KIT as a Therapeutic Target in Metastatic Melanoma Carvajal, Richard D; Antonescu, Cristina R; Wolchok, Jedd D ...
JAMA : the journal of the American Medical Association,
06/2011, Letnik:
305, Številka:
22
Journal Article
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CONTEXT Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We ...explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. OBJECTIVE To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. DESIGN, SETTING, AND PATIENTS A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. INTERVENTION Imatinib mesylate, 400 mg orally twice daily. MAIN OUTCOME MEASURES Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. RESULTS Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval CI, 2%-30%), with a median time to progression of 12 weeks (interquartile range IQR, 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele. CONCLUSIONS Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00470470
Tumor responses to immunotherapy are highly variable in onset and duration. Responses are often delayed and follow what appears to be progression. However, rapid responses also happen and can result ...in the disappearance of large lesions, leaving holes and cavities in their wake.
To the Editor:
Both ipilimumab
1
(anti–cytotoxic T-lymphocyte–associated antigen 4 monoclonal antibody) and nivolumab
2
(anti–programmed death 1 monoclonal antibody) have been approved by the Food and Drug Administration for the treatment of metastatic melanoma on the basis of increased progression-free and overall survival. A phase 1 trial of a combination of ipilimumab and nivolumab showed that 53% of patients had at least 80% tumor shrinkage.
3
We currently have treated 13 patients with melanoma with this combination as part of an expanded-access program (ClinicalTrials.gov number, NCT02186249), and we have observed a remarkable tumor response in 1 patient.
The patient is a 49-year-old . . .
Studies on protein requirements in vulnerable groups such as older adults are few, and results are conflicting.
The main objective of this study was to determine the protein requirements of ...free-living women >65 y by measuring the oxidation of l-1-(13)Cphenylalanine to (13)CO2 in response to graded intakes of protein.
Twelve subjects participated in the study, with protein intakes ranging from 0.2 to 2.0 g · kg(-1) · d(-1) for a total of 82 studies. The diets provided energy at 1.5 times each subject's resting energy expenditure and were isocaloric. Protein was given as an amino acid mixture on the basis of the egg protein pattern, except for phenylalanine and tyrosine, which were maintained constant across the protein intake amounts. All subjects were adapted for 2 d before the study day to a protein intake of 1.0 g · kg(-1) · d(-1). The mean protein requirement was determined by applying a mixed-effects change-point regression analysis to F(13)CO2 (label tracer oxidation in (13)CO2 breath), which identified a breakpoint in the F(13)CO2 in response to graded amounts of protein.
The mean estimated average requirement (EAR) and upper 95% CI (approximating the RDA) protein requirement of women >65 y were 0.96 and 1.29 g · kg(-1) · d(-1), respectively.
These estimates of protein requirements for older women are higher than the current EAR and RDA based on nitrogen balance data, which are 0.66 and 0.80 g · kg(-1) · d(-1), respectively. This trial was registered at clinicaltrials.gov as NCT01604980.
The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ⋅ kg-1 ⋅ d-1, respectively, for adults, including older men, are based on nitrogen balance data analyzed by ...monolinear regression. Recent studies in young men and older women that used the indicator amino acid oxidation (IAAO) technique suggest that those values may be too low. This observation is supported by 2-phase linear crossover analysis of the nitrogen balance data.
The main objective of this study was to determine the protein requirement for older men by using the IAAO technique.
Six men aged >65 y were studied; each individual was tested 7 times with protein intakes ranging from 0.2 to 2.0 g ⋅ kg-1 ⋅ d-1 in random order for a total of 42 studies. The diets provided energy at 1.5 times the resting energy expenditure and were isocaloric. Protein was consumed hourly for 8 h as an amino acid mixture with the composition of egg protein with L-1-13Cphenylalanine as the indicator amino acid. The group mean protein requirement was determined by applying a mixed-effects change-point regression analysis to F13CO2 (label tracer oxidation in breath 13CO2), which identified a breakpoint in F13CO2 in response to graded intakes of protein.
The estimated protein requirement and RDA for older men were 0.94 and 1.24 g ⋅ kg-1 ⋅ d-1, respectively, which are not different from values we published using the same method in young men and older women.
