Basket Trial Yields Responses for Molecular Testing in 12 Cancers

An ongoing phase 2a study is proving that treating patients based on presence of molecular abnormalities regardless of tumor type is promising strategy. The study 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 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of over 30,000 oncology professionals in Chicago, showed that 23 percent 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, the study’s presenting author at ASCO and co-founder and principal investigator at Sarah Cannon Research Institute.

“We’ve known 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, eight in Hedgehog genes and six in EGFR. Patients were then matched with drugs targeting those abnormalities, with patients receiving standard doses of Herceptin (trastuzumab) and Perjeta (pertuzumab) if they had HER2 abnormalities, Zelboraf (vemurafenib) for BRAF mutations, Erivedge (vismodegib) for Hedgehog pathway mutations and Tarceva (erlotinib) for EGFR mutations.

Only tumor types outside of current FDA-approved indications for these treatments were eligible. Patients had a median of three 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 experienced objective responses (OR), defined as tumor shrinkage of 30 percent or more. Of those patients, 14 progressed after a median six months. Fifteen responses are ongoing at 3-plus to 11-plus months.

One patient experienced a complete response (CR) and 28 patients experienced a partial response (PR). In addition, 40 patients experienced stable disease lasting four 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 six months, and probably in between six to nine 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 percent experienced a CR or PR and 15 percent experienced stable disease for more than four months. An overall clinical benefit rate of 43 percent was demonstrated.

A particularly strong signal was seen in patients with HER2-amplified colorectal cancer, with 35 percent experiencing a CR or PR and an additional 15 percent experiencing stable disease for more than four months, according to Hainsworth.

Although not as pronounced, the signal was also strong in bladder and biliary cancers, said Hainsworth. Of the eight patients in the study with HER2-amplified bladder cancer, 38 percent experienced a CR or PR and 25 percent experienced stable disease. In HER2-amplified biliary cancer, 50 percent of patients experienced a CR or PR and 50 percent experienced stable disease.

Among patients with the other cancers with HER2 abnormalities included in the group, 29 percent of patients with non—small cell lung cancer (NSCLC), 17 percent of patients with pancreas cancer, and 34 percent of patients with head and neck cancer experienced a CR or PR. No patients in those three groups experienced stable disease. Eleven patients with five other cancer types were included in the study. Among those patients none experienced a CR and only one patient experienced stable disease.

Promising results were also seen among those with BRAF-mutated disease. Among the 33 patients with this mutation included in the study, 24 percent experienced a CR or PR and 12 percent experienced stable disease. “What is interesting in this group is that seven of the eight 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.”

In the BRAF group, the most responses were seen in patients with BRAF-mutated NSCLC. Of those patients, 20 percent experienced a CR or PR and 13 percent experienced stable disease. Additionally, four patients with BRAF-mutant ovarian cancer were included in the trial, with 25 percent experiencing a CR or PR, and 50 percent experiencing stable disease.

Also in the BRAF group, one patient with colorectal cancer, one patient with pancreas cancer, one patient with head and neck cancer and one patient with an unknown primary tumor experienced a CR or PR with BRAF-targeted therapy. No stable disease was seen among these patients. The BRAF group also included six patients with cancer from five other sites but none experienced a CR, PR, or stable disease.

The responses seen in those patients with HER2-amplified colorectal, bladder and biliary cancers as well as the BRAF-mutated NSCLC lung cancers met the protocol criteria for efficacy. Those groups have been expanded to accrue more patients.

MyPathway is a nationwide study which currently has 39 participating sites. Accrual is continuing, with plans to accrue up to 500 patients.

Groups that show low benefit will be stopped early, while groups that demonstrate efficacy will be expanded. The researchers also plan to incorporate emerging new regimens targeting these pathways. For example, Cotellic (cobimetinib), a MEK inhibitor, will soon be added to Zelboraf for patients with BRAF mutations. The incorporation of new agents targeting additional molecular abnormalities is also planned in the future.

This study, as well other similar studies, may eventually lead to changes in how clinical trials are designed, said Sumanta Kumar Pal, who served as the ASCO spokesman during the press conference.

“The key here is that we are using a tumor-agnostic approach. Patients with bladder cancer may get what has been classically thought of as being a breast cancer drug, patients with pancreatic may potentially get a lung cancer drug and so on,” said Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope. “As the results of these types of studies emerge we may shift the long-standing paradigm of treating cancer based on subtypes, for insistence pancreatic cancer or stomach cancer, to treating based on specific molecular alterations.”