Molecular Targeting Yields Responses in 12 Cancers in Off-Label Indications

Laura Panjwani
Published: Saturday, Jun 04, 2016

Dr John D. Hainsworth

John D. Hainsworth, MD

Treating patients based on the presence of molecular abnormalities regardless of tumor type proved to be a promising strategy in an ongoing phase IIa basket study, which evaluated agents targeting the HER2, BRAF, Hedgehog, or EGFR pathways in tumors not indicated for those targets.

Preliminary results of the MyPathway study, presented during a press conference at the 2016 ASCO Annual Meeting, showed that 23% of patients with 12 different types of advanced cancers responded to molecularly targeted drugs outside of FDA-approved indications.

The study was motivated by the increasing number of targeted agents for advanced cancers that have shown success, most notably HER2-targeted treatments for HER2-positive breast cancer and BRAF-targeted treatment for BRAF-mutated melanoma, said John D. Hainsworth, MD, the study’s presenting author at ASCO and co-founder and principal investigator at Sarah Cannon Research Institute.

“We’ve know that the same mutations that are in those cancers are found in a wide variety of other cancers, although at a lower incidence,” said Hainsworth during a press conference. “It has been difficult to test out how effective these treatments are in the other cancers, due to the difficulty of identifying a patient population. With the increase in comprehensive genomic profiling that has been going on in the last few years, we are now identifying more of these unusual mutations in other cancers, and that is what this trial is addressing.”

The study enrolled 129 patients including 82 with alterations in HER2, 33 in BRAF, 8 in Hedgehog genes, and 6 in EGFR. Patients were then matched with drugs targeting those abnormalities, with patients receiving standard doses of trastuzumab (Herceptin) and pertuzumab (Perjeta) if they had HER2 abnormalities, vemurafenib (Zelboraf) for BRAF mutations, vismodegib (Erivedge) for Hedgehog pathway mutations, and erlotinib (Tarceva) for EGFR mutations.

Only tumor types outside of current FDA-approved indications for these treatments were eligible. Patients had a median of 3 (range, 0–10) prior lines of therapy, and all had no other approved treatment options at the time of treatment.

Of the 129 patients who have been accrued and treated thus far, 29 (23%) experienced objective responses (OR), defined as tumor shrinkage of 30% or more. Of those patients, 14 progressed after a median 6 months. Fifteen responses are ongoing at 3+ to 11+ months.

One patient experienced a complete response (CR) and 28 patients experienced a partial response (PR). In addition, 40 patients (31%) experienced stable disease lasting 4 months or longer.

“Responses have been seen with all four of the treatments in this trial and there were no new safety signals observed,” said Hainsworth. “It is a little early to know how long the responses are, but they are going to be north of 6 months, and probably in between 6 to 9 months as we get more follow-up on this study.”

The most promising efficacy was seen among the 61 patients with HER2 abnormalities.

Of those with HER2-abnormalities, which included patients with 11 different tumors types, 28% (17/61) experienced a CR or PR and 15% (9/61) experienced stable disease for more than 4 months. An overall clinical benefit rate of 43% (26/61) was demonstrated. 

A particularly strong signal was seen in patients with HER2-amplified colorectal cancer, with 35% experiencing a CR or PR (7/20) and an additional 15% (3/20) experiencing stable disease for more than 4 months, according to Hainsworth.

Although not as pronounced, the signal was also strong in bladder and biliary cancers, says Hainsworth. Of the 8 patients in the study with HER2-amplified bladder cancer, 38% (3 patients) experienced a CR or PR and 25% (2) experienced stable disease. In HER2-amplified biliary cancer, 50% of patients (3/6) experienced a CR or PR and 50% (3/6) experienced stable disease.

Among patients with the other cancers with HER2 abnormalities included in the group, 29% (2/7) of patients with non–small cell lung cancer (NSCLC), 17% (1/6) of patients with pancreas cancer, and 34% (1/3) of patients with head and neck cancer experienced a CR or PR. No patients in those 3 groups experienced stable disease. Eleven patients with 5 other cancer types were included in the study. Among those patients none experienced a CR and only 1 patient experienced stable disease.

Promising results were also see among those with BRAF-mutated disease. Among the 33 patients with this mutation included in the study, 24% (8/33) experienced a CR or PR and 12% (4/33) experienced stable disease.

“What is interesting in this group is that 7 of the 8 responses seen were in V600E mutations,” said Hainsworth. “As you know, that is the mutation that has been specifically correlated with response to BRAF inhibition in melanoma.”


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