The current intake recommendations for older adults for dietary protein of 0.66 g ⋅ kg-1 ⋅ d-1 for the EAR and 0.8 g ⋅ kg-1 ⋅ d-1 for the RDA appear to be underestimated by ∼30%. Future longer-term studies should be conducted to validate these results. This trial was registered at clinicaltrials.gov as NCT01948492.
Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, ...remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward.
The course and outcome of metastatic uveal melanoma are not well described. We evaluated the survival of our patients with metastatic uveal melanoma, described factors that correlated with survival, ...and evaluated the influence of screening tests on time of detection and survival.
All patients with metastatic uveal melanoma seen at Memorial Sloan-Kettering Cancer Center between 1994 and 2004 were identified from our database. We recorded date of initial diagnosis, date of metastatic disease, date of last follow-up, site of the first metastasis, how the first metastasis was discovered, treatment, and outcome of therapy.
The estimated median survival of the 119 patients analyzed was 12.5 months; 22% of patients were alive at 4 years. Five variates correlated independently with prolonged survival: Lung/soft tissue as only site of first metastasis, treatment with surgery or intrahepatic therapy, female sex, age younger than 60, and a longer interval from initial diagnosis to metastatic disease. Discovering metastatic disease in asymptomatic patients did not correlate with overall survival; 89% of patients had a single organ as the site of first metastasis. Although liver was the most common site, 39.5% of patients had nonliver sites, most commonly lung, as the first site of metastasis.
A substantial subset of patients with metastatic uveal melanoma survive more than 4 years with metastatic disease. Data on variates of survival and site of first metastasis may guide strategies for screening patients, although our data failed to show a survival advantage in discovering asymptomatic metastatic disease.
IMPORTANCE Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE To assess the efficacy of selumetinib, a ...selective, non–adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days investigator choice; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range IQR, 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01143402
Previous analyses of BREAK-2 and BREAK-3 showed that durable outcomes lasting ≥3 years are achievable with dabrafenib in some patients with BRAF V600-mutant metastatic melanoma (MM); however, ...additional follow-up is needed to fully characterise the long-term impact of dabrafenib in these patients.
BREAK-2 was a single-arm phase 2 study evaluating dabrafenib in treatment-naive or previously treated BRAF V600E/K-mutant MM. BREAK-3, a randomised (3:1) phase 3 study, assessed dabrafenib versus dacarbazine in previously untreated unresectable or metastatic BRAF V600E-mutant melanoma. Five-year analyses were performed.
All BREAK-2 patients (N = 92 V600E, n = 76; V600K, n = 16) discontinued treatment by the data cutoff. Median follow-up was 13.0 months. In BRAF V600E patients, 5-year progression-free survival (PFS) and overall survival (OS) were 11% and 20%, respectively. Subsequent immunotherapy was received by 22% of patients. In BREAK-3, median follow-up was 17.0 and 12.0 months in the dabrafenib (n = 187) and dacarbazine (n = 63) arms, respectively. Thirty-seven patients (59%) receiving dacarbazine crossed over to dabrafenib following disease progression as per protocol. Five-year PFS was 12% in the dabrafenib arm; all dacarbazine-arm patients progressed or were censored by 5 years. Dabrafenib improved PFS versus dacarbazine, regardless of baseline lactate dehydrogenase levels. Five-year OS rates were 24% and 22% in the dabrafenib and dacarbazine arms, respectively. Subsequent therapy in each arm included anti–CTLA-4 (dabrafenib 24% and dacarbazine 24%) and/or anti–PD-1 (8% and 2%) treatment. No new safety signals were observed.
These data, representing extended follow-up for dabrafenib monotherapy, demonstrate that durable benefit lasting ≥5 years is achievable in a subset of patients.
ClinicalTrials.gov (BREAK-2, NCT01153763; BREAK-3, NCT01227889).
•Progression-free and overall survival with dabrafenib may plateau after 36 months.•Dabrafenib demonstrates benefit ≥5 years in some patients with BRAF-mutant melanoma.•Long-term treatment with dabrafenib monotherapy is well tolerated.
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