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Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi + MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma. • Efficacy of subsequent ipilimumab or BRAFi ± MEKi after pembrolizumab was analyzed in KEYNOTE-006. • ORR with subsequent ipilimumab administration was 15.5%. • ORR with subsequent BRAFi ± MEKi was 30.5% in all patients, and 43.2% in patients with BRAFi ± MEKi-naïve disease. • Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in advanced melanoma. [ABSTRACT FROM AUTHOR]

Patients with resected stage III and IV melanoma have a high risk of recurrence. As the outcomes for patients with metastatic disease have improved dramatically over the past decade due to systemic therapy, more recently so too have the outcomes of patients with resected stage III and IV melanoma with the introduction of checkpoint inhibitor immunotherapy and targeted therapy in the adjuvant setting. This review outlines the latest clinical trial data, the current adjuvant treatment landscape and its application to clinical practice and expected future progress for the management of early-stage melanoma. Anti-programmed cell death protein 1 monotherapy and BRAF/MEK inhibitors are currently deemed standard of care for resected stage III melanoma. For patients with stage IIIB [American Joint Committee on Cancer staging system version 7 (AJCCv7)] melanoma, 2-year and 3-year recurrence-free survival is approximately 72% and 65% for nivolumab, 70% and 65.7% for pembrolizumab and 68% and 60% for dabrafenib/trametinib, respectively. For stage IIIC (AJCCv7) melanoma, 2-year and 3-year recurrence-free survival is 60% and 53.5% for nivolumab, 60% and 54.3% for pembrolizumab and 59% and 47% for dabrafenib/trametinib, respectively. Adjuvant treatment is recommended for patients with stage IIIB-IIID [AJCC staging system version 8 (AJCCv8)] melanoma, and may be considered for patients with stage IIIA melanoma. For resected stage IV, nivolumab is the only approved agent; however, recent results from a phase II clinical trial show promising efficacy for combined ipilimumab and nivolumab as well. Long-term data are required to determine which therapy has the greatest impact on overall survival. Schedules, delivery and toxicity are also important factors to consider when selecting adjuvant treatment. Randomized studies of patients with resected high-risk melanoma have shown that immunotherapy or targeted therapy improve recurrence-free survival compared with placebo/ipilimumab. In order to optimize these treatments, prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required. • Adjuvant BRAF/MEK inhibitors in stage III and programmed cell death protein 1 antibodies in stage III/IV reduce the risk of melanoma recurrence. • Nivolumab, pembrolizumab and dabrafenib/trametinib are now approved in the adjuvant setting. • Further data regarding timing of treatment (adjuvant versus at recurrence), resected stage IV melanoma and rare melanoma subtypes are required. • Prognostic and predictive biomarkers are needed to select patients for adjuvant treatment. • Future research directions include treatment-related toxicities, treatment duration and resistance during adjuvant therapy. [ABSTRACT FROM AUTHOR]

The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial. This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations. Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders. Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy. • This is a phase II clinical trial of neoadjuvant therapy in patients with resectable mucosal melanoma. • A promising pathologic response rate of 33.3% and a median recurrence-free survival of 11.7 months in responders. • Infiltration of CD3+/CD8+ T cells after neoadjuvant therapy was associated with pathologic response. • J Clin Oncol The neoadjuvant regimen appears to prolong survival while maximizing the preservation of organ function in mucosal melanoma. [ABSTRACT FROM AUTHOR]

The patients in this manuscript have given written informed consent to publication of their case details. Patient consent The patients have consented for the use of clinical images and information in this report; ethics review was not obtained as this is a retrospective case series. Regarding concomitant treatment, 5/7 patients were treated with topical steroids and 5/7 patients also received oral prednisolone (10-50 mg) for the management of associated inflammatory eruptions. [Extracted from the article]

