Two defined immune checkpoints have been exploited for cancer treatment. LAG-3 is a third immune checkpoint that blocks lymphocyte activation. Relatlimab, a monoclonal antibody against LAG-3, ...interferes with this block. Relatlimab plus nivolumab as compared with nivolumab alone in melanoma produced superior progression-free survival.
Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options ...for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
Combined BRAF-MEK inhibitor therapy is the standard of care for BRAFV600-mutant advanced melanoma. We investigated encorafenib, a BRAF inhibitor with unique target-binding properties, alone or in ...combination with the MEK inhibitor binimetinib, versus vemurafenib in patients with advanced BRAFV600-mutant melanoma.
COLUMBUS was conducted as a two-part, randomised, open-label phase 3 study at 162 hospitals in 28 countries. Eligible patients were aged 18 years or older and had histologically confirmed locally advanced (American Joint Committee on Cancer AJCC stage IIIB, IIIC, or IV), unresectable or metastatic cutaneous melanoma, or unknown primary melanoma; a BRAFV600E or BRAFV600K mutation; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and were treatment naive or had progressed on or after previous first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) via interactive response technology to receive either oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). The primary endpoint was progression-free survival by blinded independent central review for encorafenib plus binimetinib versus vemurafenib. Efficacy analyses were by intention-to-treat. Safety was analysed in patients who received at least one dose of study drug and one postbaseline safety assessment. The results of part 2 will be published separately. This study is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to either the encorafenib plus binimetinib group (n=192), the encorafenib group (n=194), or the vemurafenib group (n=191). With a median follow-up of 16·6 months (95% CI 14·8–16·9), median progression-free survival was 14·9 months (95% CI 11·0–18·5) in the encorafenib plus binimetinib group and 7·3 months (5·6–8·2) in the vemurafenib group (hazard ratio HR 0·54, 95% CI 0·41–0·71; two-sided p<0·0001). The most common grade 3–4 adverse events seen in more than 5% of patients in the encorafenib plus binimetinib group were increased γ-glutamyltransferase (18 9% of 192 patients), increased creatine phosphokinase (13 7%), and hypertension (11 6%); in the encorafenib group they were palmoplantar erythrodysaesthesia syndrome (26 14% of 192 patients), myalgia (19 10%), and arthralgia (18 9%); and in the vemurafenib group it was arthralgia (11 6% of 186 patients). There were no treatment-related deaths except for one death in the combination group, which was considered possibly related to treatment by the investigator.
Encorafenib plus binimetinib and encorafenib monotherapy showed favourable efficacy compared with vemurafenib. Overall, encorafenib plus binimetinib appears to have an improved tolerability profile compared with encorafenib or vemurafenib. Encorafenib plus binimetinib could represent a new treatment option for patients with BRAF-mutant melanoma.
Array BioPharma, Novartis.
Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAFV600-mutant melanoma in the COLUMBUS trial. Here, we report the ...results of the secondary endpoint of overall survival.
COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAFV600E or BRAFV600K mutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.
Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (95% CI 35·9–37·5). Median overall survival was 33·6 months (95% CI 24·4–39·2) with encorafenib plus binimetinib and 16·9 months (14·0–24·5) with vemurafenib (hazard ratio 0·61 95% CI 0·47–0·79; two-sided p<0·0001). The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 9% of 192 patients), increased blood creatine phosphokinase (14 7%), and hypertension (12 6%); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 14% of 192 patients), myalgia (19 10%), and arthralgia (18 9%); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 6% of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.
The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAFV600-mutant melanoma.
Array BioPharma, Novartis.
BRAF/MEK inhibitor combinations are established treatments for BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Here, we report ...an updated analysis of the COLUMBUS (COmbined LGX818 encorafenib Used with MEK162 binimetinib in BRAF mutant Unresectable Skin cancer) trial with long-term follow-up.
