On January 31 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced that initial results from the company’s ongoing SUMMIT Phase II ‘basket’ clinical trial of PB272 (neratinib) in patients with tumors harboring HER2 or HER3 mutations were published in the journal Nature . The paper, "HER kinase inhibition in patients with HER2- and HER3-mutant cancers," appears in the January 31, 2018 online issue at View Source and will be published in a future print issue of the journal.

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The Phase II SUMMIT trial is a global, multi-histology, open-label, precision-medicine ‘basket’ study evaluating the safety and efficacy of neratinib administered daily to patients with a wide variety of solid tumors with activating HER2 or HER3 mutations. SUMMIT is designed to evaluate the contributions of both genetic mutation and cancer type on individual patients’ response to neratinib. Information generated from the trial will help guide neratinib-based targeted therapy across a broad spectrum of tumor types with HER2 or HER3 mutations, including patients with rare tumors who may not otherwise have access to investigational therapies.

"Publication of the initial SUMMIT data in this prestigious journal reflects the novelty and quality of this precision-medicine trial design, as well as the growing understanding that both tumor type and gene mutations play an important role in individual patients’ response to cancer therapies such as neratinib," said Alan H. Auerbach, Puma’s Chief Executive Officer and President. "The basket trial design utilized for SUMMIT is enabling researchers to evaluate the clinical potential of neratinib in multiple cancer types, rather than limiting exploration to one tumor type at a time. SUMMIT is also significant in that it will provide the largest body of clinical data to date on the use of an irreversible pan-HER inhibitor in patients who have solid tumors with somatic HER2 or HER3 mutations."

The initial SUMMIT results published in Nature comprise data from 141 patients enrolled in the neratinib monotherapy arm of the trial, including 124 patients with HER2 mutations and 17 patients with HER3 mutations. This included patients with 21 unique tumor types, with the most common being breast, lung, bladder and colorectal cancer. Researchers observed 30 distinct HER2 and 12 distinct HER3 mutations among these patients, with the most frequent HER2 variants involving amino acids S310, L755, A755_G776insYVMA and V777.

In the HER2-mutant cohort, clinical responses were observed in tumors with S310, L755, V777, P780_Y781insGSP and A775_G776insYVMA mutations. When stratified by tumor type, responses were observed in patients with breast, cervical, biliary, salivary and non-small-cell lung cancers, which led to cohort expansions in these tumor types. No activity was observed in the HER3-mutant cohort.

The neratinib safety profile observed in the SUMMIT study is consistent with that observed previously in metastatic patients with HER2 amplified tumors. The study showed that the most frequently observed adverse reaction was diarrhea. All patients in the SUMMIT study received prophylactic loperamide (16 mg per day initially) for the first cycle of treatment in order to reduce neratinib-related diarrhea, and with this anti-diarrheal prophylaxis and management, diarrhea was not a treatment-limiting side effect in SUMMIT. For the 141 patients enrolled in the neratinib monotherapy arm with safety data available, 31 patients (22.0%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for those patients was two days. Four patients (2.8%) permanently discontinued neratinib and 21 patients (14.9%) had dose interruptions due to diarrhea.

"Results to date from the SUMMIT trial validate the ‘next-generation’ basket trial approach, which has enabled us to efficiently and effectively evaluate neratinib across numerous cancer types as well as individual and sometimes entirely novel HER2 mutations," said David Hyman, M.D., Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center (MSK). "We look forward to completing enrollment in the ongoing cohorts in the study and continuing to utilize the basket trial design to explore the most optimal treatment options for these select patient populations."

Dr. Hyman, who helped pioneer the concept of basket trials at MSK, presented the initial findings from the SUMMIT study at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2017.

"We are very pleased with these initial results," said Mr. Auerbach. "We look forward to advancing neratinib into further clinical development in multiple HER2 mutant tumor types, both as monotherapy and in novel combinations."