Imaging with FDG-PET allows early recognition of metabolic response to targeted agents. We evaluated the timing of complete metabolic response (CMR) on PET as a predictor of clinical outcome in BRAF V600 mutant melanoma patients treated with vemurafenib and cobimetinb, as part of the BRIM-7 trial.
BRAF inhibitor naïve patients from BRIM-7 were included if they had evaluable PET scans at baseline, in cycle 1 (C1) (D10-15) and in C2 (D35-49). Metabolic response was evaluated by percentage injected dose (%ID). 52 of 63 BRAF-naïve patients were eligible for analysis (3 excluded - no C1 scan; 6 no C2 scan; 2 unevaluable scans due to excessive physiological muscle uptake). The primary aim was to evaluate the prognostic significance of an early CMR to combination vemurafenib and cobimetinib therapy. We divided patients into 3 groups, based on timing of CMR attainment.
13 patients achieved CMR in cycle 1 (CMR1), 15 patients achieved CMR in cycle 2 (CMR2) and 24 patients did not achieve CMR within the first 2 cycles of treatment (noCMR). The median, 2 year and 3 year progression free survival (PFS) and overall survival (OS) of the 3 above groups are summarized in Table.Table:
|Median PFS (yrs)||Not reached||1.1||1.0|
|2 yr PFS (%, 95% CI)||83.9 (65.7-100)||13.3 (3.7-48.4)||37.5 (22.4-62.9)|
|3 yr PFS (%, 95% CI)||71.9 (48.8-100)||13.3 (3.7-48.4)||18.8 (7.9-44.5)|
|Median OS (yrs)||Not reached||2.4||2.5|
|2 yr OS (%, 95% CI)||84.6 (67.1-100)||63.0 (41.5-95.8)||58.3 (41.6-81.8)|
|3 yr OS (%, 95% CI)||74.0 (52.2-100)||21.0 (6.3-70.2)||30.9 (16.5-57.9)|
Patients achieving CMR1 had significantly better outcome than patients achieving CMR2 in terms of PFS (HR 0.18, 95% CI 0.05-0.62) and OS (HR 0.23, 95% CI 0.06-0.85). Similar results were observed comparing CMR1 over no CMR in PFS (HR 0.19, 95% CI 0.06-0.64) and in OS (HR 0.25, 95% CI 0.07-0.87). There was no difference between the CMR2 and noCMR groups in terms of PFS or OS.
Attainment of CMR on an early D10-14 PET was highly predictive of long-term survival with BRAF and MEK inhibition. However, attainment of CMR at a later time point at D35-49 did not appear predictive of a survival benefit. In fact, no difference in PFS or OS could be observed in patients who achieved CMR at D35-49, compared to those patients who did not attain CMR. Correlative science analysis to investigate the mechanism of these observations are underway.
Clinical trial identification
Legal entity responsible for the study
J. Frederickson: Employer of Genentech and has Roche stocks D. Colburn, N. Choong, M. Wongchenko: Employee of Roche-Genentech. All other authors have declared no conflicts of interest.