- Email: [email protected]
Trametinib for patients with advanced melanoma
Correspondence
Trametinib for patients with advanced melanoma Gerald Falchook and colleagues1 show clinical activity of the MEK inhibitor trametinib in patients with either BRAF-mutant or wild-type melanoma. Recently, two essential topics for melanoma have been reported: hepatocyte growth factor (HGF)-dependent resistance to therapy2,3 and new driver mutations in melanoma.4,5 Stroma-mediated resistance to treatment of BRAF-mutant melanoma is common2 and HGF secretion from stromal cells seems to be responsible for this drug resistance. Analysis of biopsy samples from patients with BRAF-mutant melanoma suggests that patients with abundant HGF from stromal cells have poor responses to treatment. Furthermore, an inverse relation has been reported between plasma HGF concentration and response to treatment in patients with BRAF-mutant melanoma.3 HGF secretion leads to activation of the HGF receptor MET, and dual inhibition of RAF and either HGF or MET results in reversal of drug resistance in BRAFmutant melanoma.2 In Falchook and colleagues’ study,1 examination by immunohistochemistry of whether HGF expression in melanoma sections correlated with poor responses to the MEK inhibitor trametinib would have been informative, not only in patients with the BRAF mutation, but also in patients with wild-type BRAF. These results would clarify the possibility that a combination of the MEK inhibitor and MET inhibitors have a synergistic effect. Moreover, although EGF is less able than HGF to reactivate ERK in most melanoma cell lines,2 EGF and EGFR mediated resistance might be of interest in melanoma and in colon cancers. For driver mutations, six genes related to melanoma have been newly www.thelancet.com/oncology Vol 13 October 2012
identified (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2),4 with RAC1 mutations also reported.5 The Illumina platform was used in Falchook and colleagues’ study1 to analyse the mutational and copy number status of 78 different genes commonly implicated in tumorigenesis. Within these data, is there any information about the six new melanoma genes? If these driver mutations are present, examination of whether they correlate with reduced responses to therapy with trametinib would be interesting, because such examination would not only contribute to drug response predictions but also might help select other treatment options, including combination therapies. Furthermore, data on amplification of BRAF, either with or without mutations, could provide information on whether copy number of this gene plays a role in response to therapy? In the context of treatment with the MEK inhibitor trametinib, an integrated examination including HGF secretion and other gene mutations would open up the possibility of prediction of drug response and combination therapy. We declare that we have no conflicts of interest.
*Shigeo Masuda, Juan Carlos Izpisua Belmonte [email protected] Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA (SM, JCIB); Center for Regenerative Medicine in Barcelona, Barcelona, Spain (JCIB) 1
2
3
4
5
Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 782–89. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500–04. Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–09. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150: 251–63. Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012; 44: 1006–14.
Authors’ reply We agree with Shigeo Masuda that BRAF-inhibitor resistance mediated by hepatocyte growth factor (HGF) could be relevant for clinical studies of the MEK inhibitor trametinib. Because our trial was a first-in-human study,1,2 our immunohistochemical assessments were constrained, and were focused mainly on showing MAPK pathway inhibition. As such, we did not assess exploratory predictive markers of response such as HGF. Our genotyping analysis identified three patients with a nontransformative mutation (R988C, also designated R970C)3 in the HGF receptor MET. We noted a reduction in tumour sizes in these patients, and two of them achieved a partial response. The small sample set and absence of additional information (eg, for activation state of the MAPK or PI3K/AKT pathways or HGF levels) restricted the interpretation of these data. Our genotyping panel was made up of genes with common somatic mutations, and did not include the recently identified genes described by Hodis and colleagues.4 Moreover, this platform reliably identified only highly amplified genes; none of the assessed samples contained highly amplified BRAF. The small amounts and limited quality of residual DNA restricts the value and scope of additional analysis with this collection. We look forward to incorporating the latest genetic discoveries and high-throughput genetic platforms in ongoing and future clinical studies of trametinib. GSF has received research funding and travel reimbursement from GlaxoSmithKline. CM and DJD are employees of GlaxoSmithKline.