In part 1 of the COLUMBUS trial, 577 patients with advanced/metastatic BRAF V600–mutant melanoma, untreated or progressed after first-line immunotherapy, were randomised 1:1:1 to 450 mg of encorafenib QD + 45 mg of binimetinib BID (COMBO450) vs 960 mg of vemurafenib BID (VEM) or 300 mg of encorafenib ENCO QD (ENCO300). An updated analysis was conducted that included PFS, OS, objective response rate, safety and tolerability and analyses of results by prognostic subgroups.
At data cutoff, there were 116, 113 and 138 deaths in the COMBO450, ENCO300 and VEM treatment arms, respectively. The median OS was 33.6 months (95% confidence interval CI, 24.4–39.2) for COMBO450, 23.5 months (95% CI, 19.6–33.6) for ENCO300 and 16.9 months (95% CI, 14.0–24.5) for VEM. Compared with VEM, COMBO450 decreased the risk of death by 39% (hazard ratio HR, 0.61; 95% CI, 0.48–0.79). The updated median PFS for COMBO450 was 14.9 months (95% CI, 11.0–20.2), ENCO300 was 9.6 months (95% CI, 7.4–14.8) and VEM was 7.3 months (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.51; 95% CI, 0.39–0.67). Landmark OS and PFS results show consistent results for each year analysed. Subgroups all favoured COMBO450 vs VEM.
Updated PFS and OS results for COMBO450 from the COLUMBUS trial demonstrate a long-term benefit in patients with advanced BRAF V600–mutated melanoma.
•MAPK pathway dual inhibition is the standard therapy in patients with BRAF V600 melanoma.•Encorafenib + binimetinib demonstrated improved efficacy vs control arms.•Encorafenib + binimetinib was generally well tolerated, with a distinct safety profile.•Updated analysis suggested a durable response with encorafenib + binimetinib.
Combination treatment with BRAF and MEK inhibitors has demonstrated benefits on progression-free survival (PFS) and overall survival (OS) and is a standard of care for the treatment of advanced
...V600-mutant melanoma. Here, we report the 5-year update from the COLUMBUS trial (ClinicalTrials.gov identifier: NCT01909453).
Patients with locally advanced unresectable or metastatic
V600-mutant melanoma, untreated or progressed after first-line immunotherapy, were randomly assigned 1:1:1 to encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, vemurafenib 960 mg twice daily, or encorafenib 300 mg once daily. An updated analysis was conducted 65 months after the last patient was randomly assigned.
Five hundred seventy-seven patients were randomly assigned: 192 to encorafenib plus binimetinib, 191 to vemurafenib, and 194 to encorafenib. The 5-year PFS and OS rates with encorafenib plus binimetinib were 23% and 35% overall and 31% and 45% in those with normal lactate dehydrogenase levels, respectively. In comparison, the 5-year PFS and OS rates with vemurafenib were 10% and 21% overall and 12% and 28% in those with normal lactate dehydrogenase levels, respectively. The median duration of response with encorafenib plus binimetinib was 18.6 months, with disease control achieved in 92.2% of patients. In comparison, the median duration of response with vemurafenib was 12.3 months, with disease control achieved in 81.2% of patients. Long-term follow-up showed no new safety concerns, and results were consistent with the known tolerability profile of encorafenib plus binimetinib. Interactive visualization of the data presented in this article is available at COLUMBUS dashboard.
In this 5-year update of part 1 of the COLUMBUS trial, encorafenib plus binimetinib treatment demonstrated continued long-term benefits and a consistent safety profile in patients with
V600-mutant melanoma.
