Several Clinical Characteristics Linked to Improved PFS with Vemurafenib in Metastatic Melanoma

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The pooled analysis looked at characteristics of 1215 patients enrolled in 4 clinical trials of vemurafenib monotherapy or combination cobimetinib plus vemurafenib compared to dacarbazine. Patients were grouped into five subgroups based on clinical characteristics.

Factors that predict improved outcomes for patients receiving vemurafenib or combination cobimetinib plus vemurafenib to treat BRAF V600-mutated melanoma have not previously been identified.

“For practicing oncologists, prognostic factors help them understand outcomes for patients, which are not well known for targeted therapy,” said study co-investigator Edward McKenna, Jr, PharmD, senior medical science director at Genentech. “One objective of this study was to identify patient subgroups that were prognostic for PFS in a pooled population of eligible patients from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. A second objective was to apply prognostic subgroups identified in the pooled analysis of all patients to assess PFS in treatment-specific cohorts for dacarbazine monotherapy, vemurafenib monotherapy, and cobimetinib plus vemurafenib combination therapy.

Eligible patients from each study were included regardless of treatment. Recursive partitioning for censored response variable in a conditional inference framework was performed in the pooled dataset to model relationships between pre-specified covariates and PFS. The pre-specified covariates included age, sex, race, geographic region, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), baseline LDH) level (elevated or normal), disease stage at enrollment, presence or absence of liver metastases, and baseline sum of the longest diameters of target lesions. The prognostic subgroups identified by this model were then applied to the pooled treatment cohorts of dacarbazine, vemurafenib, and combination cobimetinib plus vemurafenib. PFS was estimated using the Kaplan-Meier method.

Median follow-up for all patients included in the pooled analysis was 5.6 months (range, 0 to 23 months). Significant prognostic factors for PFS independent of treatment that were identified included baseline LDH level, ECOG PS, and the presence or absence of liver metastases, producing 4 subgroups with distinct outcomes. Median PFS was longest in patients (n = 503) with normal LDH levels and no liver metastases (8.48 months; 95% CI, 7.46, 11.04), and shortest in patients (n = 243) with elevated LDH levels and ECOG PS >0 (3.91 months; 95% CI, 3.58, 4.50). Intermediate PFS were seen in patients (n = 178) with LDH normal and presence of liver metastases (6.51 months; 95% CI, 5.26, 7.26) or LDH elevated and ECOG PS = 0 (n = 291; PFS = 5.36 months; 95% CI, 4.27, 6.74).

Similar results were seen when the prognostic subgroups identified in the pooled analysis were applied to the pooled cobimetinib plus vemurafenib cohorts, the pooled vemurafenib monotherapy cohorts, and the dacarbazine cohort from the BRIM-3 study.

Similar results were also seen for overall response rates (ORR) and duration of response (DOR) according to PFS prognostic subgroups for the pooled cobimetinib plus vemurafenib cohorts, the pooled vemurafenib monotherapy cohorts, and the dacarbazine cohorts. All patients receiving combination cobimetinib plus vemurafenib regardless of subgroup had better ORR, DOR, and PFS than those receiving vemurafenib monotherapy. Complete responses were seen more frequently in patients in the pooled cobimetinib plus vemurafenib cohorts and the pooled vemurafenib monotherapy cohorts who had normal LDH levels at baseline and no liver metastases compared with the other prognostic subgroups.

Although PFS was longer for patients with normal LDH levels than for those in other groups, longer follow-up is needed.

“I think the key takeaway here is that combined therapy with cobimetinib and vemurafenib benefitted all prognostic subgroups consistently, and particularly in favorable subgroups. The progression-free survival appears durable or extended at this time, but further follow-up is required, because the majority of patients have not experienced a progression event, which is good for patients,” McKenna concluded.

1. Larkin JMG, Ribas A , Flaherty K, et al. Identifying prognostic subgroups for outcomes inBRAF^V600-mutated metastatic melanoma patients (pts) treated with vemurafenib (V) ± cobimetinib (C): A pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.J Clin Oncol34, 2016 (suppl; abstr 9536).