Targeting Molecular Abnormalities with Off-Label Indications


An ongoing phase IIa basket study is evaluating treating patients who have molecular abnormalities with agents that target the HER2, BRAF, Hedgehog, or EGFR pathways, regardless of the patient's tumor type and the drug's original indication.

John D. Hainsworth, MD

An ongoing phase IIa basket study is evaluating treating patients who have molecular abnormalities with agents that target the HER2, BRAF, Hedgehog, or EGFR pathways, regardless of the patient’s tumor type and the drug’s original indication.

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 their 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 forBRAF-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 inHER2, 33 inBRAF, 8 in Hedgehog genes, and 6 inEGFR. Patients were then matched with drugs targeting those abnormalities, with patients receiving standard doses of trastuzumab (Herceptin) and pertuzumab (Perjeta) if they hadHER2abnormalities, vemurafenib (Zelboraf) for BRAFmutations, vismodegib (Erivedge) for Hedgehog pathway mutations, and erlotinib (Tarceva) for EGFRmutations.

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 withHER2abnormalities.

Of those withHER2-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 withHER2-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 withHER2-amplified bladder cancer, 38% (3 patients) experienced a CR or PR and 25% (2) experienced stable disease. InHER2-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 withHER2abnormalities 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 withBRAF-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.”

In the BRAF group, the most responses were seen in patients withBRAF-mutated NSCLC. Of those patients, 20% (3/15) experienced a CR or PR and 13% (2/15) experienced stable disease. Additionally, 4 patients withBRAF-mutant ovarian cancer were included in the trial, with 25% (1) experiencing a CR or PR, and 50% (2) experiencing stable disease.

Also in the BRAF group, 1 patient with colorectal cancer (n = 2), 1 patient with pancreas cancer (n = 2), 1 patient with head and neck cancer (n = 1), and 1 patient with an unknown primary tumor (n = 3) experienced a CR or PR with BRAF-targeted therapy. No stable disease was seen among these patients. The BRAF group also included 6 patients with cancer from 5 other sites but none experienced a CR, PR, or stable disease.

The responses seen in those patients withHER2-amplified colorectal, bladder, and biliary cancers as well as theBRAF-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, cobimetinib (Cotellic), a MEK inhibitor, will soon be added to vemurafenib for patients withBRAFmutations. 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, MD, who served as the ASCO spokesperson 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.”

Meric-Bernstam F, Swanton C, Hurwitz, H et al. Targeted therapy for advanced solid tumors based on molecular profiles: early results from MyPathway, an open-label, phase IIa multiple basket study. Presented at: 2016 ASCO Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract LBA11511.

Related Videos
Video 6 - "Current Approaches to Treatment Sequencing in HER2+ Breast Cancer"
Video 5 - "Exciting Developments in HER2+ Breast Cancer"
Video 4 - "KATHERINE: Adjuvant T-DM1 vs Trastuzumab for Residual Invasive HER2+ Breast Cancer"
Video 3 - "APHINITY Trial: Pertuzumab for Patients with HER2+ Breast Cancer"
Rebecca A. Shatsky, MD, an expert on breast cancer
Rebecca A. Shatsky, MD, an expert on breast cancer
Video 3 - "Managing Toxicities and Adverse Reactions in HR+/Her2-Low mBC Therapies"
Video 2 - "EMERALD: Underscoring Key Elacestrant Data + Subgroup Analyses for Informed Therapy Selection"
Video 1 - "A 62-Year-Old Woman with HR+ HER2-low Metastatic Breast Cancer and Lung, Liver, and Bone Metastases and Using Biomarker Testing to Guide Treatment Selection"