Results from a global, multicenter, multi-histology clinical study, SUMMIT, reported today in Nature journal, identify HER2 mutations in patients and more precisely predict those who would be most likely to respond to treatment with neratinib, a HER1/HER2 and HER4 tyrosine kinase inhibitor.
Importantly, by driving insights into the therapeutic value of HER2 and HER3 mutations, SUMMIT represents a breakthrough in molecularly guided clinical trials powered by reference molecular prescreening platforms and early clinical trial units of international excellence.
Led by David M. Hyman and colleagues from the Memorial Sloan Kettering Cancer Center (NY, USA), in collaboration with researchers, clinical investigators and medical oncologists from VHIO and the Vall d’Hebron University Hospital (Vall d’Hebron Barcelona Hospital Campus, Spain), this basket trial has succeeded in raising the bar in genome-driven oncology by demonstrating how a single study can be used to advance insights into the biological dependencies in human cancers.
As a leading example of basket study design where patients receive a matched targeted therapy according to genomic profile irrespective of cancer type, findings also reveal that response to treatment with neratinib is dependent on the characteristics of both tumour type and genomic variant – a critical discovery that failed to emerge from previous research using established preclinical models.
SUMMIT enrolled 141 patients, 125 with HER2-mutant tumours, and 16 with HER3, who, diagnosed with one of 21 unique cancer types, received neratinib. Patients were generally heavily pre-treated with approximately half having received three prior lines of systematic therapy. Tumour tissue and plasma were collected for the detailed genomic characterization of patients.
These data represent the first ever comprehensive dataset on the clinical actionability of HER2 mutations for the selection of patients to be treated with neratinib.
Despite preclinical data pointing to HER3 mutations as oncogenic drivers, findings showed no response in patients with HER3-mutant tumours, thus ruling them out as predictors of response to neratinib.
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 tumours with S310, L755, V777, P780_Y781insGSP and A775_G776insYVMA mutations.
When stratified by tumour type, responses were observed in patients with breast, cervical, biliary, salivary and non-small-cell lung cancers, which led to cohort expansions in these tumour types.
The study showed that the most frequently observed adverse reaction was diarrhoea.
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 diarrhoea, and with this anti-diarrhoeal prophylaxis and management, diarrhoea was not a treatment-limiting side effect in SUMMIT.
“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 utilise the basket trial design to explore the most optimal treatment options for these select patient populations.”
“One major strength of SUMMIT´s dynamic design is that it facilitated the necessary adjustments to our study with speed, agility and precision in order to ensure optimal outcomes for our patients”, observes Cristina Saura, Principal Investigator of VHIO’s Breast Cancer Group. “As we proceeded to identify mutations in patients, we checked them against existing databases to establish whether they were functional or not. In the majority of cases they were. Our findings therefore also represent an important forward step in the characterisation of these tumours.”
“SUMMIT serves as proof of concept now that response in pre-treated patients has been observed. While we still have important ground to cover towards prolonging response, results thus far represent an encouraging first step”, she concludes.