Lack of Response to Imatinib in Melanoma Carrying Rare KIT Mutation р.T632I

Approximately 15% of acral and mucous melanomas carry activating mutations in KIT oncogene. There is a diversity of spectrum of KIT mutations, with some of them rendering tumors responsive to imatinib, while others being imatinib-resistant or not studied yet. Here we present an acral melanoma patient with KIT р.T632I mutation, who failed to respond to imatinib

Health-related quality of life in patients with fully resected BRAFV600 mutation–positive melanoma receiving adjuvant vemurafenib

Aim of study: The aim of the study was to assess the impact of treatment with adjuvant vemurafenib monotherapy on health-related quality of life (HRQOL) in patients with resected stage IIC-IIIC melanoma. Methods: The phase 3 BRIM8 study (NCT01667419) randomized patients with BRAFV600 mutation-positive resected stage IIC-IIIC melanoma to 960 mg of vemurafenib twice daily or matching placebo for 52 weeks (13 28-day cycles). Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3 at baseline, cycle 1 (days 1, 15 and 22), cycle 2 (days 1 and 15), day 1 of every subsequent 4-week cycle, the end-of-treatment visit and each visit during the follow-up period. Results: Completion rates for the EORTC QLQ-C30 questionnaire were high (>80%). There was a mean decline in the global health status (GHS)/quality of life (QOL) score of 17.4 (22.9) and 17.3 (24.1) points at days 15 and 22 of cycle 1, respectively, among vemurafenib-treated patients who recovered to approximately 10 points below baseline for the remainder of the treatment period. A similar trend was observed in all functional scales except for cognitive function (<10-point change from baseline at all visits) and in the symptom scores for appetite loss, fatigue and pain. As observed for the GHS/QOL score, all scores rapidly returned to baseline after completion of planned vemurafenib treatment or treatment discontinuation. Conclusions: The schedule of HRQOL assessments allowed for an accurate and complete evaluation of the impact of acute treatment-related symptoms. Vemurafenib-treated patients experience clinically meaningful moderate worsening in some treatment- or disease-related symptoms and GHS/QOL that resolve over time

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.). Copyright © 2021 Massachusetts Medical Society

Combined Vemurafenib and Combimetinib in BRAF-Mutated Melanoma

Background The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.Methods We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival.Results The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68;

Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma.

BackgroundTebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.MethodsWe report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival.ResultsAt a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred.ConclusionsThis 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.)

Treatment options for renal cell carcinoma in patients with von Hippel-Lindau disease

We report on a family with von Hippel-Lindau (VHL) disease and atypically aggressive renal cell carcinoma. A woman and her brother had progressive VHL disease with multiple tumors in their kidneys. One patient developed pulmonary metastases. The patient who had localized disease received radiofrequency ablation with complete destruction of tumors. Cytoreductive nephrectomy was performed in the case of metastatic disease, following which sunitinib maleate (50 mg orally daily, 4 weeks on, 2 weeks off) was given. Examination after two treatment cycles showed complete regression of all metastases. For 19 months, the patients have been under active observation without disease progression. Also, we detected high immunohistochemical expression of vascular endothelial growth factor receptors 1 and 2 in the cytoplasm and nuclei of tumor cells

Treatment options for renal cell carcinoma in patients with von Hippel-Lindau disease

We report on a family with von Hippel-Lindau (VHL) disease and atypically aggressive renal cell carcinoma. A woman and her brother had progressive VHL disease with multiple tumors in their kidneys. One patient developed pulmonary metastases. The patient who had localized disease received radiofrequency ablation with complete destruction of tumors. Cytoreductive nephrectomy was performed in the case of metastatic disease, following which sunitinib maleate (50 mg orally daily, 4 weeks on, 2 weeks off) was given. Examination after two treatment cycles showed complete regression of all metastases. For 19 months, the patients have been under active observation without disease progression. Also, we detected high immunohistochemical expression of vascular endothelial growth factor receptors 1 and 2 in the cytoplasm and nuclei of tumor cells

Screening for Melanoma and Other Skin Cancer Shows a Higher Early Melanoma Incidence: Social Educational Program “Life Fear-Free”

Background: The screening program Life Fear-Free (LFF) aimed at early diagnosis of cutaneous melanoma (CM) was introduced in Samara, Chelyabinsk, Yekaterinburg, and Krasnodar (Russia) in 2019. Objectives: To analyze the impact of the program on early CM and non-melanoma skin cancer (NMSC) detection. Methods: According to the social educational campaign, people were informed about CM risk factors and symptoms and were invited for skin examination. The program planned to involve 3200 participants in total. Participants with suspicious lesions were invited for excisional biopsy. Results: 3143 participants, including 75.4% women, were examined for skin lesions. The average age of the participants was 43.7 years. Mostly skin phototypes II and III were registered (48.2% and 41.0%, respectively); 3 patients had CM, 15 had basal cell carcinoma, and 1 had Bowen’s disease, which were confirmed histologically. All detected melanomas had Breslow’s thickness of 1 mm. Conclusion: The participants showed high interest in early skin cancer detection programs. The incidence rate of CM and NMSCs among the program participants was higher than in general public. The early disease grade was proven for the detected CMs and NMSCs. The study has shown that it is important to continue such programs