage III or IV melanoma; median age 60 (29-78), 18 (50%) M1d disease, 32 (89%) Eastern Cooperative Oncology Group performance status 0-1. Around 35 (97%) received IPI3 with nivolumab and 1 received IPI3 alone. The response rate to IPI3 was 9/36 (25%). In patients with primary resistance, the response rate was 6/20 (30%). After a median follow-up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded; 1-year PFS and OS were 73% and 100%, respectively. CONCLUSIONS: IPI3 following recurrence/progression on low dose IPI has clinical activity, including in primary resistance. IPI dosing is therefore critical in a subset of patients.

Impact of systemic therapies in metastatic melanoma of unknown primary: A study from MELBASE, a French multicentric prospective cohort.

BACKGROUND: Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied. OBJECTIVE: To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP). METHODS: Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed. RESULTS: Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type. LIMITATIONS: No record of standard diagnostic criteria of MUP used in the participating centers. CONCLUSIONS: Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France.

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma.

BACKGROUND: Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi). METHODS: Patients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group. RESULTS: Of 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months; treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36%; 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months; 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months; 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with <10 days between BRAF/MEKi and PD1±IPI, and those with stage III/M1A/M1B melanoma. The combination of ECOG PS=0 and absence of liver metastases identified patients with >3 years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67). CONCLUSIONS: IPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy.

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma.

BACKGROUND: Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. METHODS: Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. CONCLUSION: While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Risk of irAEs in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage III or IV melanoma: results from a matched case-control study.

OBJECTIVE: To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. METHODS: Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. RESULTS: 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade ≥3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. CONCLUSION: In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

18FDG PET Assessment of Therapeutic Response in Patients with Advanced or Metastatic Melanoma Treated with First-Line Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) are currently the first-line treatment for patients with metastatic melanoma. We investigated the value of positron emission tomography (PET) response criteria to assess the therapeutic response to first-line ICI in this clinical context and explore the potential contribution of total tumor metabolic volume (TMTV) analysis. METHODS: We conducted a retrospective study in patients treated with first-line ICI for advanced or metastatic melanoma, with 18F-FDG PET/CT performed at baseline and 3 months after starting treatment. Patients' metabolic response was classified according to PERCIST5 and imPERCIST 5 criteria. TMTV was recorded for each examination. RESULTS: Twenty-nine patients were included. The median overall survival (OS) was 51.2 months (IQR 13.6-not reached), and the OS rate at 2 years was 58.6%. Patients classified as responders (complete and partial response) had a 90.9% 2-year OS rate versus 38.9% for non-responders (stable disease and progressive disease) (p = 0.03), for PERCIST5 and imPERCIST 5 criteria. The median change in metabolic volume was 9.8% (IQR -59-+140%). No significant correlation between OS and changes in TMTV was found. CONCLUSION: The evaluation of response to immunotherapy using metabolic imaging with PERCIST5 and imPERCIST5 was significantly associated with OS in patients with advanced or metastatic melanoma.

Late-onset adverse events of anti-PD1 therapy in melanoma patients: An observational study from MELBASE, a nationwide prospective cohort.

BACKGROUND: Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described. OBJECTIVES: The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting. METHODS: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab. RESULTS: AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively). CONCLUSIONS: Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs.

Positive Association Between Location of Melanoma, Ultraviolet Signature, Tumor Mutational Burden, and Response to Anti-PD-1 Therapy.

Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti-PD-1 monotherapy. METHODS: The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS: One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, -1.05; chronic sun-exposed area, 1.12; P value for the location, < 10-5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION: Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice.

Immune checkpoint inhibitors increase T cell immunity during SARS-CoV-2 infection.

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.

Real-world effectiveness of pembrolizumab in advanced melanoma: analysis of a French national clinicobiological database.

Aim: To describe real-world pembrolizumab administration and outcomes for advanced melanoma in France. Materials & methods: Using the MelBase longitudinal database, this multicenter historical-prospective study examined treatment and outcomes of patients with nonuveal, unresectable stage III/IV melanoma initiating pembrolizumab from April 2016 to September 2017, with follow-up to September 2019. Kaplan-Meier time-to-event analyses were conducted. Results: Of 223 patients (median age 67; 51% men), 134 (60%), 36 (16%) and 53 (24%) initiated pembrolizumab in first-, second- and third-line, respectively. Median overall survival (months) was 32.6 (95% CI: 20.3-not reached [NR]), 14.4 (8.6-NR) and 9.3 (6.4-NR), respectively. Best real-world tumor response of complete or partial response was recorded for 49, 39 and 26% of patients, respectively. Conclusion: Study results support benefits of pembrolizumab therapy for advanced melanoma.

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

BACKGROUND: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). METHODS: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. FINDINGS: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. INTERPRETATION: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. FUNDING: None.

The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.

INTRODUCTION: In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma. PATIENTS AND METHODS: Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation. RESULTS: We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences. CONCLUSION: Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.