Simple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the... Show moreSimple Summary: Mucosal melanoma (MM) is rare and entails a poor prognosis. MM is biologically different from cutaneous melanoma (CM). For advanced CM, overall survival has improved since the introduction of immune and targeted therapy. In contrast, little is known about the effect of their introduction on the survival of MM. This study presents the incidence, clinical characteristics, treatment characteristics, and survival of MM over 30 years (1990-2019) in the Netherlands. We conclude that the incidence of MM remained stable, and survival has slightly improved when comparing the timeframe 2014-2019 with previous years. However, the prognosis of MM remains poor as compared to CM. Future studies addressing the effect of immune and targeted therapy in MM are needed to improve outcomes for patients with MM. Background: Mucosal melanoma (MM) is a rare tumour with a poor prognosis. Over the years, immune and targeted therapy have become available and have improved overall survival (OS) for patients with advanced cutaneous melanoma (CM). This study aimed to assess trends in the incidence and survival of MM in the Netherlands against the background of new effective treatments that became available for advanced melanoma. Methods: We obtained information on patients diagnosed with MM during 1990-2019 from the Netherlands Cancer Registry. The age-standardized incidence rate and estimated annual percentage change (EAPC) were calculated over the total study period. OS was calculated using the Kaplan-Meier method. Independent predictors for OS were assessed by applying multivariable Cox proportional hazards regression models. Results: In total, 1496 patients were diagnosed with MM during 1990-2019, mostly in the female genital tract (43%) and the head and neck region (34%). The majority presented with local or locally advanced disease (66%). The incidence remained stable over time (EAPC 3.0%, p = 0.4). The 5-year OS was 24% (95%CI: 21.6-26.0%) with a median OS of 1.7 years (95%CI: 1.6-1.8). Age >= 70 years at diagnosis, higher stage at diagnosis, and respiratory tract location were independent predictors for worse OS. Diagnosis in the period 2014-2019, MM located in the female genital tract, and treatment with immune or targeted therapy were independent predictors for better OS. Conclusion: Since the introduction of immune and targeted therapies, OS has improved for patients with MM. However, the prognosis of MM patients is still lower compared to CM, and the median OS of patients treated with immune and targeted therapies remains fairly short. Further studies are needed to improve outcomes for patients with MM. Show less
IMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a... Show moreIMPORTANCE Neoadjuvant checkpoint inhibition in patients with high-risk stage III melanoma shows high pathologic response rates associated with a durable relapse-free survival. Whether a therapeutic lymph node dissection (TLND) can be safely omitted when a major pathologic response in the largest lymph node metastasis at baseline (index lymph node; ILN) is obtained is currently being investigated. A previous small pilot study (n = 12) showed that the response in the ILN may be representative of the pathologic response in the entire TLND specimen.OBJECTIVE To assess the concordance of response between the ILN and the total lymph node bed in a larger clinical trial population.DESIGN, SETTING, AND PARTICIPANTS Retrospective pathologic response analysis of a multicenter clinical trial population of patients from the randomized Study to Identify the Optimal Adjuvant Combination Scheme of Ipilimumab and Nivolumab in Melanoma Patients (OpACIN) and Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) trials. Included patients were treated with 6 weeks neoadjuvant ipilimumab plus nivolumab. Patient inclusion into the trials was conducted from August 12, 2015, to October 24, 2016 (OpACIN), and November 24, 2016, and June 28, 2018 (OpACIN-neo). Data were analyzed from April 1, 2020, to August 31, 2021.MAIN OUTCOMES AND MEASURES Concordance of the pathologic response between the ILN and the TLND tumor bed. The pathologic response of the ILN was retrospectively assessed according to the International Neoadjuvant Melanoma Consortium criteria and compared with the pathologic response of the entire TLND specimen.RESULTS A total of 82 patients treated with neoadjuvant ipilimumab and nivolumab followed by TLND (48 [59%] were male; median age, 58.5 [range, 18-80] years) were included. The pathologic response in the ILN was concordant with the entire TLND specimen response in 81 of 82 patients (99%) and in 79 of 82 patients (96%) concordant when comparing the ILN response with the response in every individual lymph node. In the single patient with a discordant response, the ILN response (20% viable tumor, partial pathologic response) underestimated the entire TLND specimen response (5% viable, near-complete pathologic response). Two other patients each had 1 small nonindex node that contained 80% viable tumor (pathologic nonresponse) whereas all other lymph nodes (including the ILN) showed a partial pathologic response. In these 2 patients, the risk of regional relapse might potentially have been increased if TLND had been omitted.CONCLUSIONS AND RELEVANCE The results of this study suggest that the pathologic response of the ILN may be considered a reliable indicator of the entire TLND specimen response and may support the ILN response-directed omission of TLND in a prospective trial. Show less
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32... Show moreSurgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3-4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90-100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. . Show less
Background: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As... Show moreBackground: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-Iymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS.Patients and methods: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry.Results: There was strong interobserver reproducibility in assessment of pathological response (kappa = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had >= 70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P <= 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046).Conclusions: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of >= 70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation. Show less
Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2).... Show moreNeoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN () and phase 2 OpACIN-neo () studies(1,2). While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-gamma score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-gamma score/high TMB; patients with high IFN-gamma score/low TMB or low IFN-gamma score/high TMB had pRRs of 91% and 88%; while patients with low IFN-gamma score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-gamma score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Show less
