Open AccessAdjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy
Author(s) -
Latimer Nicholas R.,
Bell Helen,
Abrams Keith R.,
Amonkar Mayur M.,
Casey Michelle
Publication year - 2016
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.643
Subject(s) - trametinib , hazard ratio , medicine , mek inhibitor , oncology , chemotherapy , population , survival analysis , melanoma , surgery , cancer research , biology , mapk/erk pathway , kinase , confidence interval , microbiology and biotechnology , environmental health
Trametinib, a selective inhibitor of mitogen‐activated protein kinase kinase 1 ( MEK 1) and MEK 2, significantly improves progression‐free survival compared with chemotherapy in patients with BRAF V600E/K mutation–positive advanced or metastatic melanoma ( MM ). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival ( OS ) advantage of trametinib. Our purpose was to estimate the switching‐adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank‐preserving structural failure time model, inverse probability of censoring weights, and a two‐stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent‐to‐treat ( ITT ) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [ HR ], 0.72; 95% CI , 0.52–0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first‐line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation–positive advanced melanoma or MM . Adjusting for switching resulted in lower HR s than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.