Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy

Nicholas R Latimer, Helen Bell, Keith R Abrams, Mayur M Amonkar, Michelle Casey, Nicholas R Latimer, Helen Bell, Keith R Abrams, Mayur M Amonkar, Michelle Casey

Abstract

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, 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 HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.

Trial registration: ClinicalTrials.gov NCT01245062.

Keywords: BRAF protein human; clinical trial; drug therapy; melanoma; trametinib.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Treatment switching bias. OS, overall survival; PFS, progression‐free survival; PPS, postprogression survival; RCT, randomized controlled trial. (Reproduced with permission from Latimer et al. 6 .
Figure 2
Figure 2
METRIC study design. FPFV, first patient, first visit; ITT, intent‐to‐treat; LDH, lactate dehydrogenase; LPLV, last patient, last visit; OS, overall survival; PCR, polymerase chain reaction; PEP, primary efficacy population; PFS, progression‐free survival; QD, once daily; RGI, Response Genetics, Inc; RR, response rate; ULN, upper limit of normal.
Figure 3
Figure 3
Time to switch from progression for patients on the chemotherapy control arm of the METRIC study who switched to trametinib treatment.
Figure 4
Figure 4
Overall survival in primary efficacy population. (A). Rank‐preserving structural failure time models (RPSFTM) with recensoring. (B). RPSFTM without recensoring. (C). Two‐stage method with recensoring. (D). Two‐stage method without recensoring.
Figure 5
Figure 5
Overall survival in first‐line metastatic primary efficacy population. (A). Rank‐preserving structural failure time models (RPSFTM) with recensoring. (B). RPSFTM without recensoring. (C). Two‐stage method with recensoring. (D). Two‐stage method without recensoring.

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