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New Paradigm: Matching Therapy to Molecular Alterations

Johnhainsworth98pxOngoing 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 site of cancer.

MyPathway is one such effort that appears to be paying off, according to preliminary results presented at the 2016 ASCO Annual Meeting.

MyPathway is evaluating agents that target 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 presenting author, John D. Hainsworth, MD, Sarah Cannon Research Institute, and Tennessee Oncology, PLLC, Nashville.

The most impressive responses were found in 4 major tumor cohorts: HER2-positive (HER2+) colorectal (CRC), bladder, and biliary cancers (treated with trastuzumab and pertuzumab), and BRAF-mutated non–small cell lung cancer (NSCLC, treated with vemurafenib), in particular, patients with the BRAF V600E mutation.

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

Similar programs matching molecular abnormality to targeted therapy rather than tumor site are the “basket trials” at Memorial Sloan Kettering Cancer Center and other centers, the NCI Match trial, and the ASCO TAPUR 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. 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,” Dr Hainsworth told listeners.

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

Overall, 29 of 129 patients (23%) had a major response. Thirty-one percent had stable disease. Fourteen of the 29 objective responders progressed after a median of 6 months, while 15 patients had ongoing responses at the time of the ASCO meeting ranging from 3+ months to 11+ months.

The largest group was 61 patients with HER2+ tumors: CRC, bladder, biliary, NSCLC, pancreatic, head and neck, and other sites.

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

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

“This is a strong signal in HER2+ CRC, and also there was a strong signal in biliary and bladder cancer,” he said, although the numbers were smaller.

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

Of the 33 BRAF-mutated patients, 19 had the BRAF V600 mutation, and 14 had other BRAF mutations. Among 8 responders, 7 had the V600E mutation.

MyPathway is an ongoing study and is continuing to accrue patients.

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