In the Journals Plus

Disease factors predict outcomes across treatments for BRAF V600-mutated melanoma

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October 11, 2018

Axel Hauschild

Baseline lactate dehydrogenase level, ECOG performance status and disease burden strongly predicted PFS and OS among patients with BRAF V600-mutant metastatic melanoma treated with BRAF or MEK inhibitors, according to a retrospective and exploratory recursive partitioning analysis of four trials.

“Conventionally accepted prognostic factors for survival in patients with metastatic melanoma include disease stage, baseline lactate dehydrogenase (LDH) levels, and baseline ECOG performance status,” Axel Hauschild, MD, PhD, professor and head of the Interdisciplinary Skin Cancer Center at University Hospital Schleswig-Holstein in Germany, and colleagues wrote. “However, these prognostic factors were identified prior to the introduction of BRAF and MEK inhibitors.”

Hauschild and colleagues pooled data from four randomized clinical trials to identify subgroups of patients with melanoma with distinct survival outcomes.

The analysis included 1,365 patients (57.4% men; 75.6% older than 65 years) with BRAF V600-mutated metastatic melanoma.

Across the trials, patients received:

  • cobimetinib (Cotellic; Exelixis, Genentech) plus vemurafenib (Zelboraf, Genentech; n = 310);
  • vemurafenib alone (n = 717); or
  • dacarbazine (n = 338).

Median follow-up was 14.1 months.

Researchers identified baseline LDH level, ECOG performance status, presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLD) as significant prognostic factors for PFS in a recursive partitioning analysis that included all patients.

The longest median PFS (11.1 months; 95% CI, 7-18.4) occurred among patients with LDH of 2 times the upper limit of normal or less, ECOG performance status of 0 and SLDs of 44 mm or less.

Patients with LDH of greater than 2 times the upper limit of normal had the shortest median PFS (3.5 months; 95% CI, 3-3.8).

Baseline LDH, ECOG performance status and SLD significantly predicted OS in the recursive partitioning analysis that included all patients.

In the OS analysis, patients with normal LDH and SLDs of 45 mm or less had the longest median OS of 27.2 months (95% CI, 22.1-32.1). The 3-year OS rates in this cohort were 53.3% (95% CI, 39.5-67.1) among those treated with cobimetinib plus vemurafenib, 35.6% (95% CI, 27.4-43.8) for those treated with vemurafenib alone and 35.6% (95% CI, 24.8-46.4) for those treated with dacarbazine.

Those with LDH greater than 2 times the upper limit of normal had the shortest median OS (6 months; 95% CI, 5.6-6.8).

Similar associations occurred across the three treatment cohorts for PFS and OS. Researchers then evaluated the prognostic value of previously defined cell cycle and immune gene expression signatures.

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Multivariate analyses showed the immune signature was associated with improved PFS (adjusted HR = 0.75; 95% CI, 0.62-0.89) and OS (adjusted HR = 0.74; 95% CI, 0.61-0.9) compared with the cell cycle signature.

Among patients with gene expression data available (n = 608), researchers determined gene signature, baseline LDH and SLD were significant prognostic factors for PFS. The subgroup with normal baseline LDH and immune signature demonstrated the longest median PFS (9 months; 95% CI, 7.1-11.2), whereas the subgroup with elevated LDH and SLD greater than 60 mm had the shortest (4 months; 95% CI, 3.5-4.7).

Gene signature did not appear to be a significant prognostic factor for OS. In this analysis, the subgroup with normal baseline LDH and no liver metastases as the longer median OS (22.7 months; 95% CI, 20.3-27.2), whereas the subgroup with elevated baseline LDH greater than two times the upper limit of normal had the shortest (median, 6 months; 95% CI, 5.1-8).

Researchers cited the use of data from an 8-year span, during which treatment availability and approval may have shifted, as a limitation of the study.

“The results of this exploratory pooled analysis are consistent with previously observed PFS and OS benefits of cobimetinib plus vemurafenib over vemurafenib monotherapy in the pivotal phase 3 study,” the researchers wrote. “The results of this analysis provide a framework that may be used to compare outcomes across trials and regimens in patients with metastatic melanoma. Understanding treatment effects of different regimens across prognostic groups, as described by us and others, may aid clinicians in clinical decision making for individual patients.” – by Cassie Homer

Disclosures: Hauschild reports consultant/advisory board roles with and honoraria from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, Medimmune, Mela Sciences, Merck, Merck Serono, Novartis, Oncosec and Roche, and research grants from Amgen, Bristol-Myers Squibb, Celgene, Eisai, GlaxoSmithKline, Mela Sciences, Merck, Merck Serono, Novartis, Oncosec and Roche. Please see the study for all other authors’ relevant financial disclosures.