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KIT as a Therapeutic Target in Metastatic Melanoma

Forums Mucosal Melanoma Community KIT as a Therapeutic Target in Metastatic Melanoma

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    JerryfromFauq
    Participant

      http://oncologystat.com/journals/journal_scans/KIT_as_a_Therapeutic_Target_in_Metastatic_Melanoma.htm
       

      http://oncologystat.com/journals/journal_scans/KIT_as_a_Therapeutic_Target_in_Metastatic_Melanoma.htm
       

      KIT as a Therapeutic Target in Metastatic Melanoma

      JAMA. 2011 Jun 8;305(22):2327-2334, RD Carvajal, CR Antonescu, JD Wolchok, PB Chapman, R-A Roman, J Teitcher, KS Panageas, KJ Busam, B Chmielowski, J Lutzky, AC Pavlick, A Fusco, L Cane, N Takebe, S Vemula, N Bouvier, BC Bastian, GK Schwartz

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      In this open-label phase II trial, significant clinical response to imatinib was observed in a subset of patients with metastatic melanoma harboring KIT gene alterations.

       

      SUMMARY

      OncologySTAT Editorial Team

      Melanoma is a disease of biologically distinct subtypes and generally poor prognosis once advanced. A key goal is to identify therapeutic targets that may allow improved treatment and survival. One target of interest is the KIT tyrosine kinase receptor gene. Melanomas arising from acral, mucosal, and chronically sun-damaged (CSD) sites often harbor KIT-activating mutations or amplifications. Tyrosine kinase inhibitors have proved beneficial in other cancers that harbor KIT mutations (gastrointestinal stromal tumors), and there have been reports of response to imatinib (a KIT inhibitor) in patients with KIT-mutant melanoma. In this open-label phase II trial of imatinib in patients with KIT-mutant melanoma, Carvajal et al hypothesized that KIT inhibition would result in an objective clinical response and disease control and that specific KIT alterations would correlate with clinical response.

      Adult patients with metastatic melanoma arising from acral, mucosal, or CSD sites were enrolled between April 2007 and April 2010 from six cancer centers in the United States and were eligible if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, life expectancy of ≥ 3 months, and measurable disease according to RECIST criteria. Tumor samples from study patients were evaluated for KIT mutations and amplification as well as coexisting BRAF, NRAS, and GNAQ mutations. Patients with tumors harboring KIT alterations were eligible for 6-week cycles of imatinib, which was continued until unacceptable toxicity or disease progression. Imatinib was started at 400 mg twice daily, with the dose reduced to 400 mg daily and then 300 mg daily in the event of toxicity; study treatment was discontinued if toxicity persisted. Tumor assessments consisted of radiographic tumor measurements and occurred within 4 weeks of the first dose of imatinib, then every 6 weeks for 18 weeks, and every 12 weeks thereafter. The primary endpoint was durable partial or complete response according to RECIST criteria. Secondary endpoints were overall survival (OS), time to progression, and association of molecular alterations with clinical response.

      Of 295 patients whose tumor samples underwent molecular screening, 51 had tumors harboring KIT alterations; 26 tumors (51%) had only KIT mutations, 9 (18%) had only KIT amplification, and 16 (31%) had both mutations and amplification. Of the patients with KIT-mutant tumors, 28 were treated with imatinib and included 13 patients (46%) with mucosal melanoma, 10 (36%) with acral melanoma, and 5 (18%) with melanoma arising from CSD sites; none of the patients who received imatinib had BRAF, NRAS, or GNAQ mutations. Reasons the remaining 23 patients did not receive imatinib included absence of active disease, death, ineligibility due to other treatment or medical condition, and contraindications to imatinib.

      Of the 28 patients who received imatinib, 25 were evaluable for clinical response. Of these, 2 patients achieved durable complete responses (94 [ongoing] and 95 weeks, respectively), and 2 achieved durable partial responses (53 and 89 [ongoing] weeks, respectively); the predetermined endpoint of five responses of 25 evaluable patients was not met. The overall durable response rate was 16% (95% CI, 2%–30%), median time to progression was 12 weeks (interquartile range [IQR], 6–18 weeks; 95% CI, 11–18 weeks), and median OS was 46.3 weeks (IQR, 28 weeks–not achieved; 95% CI, 28 weeks–not achieved). A total of 10 patients (40%) were alive at the time of analysis.

      KIT mutations were widely distributed over the coding region, but all responses occurred in tumors with L576P and K642E mutations. Subgroup analysis revealed a higher response rate in cases with a mutant to wild-type KIT allelic ratio > 1 (71% vs 6%; P =.002).

      In conclusion, significant clinical response to imatinib was observed in a subset of patients with metastatic melanoma harboring KIT alterations. Further studies are needed to confirm KIT alterations of functional relevance in order to better predict response to KIT inhibition.

       

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        mombase
        Participant

          Dear JerryfromFauq,

          Thank you for your research diligence and passing the articles along! I never thought I would be a science buff, but these studies are fascinating!

          Cristy, Stage IV

          mombase
          Participant

            Dear JerryfromFauq,

            Thank you for your research diligence and passing the articles along! I never thought I would be a science buff, but these studies are fascinating!

            Cristy, Stage IV

            Phil S
            Participant
              Jerry. Thanks for sharing the article, definitely interesting reading. As you are aware the vast majority of mucosal melanoma do not harbor ckit mutation. I think that the number is only around 15 percent that has kit, that leaves 85 percent of us, that don’t have those treatment options. So I hope the researchers are also plugging away for better treatment for those of us whose melanoma doesn’t fall into those categories.Phil is braf, ckit, and hla02negative, and at times is it so frustrating. Hope you are having a wonderful vacation. Valerie (phil’s wife).
              Phil S
              Participant
                Jerry. Thanks for sharing the article, definitely interesting reading. As you are aware the vast majority of mucosal melanoma do not harbor ckit mutation. I think that the number is only around 15 percent that has kit, that leaves 85 percent of us, that don’t have those treatment options. So I hope the researchers are also plugging away for better treatment for those of us whose melanoma doesn’t fall into those categories.Phil is braf, ckit, and hla02negative, and at times is it so frustrating. Hope you are having a wonderful vacation. Valerie (phil’s wife).
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