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A New Paradigm Matching Targeted Therapy to Molecular Alterations Independent of Tumor Type

August 2016 Vol 9, Special Issue: Payers' Perspectives in Oncology

Ongoing clinical trials at academic centers around the country are testing a new strategy of matching available targeted therapies to molecular abnormalities in tumors instead of treating the cancer site.

The MyPathway study is one such effort that is paying off, according to its preliminary results, which were presented at ASCO 2016.

The MyPathway Study

The open-label MyPathway study is evaluating drugs that target the HER2, BRAF, Hedgehog, or EGFR pathways in nonindicated tumors with relevant genetic abnormalities.

“There are approved treatments [that target these pathways] for at least 1 other indication,” said John D. Hainsworth, MD, Tennessee Oncology, PLLC, and Co-Founder, Sarah Cannon Research Institute, Nashville, TN, who presented the results.

MyPathway enrolled 129 patients with advanced cancers that harbored 1 of the 4 abnormalities and were refractory to other treatments.

Overall, 29 (23%) of the 129 patients in the study had a major response; 31% had stable disease. Of the 29 objective responders, 15 patients had ongoing ­responses at the time of the meeting, ranging from ≥3 months to ≥11 months; 14 had disease progression after a median of 6 months.

HER2-Positive and BRAF  Mutation–Positive Tumors

The largest group of patients included 61 with HER2-positive tumors, including colorectal cancer (CRC), non–small-cell lung cancer (NSCLC), and bladder, biliary, pancreatic, head and neck, and other cancers.

In patients with HER2-positive tumors, the overall response rate (ORR) was 28%, and stable disease for more than 120 days was seen in 15% of patients, for a total clinical benefit rate of 43%.

The most impressive responses were seen in HER2-positive CRC, bladder and biliary cancers (treated with trastuzumab and pertuzumab), and in BRAF mutation–positive NSCLC (treated with vemurafenib), in particular patients with the BRAF V600E mutation.

Patients with HER2-positive CRC had a median of 4 previous therapies, said Dr Hainsworth. In this group, the clinical benefit rate was 50% (ORR, 35%; stable disease, 15%).

“This is a strong signal in HER2-positive CRC, and also there was a strong signal in biliary and bladder cancers,” he said, although the number of patients was smaller.

Targeting the BRAF mutation in 33 patients with 6 different tumor types also showed promise. The ORR was 24%, and the rate of stable disease was 12%, for a clinical benefit rate of 36%. The tumor types included NSCLC, CRC, and ovarian, unknown primary, pancreas, and head and neck cancers.

Of the 33 patients with a BRAF mutation, 19 had the BRAF V600 mutation, and 14 had other BRAF mutations. Among 8 responders, 7 had the BRAF V600E mutation, and 1 of 8 had a different BRAF mutation.

New Promise for Targeted Therapies

Although these are phase 2b study results, experts believe that this approach holds promise for the treatment of patients with cancers that have tar­getable molecular abnormalities, and may change the treatment paradigm for some cancers.

Similar programs that match molecular abnormality to targeted therapy rather than to tumor site include the “basket trials” at Memorial Sloan Kettering Cancer Center and other centers, the National Cancer Institute Molecular Analysis for Therapy Choice trial, and the ASCO Targeted Agent and Profiling Utilization Registry trial.

“Our preliminary results show that treating patients according to tumor alterations independent of tumor type is feasible and is important for benefiting unmet medical needs,” Dr Hainsworth told attendees. “This approach offers new opportunities to patients with solid tumors that have molecular abnormalities that can be treated with targeted therapies. Activity was observed in patients with 12 different tumor types outside of current indications for these targeted agents.”

MyPathway is ongoing and is continuing to accrue patients.

Last modified: August 30, 2021