*Gerald S Falchook, Christopher Moy, Douglas J DeMarini, on behalf of the authors [email protected] Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA (GSF); and GlaxoSmithKline Research and Development, Collegeville, PA, USA (CM, DJD)
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Trametinib for patients with advanced melanoma Gerald Falchook and colleagues1 show clinical activity of the MEK inhibitor trametinib in patients with either BRAF-mutant or wild-type melanoma. Recently, two essential topics for melanoma have been reported: hepatocyte growth factor (HGF)-dependent resistance to therapy2,3 and new driver mutations in melanoma.4,5 Stroma-mediated resistance to treatment of BRAF-mutant melanoma is common2 and HGF secretion from stromal cells seems to be responsible for this drug resistance. Analysis of biopsy samples from patients with BRAF-mutant melanoma suggests that patients with abundant HGF from stromal cells have poor responses to treatment. Furthermore, an inverse relation has been reported between plasma HGF concentration and response to treatment in patients with BRAF-mutant melanoma.3 HGF secretion leads to activation of the HGF receptor MET, and dual inhibition of RAF and either HGF or MET results in reversal of drug resistance in BRAFmutant melanoma.2 In Falchook and colleagues’ study,1 examination by immunohistochemistry of whether HGF expression in melanoma sections correlated with poor responses to the MEK inhibitor trametinib would have been informative, not only in patients with the BRAF mutation, but also in patients with wild-type BRAF. These results would clarify the possibility that a combination of the MEK inhibitor and MET inhibitors have a synergistic effect. Moreover, although EGF is less able than HGF to reactivate ERK in most melanoma cell lines,2 EGF and EGFR mediated resistance might be of interest in melanoma and in colon cancers. For driver mutations, six genes related to melanoma have been newly www.thelancet.com/oncology Vol 13 October 2012
identified (PPP6C, RAC1, SNX31, TACC1, STK19, and ARID2),4 with RAC1 mutations also reported.5 The Illumina platform was used in Falchook and colleagues’ study1 to analyse the mutational and copy number status of 78 different genes commonly implicated in tumorigenesis. Within these data, is there any information about the six new melanoma genes? If these driver mutations are present, examination of whether they correlate with reduced responses to therapy with trametinib would be interesting, because such examination would not only contribute to drug response predictions but also might help select other treatment options, including combination therapies. Furthermore, data on amplification of BRAF, either with or without mutations, could provide information on whether copy number of this gene plays a role in response to therapy? In the context of treatment with the MEK inhibitor trametinib, an integrated examination including HGF secretion and other gene mutations would open up the possibility of prediction of drug response and combination therapy. We declare that we have no conflicts of interest.
*Shigeo Masuda, Juan Carlos Izpisua Belmonte [email protected] Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA (SM, JCIB); Center for Regenerative Medicine in Barcelona, Barcelona, Spain (JCIB) 1
2
3
4
5
Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 2012; 13: 782–89. Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012; 487: 500–04. Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012; 487: 505–09. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012; 150: 251–63. Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012; 44: 1006–14.
Authors’ reply We agree with Shigeo Masuda that BRAF-inhibitor resistance mediated by hepatocyte growth factor (HGF) could be relevant for clinical studies of the MEK inhibitor trametinib. Because our trial was a first-in-human study,1,2 our immunohistochemical assessments were constrained, and were focused mainly on showing MAPK pathway inhibition. As such, we did not assess exploratory predictive markers of response such as HGF. Our genotyping analysis identified three patients with a nontransformative mutation (R988C, also designated R970C)3 in the HGF receptor MET. We noted a reduction in tumour sizes in these patients, and two of them achieved a partial response. The small sample set and absence of additional information (eg, for activation state of the MAPK or PI3K/AKT pathways or HGF levels) restricted the interpretation of these data. Our genotyping panel was made up of genes with common somatic mutations, and did not include the recently identified genes described by Hodis and colleagues.4 Moreover, this platform reliably identified only highly amplified genes; none of the assessed samples contained highly amplified BRAF. The small amounts and limited quality of residual DNA restricts the value and scope of additional analysis with this collection. We look forward to incorporating the latest genetic discoveries and high-throughput genetic platforms in ongoing and future clinical studies of trametinib. GSF has received research funding and travel reimbursement from GlaxoSmithKline. CM and DJD are employees of GlaxoSmithKline.
*Gerald S Falchook, Christopher Moy, Douglas J DeMarini, on behalf of the authors [email protected] Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA (GSF); and GlaxoSmithKline Research and Development, Collegeville, PA, USA (CM, DJD)
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