Vemurafenib Elicits Response in Some Nonmelanoma Malignancies

A phase II “basket” trial suggests that the BRAF V600 mutation is a targetable oncogene in certain nonmelanoma cancers

medwireNews: The selective BRAF V600 kinase inhibitor vemurafenib shows activity in patients with some, but not all, BRAF V600 mutation-positive nonmelanoma cancers, according to a study published in The New England Journal of Medicine.

Specifically, a response rate of around 40% was seen in non-small-cell lung cancer (NSCLC) patients and those with Erdheim–Chester disease or Langerhans’-cell histiocytosis, report José Baselga, from Memorial Sloan Kettering Cancer Center in New York, USA, and colleagues.

And although partial responses were observed among patients with other cancer types, some of which have “limited therapeutic options”, the researchers urge caution when interpreting these findings owing to the small sample sizes.

This histology-independent, phase II “basket” study included seven tumour-specific cohorts – NSCLC, colorectal cancer, cholangiocarcinoma, Erdheim–Chester disease or Langerhans’-cell histiocytosis, anaplastic thyroid cancer, ovarian cancer and multiple myeloma – and an “all others” cohort that included patients with any other BRAF V600 mutation-positive malignancies. All 122 participants received oral vemurafenib 960 mg twice daily, and 27 of the 37 colorectal cancer patients were also given cetuximab , as vemurafenib alone had “insufficient activity” in this cohort, the team explains.

Among 19 NSCLC patients with at least one post-baseline evaluation, eight achieved a partial response, giving an objective response rate (ORR) of 42%. Median progression-free survival (PFS) was 7.3 months and estimated 1-year PFS rate was 23%.

In the Erdheim–Chester disease or Langerhans’-cell histiocytosis cohort, one of the 14 evaluable patients had a complete response while five had a partial response to treatment, equating to an ORR of 43%. No patient had progressive disease during a median treatment duration of 5.9 months.

One complete and one partial response were recorded in the anaplastic thyroid cancer cohort, comprising seven participants. And one of eight cholangiocarcinoma patients achieved a partial response as did one of the 26 evaluable colorectal cancer patients treated with vemurafenib plus cetuximab.

The adverse event profile of vemurafenib monotherapy in this study was similar to previous reports of the drug in melanoma patients, say José Baselga et al. Across all the cohorts, the most frequent adverse events were rash (68%), fatigue (56%) and arthralgia (40%).

Noting that response rates in several cohorts were lower than rates reported for cutaneous melanoma, the researchers conclude that their findings show that “BRAF V600–mutated tumor types do not respond uniformly to BRAF-targeted therapy.”

They add: “An important implication is that conventional tumor nosology based on organ site (with molecular subtypes) cannot be entirely replaced by molecular nosology (e.g., BRAF-mutated cancers).”


Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med2015; 373: 726–736. doi:10.1056/NEJMoa1502309

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