Using molecular profiling to identify rare but highly actionable variants of tumors, Duke clinical investigators have helped patients with advanced, resistant metastatic cancers to find targeted therapy clinical trials that offer a promising alternative to traditional cytotoxic chemotherapy.

Two recent clinical trials highlight the impact that the integration of next-generation sequencing can have on providing patients access to treatment options that are well-tolerated and demonstrate clinically meaningful anticancer activity. John H. Strickler, MD, a Duke medical oncologist specializing in gastrointestinal cancers, is a site leader for both multicenter trials:

• MOUNTAINEER, a Duke-led study on the combination of tucatinib — a highly selective tyrosine kinase inhibitor against human epidermal growth factor receptor 2 (HER2) — and trastuzumab — a well-known HER2 antibody—in patients with previously treated HER2-positive metastatic colorectal cancer
• CodeBreaK 100, a study on the drug sotorasib in patients with heavily treated KRASG12C-mutated advanced solid tumors

“Through these trials and others like them, we have been able to generate tremendous clinical benefit for patients based on the molecular profile of their tumors,” says Strickler. “This approach allows patients to be treated with highly active regimens that offer a good quality of life, because the side effect profile is often better than conventional chemotherapy.”

Although HER2 amplification is found in only about 3% of patients with metastatic colorectal cancer, it is actionable in other tumor types, including stomach and breast cancers. There is currently no FDA-approved treatment targeting HER2 in colon cancer.

However, using that targeted therapy in the phase 2 MOUNTAINEER trial, the topline results showed a 38.1% confirmed objective response rate and a median duration of response of 12.4 months — numbers more often associated with the first line setting using conventional chemotherapy. Strickler presented the most recent results from this trial at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona, Spain, in June 2022.

“This is an impactful study that will likely redefine our standard of care for how we manage patients with HER2 positive colorectal cancer, not just in the United States, but potentially globally,” Strickler says.

The idea to test these drugs in HER2-positive patients with metastatic colorectal cancer came from Duke-initiated research on resistance to anti-epidermal growth factor receptor (EGFR) therapies, which is Strickler’s area of focus. Through his research, Strickler and his team noted a pattern of HER2 amplification in patients with resistance to EGFR antibodies, which made the opportunity to target that genetic alteration clear.

Another trial evaluated the efficacy and safety of the drug sotorasib in patients with rare KRASG12C-mutated advanced solid tumors who have undergone at least one prior systemic therapy. The KRAS mutation is present in 90% of pancreatic ductal adenocarcinomas with p.G12C, accounting for 1% to 2% of these mutations. Sotorasib is known to be active in lung cancer, but it is not as well studied in other tumor types, says Strickler, the lead author on the study.

Results from the phase 1/2 CodeBreaK 100 trial demonstrated promising response rates and provided some degree of disease control in many other patients. While cytotoxic chemotherapy has many side effects, this treatment targets only the mutation, providing a benefit on par with the current standard of care, with far fewer side effects.

“These data are promising for pancreatic cancer patients with high unmet medical need who have limited treatment options,” he adds.

Recruitment for these studies has been supported in large part by the work of Duke’s Molecular Tumor Board, of which he is a co-leader. “Our goal is always to help our trial teams identify patients with these variants so that we can ensure that they go on the right studies that target their specific genetic pathways,” Stricker adds.

Genetic testing results are integrated into Duke’s Molecular Registry of Tumors, which notifies providers of patients with a specific genetic alteration — such as KRASG12C or HER2 amplification — which may make them eligible for new trials and treatment options. The integration of test results with clinical care provides “just in time” clinical decision-making support, and offers patients access to the most innovative treatments.

“This approach breaks down disparities in access to care and takes the burden off patients and individual doctors, allowing people to focus on their care of their patient and giving them confidence that all patients who come to Duke are going to have access to the best we have to offer,” Strickler says.