Abstract Although obesity is an established risk factor for several cancer types, its possible role in the aetiology of malignant melanoma remains unclear. This meta-analysis aims to examine the ...association between obesity and melanoma risk, exploring any tentative gender-specific associations. After the identification of eligible studies, we estimated pooled effect estimates (odds ratios and relative risks), undertook a meta-regression analysis and analysed separately risk of malignant melanoma among males and females in relation to body mass index (BMI) and body surface area (BSA). Out of the 21 eligible articles, 11 used a case–control design encompassing 4460 cases/6342 controls; 10 used a cohort design whose total size comprised 7895 incident cases/6,368,671 subjects. Among males, the pooled effect estimate was 1.31 (95% confidence interval (CI): 1.18–1.45) for overweight and 1.31 (95% CI: 1.19–1.44) for obese. Meta-regression revealed no significant slope, most probably due to the underlying plateau in effect estimates. Among females, no significant association was documented; the pooled effect estimate for overweight and obese subjects was 0.98 (95% CI: 0.92–1.05) and 0.99 (95% CI: 0.83–1.18), respectively. Noticeably, there was evidence for confounding between sunlight exposure and obesity in females. All results were reproducible upon analyses on BSA. In conclusion, overweight and obesity are associated with increased risk of malignant melanoma among males. Meticulous assessment of sunlight exposure is needed especially in women, since self limited public sun exposure may be prevalent among overweight or obese females. Higher-order associations between BMI and melanoma risk should be addressed and examined by the future studies.
Dual inhibition of the mitogen-activated protein kinase pathway with BRAF/MEK inhibitor (BRAFi/MEKi) therapy is a standard treatment for BRAFV600-mutant metastatic melanoma and has historically been ...associated with grade III pyrexia or photosensitivity depending on the combination used. The objective of this study was to fully describe adverse events from the COLUMBUS study evaluating the most recent BRAF/MEK inhibitor combination encorafenib+binimetinib.
Patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma were randomised to receive encorafenib 450 mg once daily plus binimetinib 45 mg twice daily, encorafenib 300 mg once daily or vemurafenib 960 mg twice daily. Adverse events that represent known effects of available BRAFi and/or MEKi were evaluated.
The safety population included a total of 570 patients (encorafenib+binimetinib = 192; encorafenib = 192; vemurafenib = 186). Median duration of exposure was longer with encorafenib+binimetinib (51 weeks) than with encorafenib (31 weeks) or vemurafenib (27 weeks). Common BRAFi/MEKi toxicities with encorafenib+binimetinib were generally manageable, reversible and infrequently associated with discontinuation. Pyrexia was less frequent with encorafenib+binimetinib (18%) and encorafenib (16%) than with vemurafenib (30%) and occurred later in the course of therapy with encorafenib+binimetinib (median time to first onset: 85 days versus 2.5 days and 19 days, respectively). The incidence of photosensitivity was lower with encorafenib+binimetinib (5%) and encorafenib (4%) than with vemurafenib (30%). The incidence of serous retinopathy was higher with encorafenib+binimetinib (20%) than with encorafenib (2%) or vemurafenib (2%), but no patients discontinued encorafenib+binimetinib because of this event.
Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies.
ClinicalTrials.gov (Identifier: NCT01909453) and with EudraCT (number 2013-001176-38).
•MAPK pathway dual inhibition is standard therapy in patients with BRAFV600 melanoma.•Encorafenib+binimetinib demonstrated improved efficacy vs control arms.•Encorafenib+binimetinib was generally well tolerated, with a distinct safety profile.•Encorafenib+binimetinib was associated with low levels of pyrexia and photosensitivity.
Next Generation of Immunotherapy for Melanoma KIRKWOOD, John M; TARHINI, Ahmad A; PANELLI, Monica C ...
Journal of clinical oncology,
07/2008, Letnik:
26, Številka:
20
Journal Article
Recenzirano
Immunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma ...in the United States.
Tumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed.
The limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies.
The successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.
Melanoma is a neoplasm with a rising incidence. Early-stage melanoma is curable, but advanced, metastatic melanoma almost uniformly is fatal, and patients with such advanced disease have a short ...median survival. Systemic therapy remains unsatisfactory, inducing complete durable responses in a small minority of patients. For the current review, the authors focused on the current role of cytotoxic chemotherapy in the treatment of metastatic melanoma and the future prospects for improvements for multiagent chemotherapy and chemotherapy combined with immunomodulatory and/or molecularly targeted agents. They discuss roles of single-agent chemotherapy, combination chemotherapy, combinations of chemotherapy with immunomodulatory or hormone agents, biochemotherapy, and combination chemotherapy with targeted therapies.
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