We have previously shown that 75% of patients treated with programmed cell death protein 1 (PD-1) with or without CTLA4 who have not progressed by 1 year have complete metabolic response (CMR), including two-thirds of patients with partial response (PR). We now report 5-year outcomes. Retrospective analysis of 104 patients with baseline and 1-year positron emission tomography (PET) and computed tomography (CT). The 1-year response was determined using RECIST for CT and European Organisation for Research and Treatment of Cancer (EORTC) criteria for PET. Progression-free survival (PFS) and overall survival (OS) were determined from the 1-year landmark. At the median follow-up of 61 months (range 58-64 months) from 1-year PET, 94% remained alive and all but one had discontinued treatment after a median treatment duration of 23 months (range 1-59 months). Disease progression occurred in 19 patients (18%): 10 (53%) while on treatment and 12 (63%) in solitary sites for which 8 (67%) received local treatment. RECIST PFS rate at 5 years after PET was higher in complete response (CR) compared with PR/stable disease (SD) (93% versus 76%, respectively) and CMR compared with non-CMR (90% versus 54%, respectively). In patients with PR, 5-year PFS rate was superior in CMR (88% and 59%). A total of 35 (34%) patients (14/29 in CR, 31/78 in CMR) discontinued treatment within 12 months, largely due to toxicity, with no impact on PFS rate compared with those that continued (84% versus 78%). Despite progression events, OS rate at 5 years was excellent and similar in patients with CR and PR/SD (100% versus 91%, respectively) as well as in those with CMR and non-CMR (96% versus 87%, respectively). Five years after the 1-year PET, sustained responses are observed in the majority of patients, particularly in those with CMR. PET continues to predict progression better than CT, particularly in those with residual disease on CT. In the minority that progress, often in solitary sites and managed locally, OS rate remains excellent. PET is effective in evaluating residual lesions on CT and can predict long-term benefit. • FDG-PET has been shown to predict short-term outcomes with anti-PD1 therapy better than CT. • At 5 years, patients with CMR on 1-year PET had sustained responses (PFS 90%). • This was greater in those with CR (PFS 93%), as most patients with PR have CMR (PFS 88%). • In the minority that progress, often in solitary sites and managed locally, OS remains excellent. • PET may have utility in predicting long-term benefit and help guide discontinuation of therapy. [ABSTRACT FROM AUTHOR]

In vivo Reflectance confocal microscopy (RCM) can non-invasively evaluate early treatment response to ICIs in patients with cutaneous primary melanomas and in-transit metastases (ITMs), as illustrated in the following case. A punch biopsy of the primary melanoma showed no residual viable melanoma histologically (confirmed with SOX-10 immunohistochemistry), correlating with RCM. Reflectance confocal microscopy - a non-invasive tool for monitoring systemic treatment response in stage III unresectable primary scalp melanoma. [Extracted from the article]

Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy. • The extent and composition of the pathological response after neoadjuvant DT in BRAFV600E/K melanoma correlates with RFS. • Patients achieving pCR had longer RFS compared with patients who did not. • Hyalinized fibrosis correlated with longer RFS, while necrosis and proliferative fibrosis correlated with shorter RFS. • Absence of pCR or presence of immature fibrosis independently predicted shorter RFS. • Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS. [ABSTRACT FROM AUTHOR]

Somatic mutations in key oncogenes in non-small cell lung cancer ( NSCLC) and melanoma are important determinants of tumour sensitivity to targeted therapies. Molecular screening for these predictive biomarkers is routinely used to inform treatment decisions; however, little is known about how best to communicate testing and results to patients. This qualitative study aimed to explore advanced cancer patients' attitudes and experiences regarding somatic tumour screening to identify their information and support needs. Sixteen NSCLC and eight melanoma patients who had undergone screening participated in a semi-structured face-to-face or telephone interview exploring their understanding, views, preferences and needs regarding screening. Interviews were audiotaped, transcribed and analysed for thematic patterns. Participants expressed positive views and unequivocal acceptance of screening, and understood its role in guiding treatment selection. They preferred to receive information verbally through simple, non-technical language from their oncologist with additional take-home materials. Patients were interested in learning about their test results, but wanted discussion to be focused on practical matters relevant to treatment. While receiving their screening results was not considered burdensome, information overload and cancer-related distress were identified as barriers to test comprehension. Patients may benefit from information and decision-related tools to better understand genomic information and adequately support psychosocial outcomes. [ABSTRACT FROM AUTHOR]