The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six ...clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%, P < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, P = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.
Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events ...(irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients.
Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab.
Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8–786) and from irAE onset to tocilizumab 32 days (range 1–192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1–93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3–99), at the onset of irAE 49.5 mg/L (range 0.3–251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3–18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9–18.8) and median overall survival was not reached.
Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
•Anti-IL6 (interleukin-6) was effective for management of immunotherapy-related toxicities.•In pre-existing auto-immune disorders, anti-IL6 could prevent flare during immune checkpoint inhibitor.•Clinical improvement/benefit was demonstrated in 21/22 patients (96%).•Anti-IL6 was well-tolerated in 21 patients, with transient toxicities in 50%.•Caution is required in patients with underlying bowel disease (bowel perforation).
Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, ...efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.
This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis.
Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8–25), intracranial responses were achieved by 16 (46%; 95% CI 29–63) of 35 patients in cohort A, five (20%; 7–41) of 25 in cohort B, and one (6%; 0–30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred.
Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases.
Melanoma Institute Australia and Bristol-Myers Squibb.
Abstract
Context
Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation ...can be variable.
Objective
This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.
Methods
We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed.
Results
A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range IQR 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio OR 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio HR 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes.
Conclusion
Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with ...metastatic melanoma.
Fifty-nine BRAF(V600)-mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.
Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.
Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required.
Cutaneous melanoma Long, Georgina V; Swetter, Susan M; Menzies, Alexander M ...
The Lancet (British edition),
08/2023, Letnik:
402, Številka:
10400
Journal Article
Recenzirano
Cutaneous melanoma is a malignancy arising from melanocytes of the skin. Incidence rates are rising, particularly in White populations. Cutaneous melanoma is typically driven by exposure to ...ultraviolet radiation from natural sunlight and indoor tanning, although there are several subtypes that are not related to ultraviolet radiation exposure. Primary melanomas are often darkly pigmented, but can be amelanotic, with diagnosis based on a combination of clinical and histopathological findings. Primary melanoma is treated with wide excision, with margins determined by tumour thickness. Further treatment depends on the disease stage (following histopathological examination and, where appropriate, sentinel lymph node biopsy) and can include surgery, checkpoint immunotherapy, targeted therapy, or radiotherapy. Systemic drug therapies are recommended as an adjunct to surgery in patients with resectable locoregional metastases and are the mainstay of treatment in advanced melanoma. Management of advanced melanoma is complex, particularly in those with cerebral metastasis. Multidisciplinary care is essential. Systemic drug therapies, particularly immune checkpoint inhibitors, have substantially increased melanoma survival following a series of landmark approvals from 2011 onward.
Transcriptomic signatures designed to predict melanoma patient responses to PD-1 blockade have been reported but rarely validated. We now show that intra-patient heterogeneity of tumor responses to ...PD-1 inhibition limit the predictive performance of these signatures. We reasoned that resistance mechanisms will reflect the tumor microenvironment, and thus we examined PD-1 inhibitor resistance relative to T-cell activity in 94 melanoma tumors collected at baseline and at time of PD-1 inhibitor progression. Tumors were analyzed using RNA sequencing and flow cytometry, and validated functionally. These analyses confirm that major histocompatibility complex (MHC) class I downregulation is a hallmark of resistance to PD-1 inhibitors and is associated with the MITF
/AXL
de-differentiated phenotype and cancer-associated fibroblast signatures. We demonstrate that TGFß drives the treatment resistant phenotype (MITF
/AXL
) and contributes to MHC class I downregulation in melanoma. Combinations of anti-PD-1 with drugs that target the TGFß signaling pathway and/or which reverse melanoma de-differentiation may be effective future therapeutic strategies.
To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome.
Consecutive BRAF-tested Australian patients ...with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted.
Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor.
V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.
One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 ...BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.
The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high ...proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.
OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0–1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3–4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.
Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3–4 toxicity between group B and A was −20% (95% CI −46 to 6; p=0·158) and between group C and group A was 10% (−20 to 40; p=0·591). The most common grade 3–4 adverse events were elevated liver enzymes in group A (six 20%)) and colitis in group C (five 19%); in group B, none of the grade 3–4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% 95% CI 44–80) of 30 patients in group A, 17 (57% 37–75) of 30 in group B, and nine (35% 17–56) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% 61–92) patients in group A, 23 (77% 58–90) in group B, and 17 (65% 44–83) in group C.
OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.
Bristol-Myers Squibb.
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