Findings from the phase II SUMMIT basket trial indicate that among patients with solid cancers harboring HER2/3 mutations, responses to the investigational pan-HER inhibitor neratinib vary by specific alteration and tumor type. Neratinib showed promising single-agent activity in breast, biliary tract, and cervical cancers, but was ineffective against bladder and colorectal cancers; among a small subset of patients with HER3 mutations, no responses were seen.

According to findings from a global basket trial, responses to neratinib (Puma Biotechnology) among patients with solid cancers harboring HER2 mutations vary by specific alteration and tumor type. The phase II SUMMIT study data—the most definitive to date on the use of this investigational pan-HER inhibitor—were presented on April 2 during the American Association for Cancer Research's Annual Meeting 2017 in Washington, DC.

Somatic HER2 mutations “tend to be widely distributed across the gene, localizing to the extracellular, transmembrane, or kinase domains,” said principal investigator David Hyman, MD, director of developmental therapeutics at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. They occur at relatively low frequencies (1% to 3%) across multiple cancers, provoking constitutive signaling that activates cell proliferation and survival pathways.

SUMMIT is a “second-generation” basket study, Hyman said; he and his colleagues pioneered this trial design at MSKCC. “First-generation basket studies looked at extending approved drug indications; now we'd like to credential experimental agents,” he explained. “We're also trying to target not just a given gene, but individual variants within.”

The investigators evaluated neratinib in 141 patients with a variety of tumor types, most commonly bladder, breast, and colorectal cancers, as well as non–small cell lung cancer (NSCLC). The majority harbored HER2 mutations, with the most frequent variants including S310F in the extracellular domain, as well as exon 20 insertions and V777L missense mutations in the kinase domain. A small number of patients, 17 in all, had HER3 mutations instead.

Neratinib looked most promising in breast cancer, Hyman reported, with an objective response rate (ORR) of 32%. In biliary tract and cervical cancers, the ORR was 22% and 20%, respectively. However, there was “a general lack of clinical activity in the bladder and colorectal cancer cohorts,” he said, and no responses were seen among the patients with HER3 mutations.

Grouping neratinib's efficacy data by specific HER2 mutation yielded some interesting differences, Hyman noted. For instance, “one patient with breast cancer and an S310 hotspot mutation responded robustly, but not another patient with the same variant in bladder cancer,” he said. A different patient with breast cancer, but no hotspot HER2 mutations, also responded well to neratinib. “She had a complex insertion and substitution event in the kinase domain that, to our knowledge, has never been seen before,” Hyman explained. “This suggests that certain patients will have truly one-off genomic alterations driving their particular cancer, so they still benefit from targeted therapy.”

“Who knew HER2 could be so complicated?” remarked George Demetri, MD, director of Dana-Farber Cancer Institute's Center for Sarcoma and Bone Oncology in Boston, MA. Unraveling this kinase's intricacies, in terms of its myriad mutations, will be “different than that of HER2 amplification, which remains a big part of breast cancer,” he added.

Not only are tumor type and mutation identity both important in influencing the likelihood of response to neratinib, Hyman concluded, but this drug will likely be most effective in combination with other agents, not as monotherapy. “It's not surprising—this has been the story of all drugs developed against amplified HER2 to date,” he observed. –Alissa Poh