Basket Study Shows Early Efficacy Targeting Cancer Only On Alterations

Early results from an ongoing "basket study" show that targeted therapies may be effective strictly based on the tumor’s molecular profile, and not primary tumor type, according to a rapid communication published Jan. 10 in the Journal of Clinical Oncology. The ongoing MyPathway study is testing off-label use of four approved targeted therapies in multiple tumor types.

Molecular profiling is becoming the standard of care to guide the selection of targeted therapies for the treatment of patients with lung, breast, and colon cancers based upon molecular alterations in human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), v-raf murine sarcoma viral oncogene homolog B1 (BRAF) genes, and the Hedgehog pathway.

"Molecular alterations in these genes and pathways also occur in a variety of nonindicated tumor types," write the authors led by John D. Hainsworth, from the Sarah Cannon Research Institute in Nashville, Tenn. "The low incidence of the targeted molecular alterations in these tumor types (usually less than 5 percent) has made it difficult to recruit sufficient numbers of patients into traditional drug development studies, although activity has been documented in anecdotal reports."

"Molecular alterations in these genes and pathways also occur in a variety of nonindicated tumor types."

—John D. Hainsworth

The MyPathway study, supported by Roche/Genentech, is a nonrandomized, phase IIa multiple basket study that is evaluating the efficacy of four treatments targeting molecular alterations in HER2 (pertuzumab plus trastuzumab), BRAF (vemurafenib), Hedgehog pathway (vismodegib), or EGFR (erlotinib) in patients with tumor types outside of current labeling for these treatments. Eligible patients were required to have previous genomic profiling demonstrating one of the target alterations at a CLIA-approved laboratory.

Between April 1, 2014, and Nov. 1, 2016, 251 patients with 35 different tumor types received study treatment at 38 different centers, but analysis only included the 230 who had reached the first efficacy evaluation. Participants had completed a median of 2.5 prior systemic treatment regimens. Identified tumor molecular alterations included HER2 (66 percent), BRAF (21 percent), Hedgehog (9 percent), and EGFR (4 percent).

Nearly one-quarter of patients (23 percent) had objective treatment responses (complete, n = 4; partial, n = 48). All four targeted treatments produced meaningful responses in 14 different tumor types. Four tumor-pathway cohorts enrolled at least 12 patients and had protocol-mandated efficacy review: HER2 amplified/overexpressing in colorectal cancer (objective response in 14 of 37), HER2 amplified/overexpressing non-small cell lung cancer (NSCLC; objective response in two of 16), HER2-mutated NSCLC (n = 14), and BRAF V600E-mutated NSCLC (objective response in six of 14). The study was closed to further accrual of BRAF non-V600 mutations because of the low response rate (one of 23 patients with diverse tumor types).

"To date, most basket trials have reported mixed results, which may be due to the pathways being targeted, the methods of molecular testing, or the therapeutic agents being tested," writes Hainsworth and colleagues. "The design of MyPathway maximizes the chance of success by using CLIAapproved molecular testing readily available in the clinic and by selecting FDA-approved targeted agents backed by more than a decade of translational science and clinical experience."

Takeaway: Early results from an ongoing basket trial show that targeting treatment strictly based on molecular alterations and not tissue of origin is a promising strategy.


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