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Colorectal Cancer Patients Benefit from Biomarker-Guided Treatments in TAPUR Study

NEW YORK – The American Society of Clinical Oncology's basket trial has reported positive results from three treatment arms involving patients with biomarker-defined advanced colorectal cancer.

At the Gastrointestinal Cancer Symposium in San Francisco this week, ASCO announced findings from three arms in its Targeted Agent and Profiling Utilization Registry (TAPUR) study. In one arm, colorectal cancer patients with high tumor mutational burden (defined as nine or more mutations per megabase) received pembrolizumab (Merck's Keytruda); in another arm, those with ERBB2 amplifications were treated with pertuzumab plus trastuzumab (Genentech's Perjeta/Herceptin); and in the third arm, patients with BRAF V600E mutations received cobimetinib plus vemurafenib (Genentech's Cotellic/Zelboraf).

ASCO launched TAPUR in 2015 to explore the off-label activity of marketed drugs in advanced cancer patients who harbor specific genomic alterations but are out of treatment options. The design of the study allows researchers to identify new signals of activity for cancer drugs in specific biomarker indications and study them in larger cohorts, or if no activity is seen, to retire the arm.

For example, if at least two of 10 patients experience disease control (defined as objective response rate or stable disease at 16 weeks), then 18 more patients are enrolled. If at least seven of 28 patients have disease control, then the drug is flagged for further study. All three arms reported at the Gastrointestinal Cancer Symposium met TAPUR's efficacy threshold, leading investigators to conclude that these drugs warrant further study in these indications.

In the arm where 27 advanced CRC patients received pembrolizumab, tumor mutational burden ranged from nine mutations per Mb to 54 mutations per Mb. Tumor mutational burden was determined by Foundation Medicine's FoundationOne assay or other tests approved by TAPUR's molecular tumor board.

One patient had tumor shrinkage, and seven had stable disease for 16 or more weeks. There was a 28 percent disease control rate and 4 percent objective response rate. Two patients had a grade 3 adverse event and one patient had a serious incident of acute kidney injury.

In the second arm, 28 heavily pretreated CRC patients with ERBB2 amplification could be evaluated for their responses to pertuzumab and trastuzumab. Four patients experienced tumor shrinkage and 10 patients had stable disease for 16 or more weeks, resulting in a disease control and objective response rate of 50 percent and 14 percent, respectively. Two patients experienced grade 3 toxicity or a serious adverse event.

The investigators noted that this combination should be further studied in advanced CRC with ERBB2 amplifications. They also plan to explore responses in this setting based on patients' RAS mutation status.

In order to be eligible for enrollment in the third TAPUR arm, advanced CRC patients had to have a BRAF V600E, V600D, V600K, or V600R mutation, but could not harbor MAP2K1, MAP2K2, MEK1, MEK2, or NRAS mutations.

In the study, all 28 patients evaluable for treatment response had BRAF V600E mutations. Eight patients saw their tumors shrink and eight had stable disease for 16 weeks or longer, which amounted to a disease control rate of 57 percent and a objective response rate of 29 percent. Twelve patients had at least one grade 3 toxicity event or a serious adverse event.

The latest results add to the positive data that TAPUR investigators reported at ASCO's annual meeting last year. Those were the first positive readouts from the trial, involving palbociclib (Pfizer's Ibrance) in non-small cell lung cancer characterized by CDKN2A alterations and pembrolizumab in metastatic breast cancer with high tumor mutational burden.