Skip to main content

HER2 Mutant Basket Trial Confirms Drug Response Depends on Mutation, Cancer Type

NEW YORK (GenomeWeb) – Results from the Phase II SUMMIT trial, presented this weekend at the annual meeting of the American Association for Cancer Research in Washington, DC, have upheld the expectation that mutation status, regardless of tumor type or location, can contribute to response to targeted therapy.

The findings reiterate the importance of basket clinical trials that recruit patients not solely based on the location or clinical presentation of their tumor, but on the presence or absence of a particular mutation.

In SUMMIT, investigators have been evaluating the investigational pan-HER-targeted therapy neratinib.

Prior to the trial, there have been reports on responsiveness of HER2-mutated cancers to off-label use of US Food and Drug Administration-approved HER2-targeting drugs, but HER2 and HER3 gene mutations are infrequent in most cancer types. As such, the trial was designed to accept patients with a variety of different tumors and with different mutations in these genes, with the hope that the results could help unravel some of the complexity around which mutations confer response and in which clinical contexts.

At the interim data cutoff last December, 141 patients with cancers harboring HER2 or HER3 mutations had received neratinib as part of the trial, investigators reported at the AACR meeting.

Within the cohort there were 21 unique types of cancer, 30 unique HER2 gene mutations, and 12 HER3 gene mutations. The most common types of cancer were bladder, breast, colorectal, and non-small cell lung cancer.

Importantly, patient responses to the drug revealed that both cancer type and the particular gene mutation present in a tumor appear to contribute to outcomes.

"It appears that there is not a binary relationship and that both cancer type and mutation identity are important," study leader David Hyman, director of developmental therapeutics at Memorial Sloane Kettering, said in a statement.

When researchers divided the cohort by cancer type, the best response rate was seen for breast cancer, while biliary and cervical cancers held up the middle, and colorectal cancer had the lowest response rate.

But molecular information also told an important story, researchers said. "Analyzing the data in this way shows that cancer type is important, but it is not the whole answer; for example, there were no responses for any cancer type harboring a HER3 mutation, and when considering individual cancer types, different HER2 mutations had different sensitivity to neratinib," Hyman explained.

Despite these important insights, Hyman said that there remain hurdles for trials like SUMMIT and other basket protocols, for example, recruitment of sufficient numbers of patients with rare mutations.

Even though SUMMIT has enrolled a comparatively large number of patients for a phase II clinical trial, investigators still have still not saturated enrollment in terms of each combination of cancer type and specific mutation, Hyman said.