Basket Study Suggests New Combination Therapy in Colorectal Cancer

David Hyman, MD

David Hyman, MD

A novel basket trial has reported results on the treatment of vemurafenib in variety of nonmelanoma cancers withBRAF V600mutation. Patients with colorectal cancer, cholangiosarcoma, pancreatic cancer, and salivary gland cancer were included.^1,2

The authors noted that cancers with theBRAF V600mutation have been identified by The Cancer Genome Atlas³and other studies. However, no systematic study of the efficacy of vemurafenib, a BRAF inhibitor, in these cancers, has been conducted. There are a number of reasons: for example, in more than 50% of cancers, the incidence ofBRAF V600mutations is less than 5%, and these include rare subtypes.¹

To navigate this problem, the authors designed the histology-independent basket study, which included six cohorts ofBRAF V600-mutation—positive prespecified cancers and an additional cohort that included any otherBRAF V600-mutation—positive cancers. The principle aim was to discover clinically relevant indications of activity of BRAF inhibition in a range of tumor types that would lead to further studies or expansion of the basket study.¹

The international study enrolled 122 patients withBRAF V600-mutation—positive tumors, from 23 centers. Exclusion criteria included previous treatment with a BRAF or MEK inhibitor, and patients with melanoma, papillary thyroid cancer, leukemia, or lymphoma. The primary endpoint was response rate at week 8. Among the diverse range of cancers included were the gastrointestinal-related malignancies, colorectal (the most common, at 37 patients), cholangiocarcinoma (8 patients), and pancreatic cancer (2 patients).¹

Results with vemurafinib monotherapy in the colorectal cancer cohort were negligible, in agreement with findings of a previous phase I trial,⁴so the study included an arm of combination vemurafenib/cetuximab therapy.

Evaluable Patients With Colorectal Cancer

(n = 10 monotherapy; n = 27 combination therapy)

Of the total monotherapy and combination population, 100% had received prior therapy, with a median of two previous treatments (range 1-6). In the combination therapy group, one overall response was noted, and although about 50% of patients experienced tumor regression, these patients did not meet the criteria for partial response. Actual partial response was 4%. Median overall survival was 7.1 months (95% CI, 4.4 to not reached), and median progression-free survival was 3.7 months (95% CI, 1.8-5.1).¹

Fifty percent of patients on monotherapy exhibited stable disease, and 50% had progressive disease, versus 69% and 27% for those patients receiving combination therapy.¹

Evaluable Patients With Cholangiosarcoma

(n = 8)

In this population, one (12%) patient experienced a partial response, four (50%) reached stable disease, and three (38%) had progressive disease. There was one overall response.¹

Other

The authors stated that there were anecdotal responses in patients with pancreatic cancer (n = 2) and salivary duct cancer (NA).¹

Implications

The authors acknowledge the modest results with combination therapy in patients with colorectal cancer, but emphasized that 44% of the patients (12/27 had been previously treated with anti-EGFR therapy (cetuximab or panitumumab). They concluded that in light of the very aggressive and powerful resistance to chemotherapy ofBRAF V600-mutated colorectal cancers, serious consideration should be given to the use of combination therapy of an anti-EGFR agent with a BRAF inhibitor.¹

The overall the basket study showed that tumors withBRAF V600mutations do not respond equally to BRAF inhibition.¹“It’s encouraging that we saw responses across a wide variety of diseases,” said medical oncologist David Hyman, MD, the study’s first author and acting director, developmental therapeutics at Memorial Sloan Kettering Cancer Center. “At the same time, these results also show that you can’t simply extrapolate from the experience in one disease to all diseases. You can’t assume a drug that works well blocking the BRAF protein in melanoma will by itself be just as effective in other cancer types with the same mutation.”²

The unique design of the trial permits doctors to conduct quick investigations of therapeutic approaches based on laboratory data.¹“While we can and should be cautiously optimistic, this is what the future of precision medicine looks like,” said lead study author Jose Baselga, MD, PhD Memorial Sloane Kettering’s physician-in-chief and chief medical officer, in a statement.²

References:

1.     Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.N Engl J Med. 2015;373:726-736.

2.     Memorial Sloan Kettering Cancer Center. Clinical trial shows promise of “basket studies” for cancer drugs.https://www.mskcc.org/blog/clinical-trial-shows-promise-basket-studies-drugs. Accessed August 27, 2015.

3.     Weinstein JN, Collisson EA, Mills GB, et al. The Cancer  Genome Atlas pan-cancer analysis project.Nat Genet. 2013;45:1113-1120.

4.     Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors.J Clin Oncol. 2010;28; (suppl:15s. abstract).