Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma in patients with concomitant chronic lymphocytic leukemia.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced melanoma (AM). However, data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia and is associated with increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICIs in patients with CLL. We, therefore, sought to examine the efficacy of ICI in patients with these co-occurring diagnoses. PATIENTS AND METHODS: In this international multicenter study, a retrospective review of clinical databases identified patients with concomitant diagnoses of CLL and AM treated with ICI (US-MD Anderson Cancer Center, N = 24; US-Mayo Clinic, N = 15; AUS, N = 19). Objective response rates (ORRs), assessed by RECIST v1.1, and survival outcomes [overall survival (OS) and progression-free survival (PFS)] among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Additionally, ORR and survival outcomes were compared between the Australian CLL/AM cohort and a control cohort of 148 Australian patients with AM alone. RESULTS: Between 1997 and 2020, 58 patients with concomitant CLL and AM were treated with ICI. ORRs were comparable between AUS-CLL/AM and AM control cohorts (53% versus 48%, P = 0.81). PFS and OS from ICI initiation were also comparable between cohorts. Among CLL/AM patients, a majority were untreated for their CLL (64%) at the time of ICI. Patients with prior history of chemoimmunotherapy treatment for CLL (19%) had significantly reduced ORRs, PFS, and OS. CONCLUSIONS: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI. However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.

BACKGROUND: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. PATIENTS AND METHODS: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery. RESULTS: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. CONCLUSIONS: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections.

BACKGROUND: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1-5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. METHODS: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. RESULTS: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. CONCLUSION: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

FDG-PET to predict long-term outcome from anti-PD-1 therapy in metastatic melanoma.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Behavioural adjustments of predators and prey to wind speed in the boreal forest.

Wind speed can have multifaceted effects on organisms including altering thermoregulation, locomotion, and sensory reception. While forest cover can substantially reduce wind speed at ground level, it is not known if animals living in forests show any behavioural responses to changes in wind speed. Here, we explored how three boreal forest mammals, a predator and two prey, altered their behaviour in response to average daily wind speeds during winter. We collected accelerometer data to determine wind speed effects on activity patterns and kill rates of free-ranging red squirrels (n = 144), snowshoe hares (n = 101), and Canada lynx (n = 27) in Kluane, Yukon from 2015 to 2018. All 3 species responded to increasing wind speeds by changing the time they were active, but effects were strongest in hares, which reduced daily activity by 25%, and lynx, which increased daily activity by 25%. Lynx also increased the number of feeding events by 40% on windy days. These results highlight that wind speed is an important abiotic variable that can affect behaviour, even in forested environments.

Novel adjuvant options for cutaneous melanoma.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Immunotherapy use outside clinical trial populations: never say never?

BACKGROUND: Based on favourable outcomes in clinical trials, immune checkpoint inhibitors (ICIs), most notably programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, are now widely used across multiple cancer types. However, due to their strict inclusion and exclusion criteria, clinical studies often do not address challenges presented by non-trial populations. DESIGN: This review summarises available data on the efficacy and safety of ICIs in trial-ineligible patients, including those with autoimmune disease, chronic viral infections, organ transplants, organ dysfunction, poor performance status, and brain metastases, as well as the elderly, children, and those who are pregnant. In addition, we review data concerning other real-world challenges with ICIs, including timing of therapy switch, relationships to radiotherapy or surgery, re-treatment after an immune-related toxicity, vaccinations in patients on ICIs, and current experience around ICI and coronavirus disease-19. Where possible, we provide recommendations to aid the often-difficult decision-making process in those settings. CONCLUSIONS: Data suggest that ICIs are often active and have an acceptable safety profile in the populations described above, with the exception of PD-1 inhibitors in solid organ transplant recipients. Decisions about whether to treat with ICIs should be personalised and require multidisciplinary input and careful counselling of patients with respect to potential risks and benefits. Clinical judgements need to be carefully weighed, considering factors such as underlying cancer type, feasibility of alternative treatment options, or activity in trial-eligible patients.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: 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-lymphocyte-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 (κ = 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.

Optimisation of energetic and reproductive gains explains behavioural responses to environmental variation across seasons and years.

Animals switch between inactive and active states, simultaneously impacting their energy intake, energy expenditure and predation risk, and collectively defining how they engage with environmental variation and trophic interactions. We assess daily activity responses to long-term variation in temperature, resources and mating opportunities to examine whether individuals choose to be active or inactive according to an optimisation of the relative energetic and reproductive gains each state offers. We show that this simplified behavioural decision approach predicts most activity variation (R2  = 0.83) expressed by free-ranging red squirrels over 4 years, as quantified through accelerometer recordings (489 deployments; 5066 squirrel-days). Recognising activity as a determinant of energetic status, the predictability of activity variation aggregated at a daily scale, and the clear signal that behaviour is environmentally forced through optimisation of gain, provides an integrated approach to examine behavioural variation as an intermediary between environmental variation and energetic, life-history and ecological outcomes.

Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: review of the literature and personalized risk-based prevention strategy.

Patients with cancer and with preexisting active autoimmune diseases (ADs) have been excluded from immunotherapy clinical trials because of concerns for high susceptibility to the development of severe adverse events resulting from exacerbation of their preexisting ADs. However, a growing body of evidence indicates that immune-checkpoint inhibitors (ICIs) may be safe and effective in this patient population. However, baseline corticosteroids and other nonselective immunosuppressants appear to negatively impact drug efficacy, whereas retrospective and case report data suggest that use of specific immunosuppressants may not have the same consequences. Therefore, we propose here a two-step strategy. First, to lower the risk of compromising ICI efficacy before their initiation, nonselective immunosuppressants could be replaced by specific selective immunosuppressant drugs following a short rotation phase. Subsequently, combining ICI with the selective immunosuppressant could prevent exacerbation of the AD. For the most common active ADs encountered in the context of cancer, we propose specific algorithms to optimize ICI therapy. These preventive strategies go beyond current practices and recommendations, and should be practiced in ICI-specialized clinics, as these require multidisciplinary teams with extensive knowledge in the field of clinical immunology and oncology. In addition, we challenge the exclusion from ICI therapy for patients with cancer and active ADs and propose the implementation of an international registry to study such novel strategies in a prospective fashion.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

Pre-operative ctDNA predicts survival in high-risk stage III cutaneous melanoma patients.

BACKGROUND: The outcomes of patients with stage III cutaneous melanoma who undergo complete surgical resection can be highly variable, and estimation of individual risk of disease recurrence and mortality remains imprecise. With recent demonstrations of effective adjuvant targeted and immune checkpoint inhibitor therapy, more precise stratification of patients for costly and potentially toxic adjuvant therapy is needed. We report the utility of pre-operative circulating tumour DNA (ctDNA) in patients with high-risk stage III melanoma. PATIENTS AND METHODS: ctDNA was analysed in blood specimens that were collected pre-operatively from 174 patients with stage III melanoma undergoing complete lymph node (LN) dissection. Cox regression analyses were used to evaluate the prognostic significance of ctDNA for distant metastasis recurrence-free survival and melanoma-specific survival (MSS). RESULTS: The detection of ctDNA in the discovery and validation cohort was 34% and 33%, respectively, and was associated with larger nodal melanoma deposit, higher number of melanoma involved LNs, more advanced stage and high lactate dehydrogenase (LDH) levels. Detectable ctDNA was significantly associated with worse MSS in the discovery [hazard ratio (HR) 2.11 P < 0.01] and validation cohort (HR 2.29, P = 0.04) and remained significant in a multivariable analysis (HR 1.85, P = 0.04). ctDNA further sub-stratified patients with AJCC stage III substage, with increasing significance observed in more advanced stage melanoma. CONCLUSION: Pre-operative ctDNA predicts MSS in high-risk stage III melanoma patients undergoing complete LN dissection, independent of stage III substage. This biomarker may have an important role in determining prognosis and stratifying patients for adjuvant treatment.

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.

BACKGROUND: Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. PATIENTS AND METHODS: This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N = 167) or nivolumab (N = 18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. RESULTS: Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. CONCLUSIONS: In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. CLINICAL TRIAL REGISTRATION: NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3).

FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma.

Background: Immune checkpoint inhibitor therapy has resulted in impressive and durable clinical activity for many cancers including melanoma; however, there remain few reliable predictors for long-term response. This study investigated whether [18F]2-fluoro-2-deoxy-D-glucose (FDG-PET) imaging may better predict long-term outcomes compared with standard computed tomography (CT) response criteria. Patients and methods: Retrospective analysis of metastatic melanoma patients treated with anti-PD-1-based immunotherapy with baseline and 1-year FDG-PET and CT imaging at Melanoma Institute Australia. One-year response was determined using RECIST for CT and EORTC criteria for PET, coded as complete response (CR or CMR), partial response (PR or PMR), stable disease (SD or SMD) or progressive disease (PD or PMD). Progression-free survival (PFS) was determined from the 1-year landmark. Results: Patients (n = 104) were evaluated with median follow-up 30.1 months and 98% remain alive. Most received anti-PD-1 as monotherapy (67%) or combined with ipilimumab (31%). At 1 year, 28% had CR, 66% had PR and 6% had SD on CT, while 75% had CMR, 16% PMR and 9% SMD/PMD on PET. CMR was observed in 68% of patients with PR on CT. RECIST PFS post 1-year landmark was similar in patients with CR versus PR/SD, but improved in patients with CMR versus non-CMR {median not reached [NR] versus 12.8 month; hazard ratio [HR] 0.06 [95% confidence interval (CI) 0.02-0.23]; P < 0.01}. In patients with PR on CT, PFS was improved in patients with PR + CMR versus PR + non-CMR (median NR versus 12.8 months; HR 0.07 [95% CI 0.02-0.27]; P < 0.01). In the 78 CMR patients, 78% had discontinued treatment and 96% had ongoing response. Conclusions: Whilst only a small proportion of patients have a CR at 1 year, most patients with a PR have CMR on PET. Almost all patients with CMR at 1 year have ongoing response to therapy thereafter. PET may have utility in predicting long-term benefit and help guide discontinuation of therapy.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.