A New Approach to Overcome Drug Resistance

In their quest to impact the difficult-to-target KRAS protein (found in more than 90 percent of pancreatic cancers), researchers set their sights
on proteins related to KRAS signaling, named MEK1 and MEK2.

The development of MEK inhibitors such as binimetinib and trametinib were a welcome addition to the targeted therapy arsenal. These drugs showed good potential in the treatment of BRAF-mutated melanoma and KRAS/BRAF-mutated colorectal cancer.

But cancer tends to find workarounds in order to survive. Scientists soon realized that blocking a single node in the RAS pathway was not enough for many patients; tumor cells responded by reactivating the pathway elsewhere, or activating a parallel pathway. To overcome such a hurdle, scientists at Verastem Oncology looked at other ways to control the RAS signaling network. 

They developed avutometinib, a pill that blocks both RAF and MEK, as well as defactinib, a selective FAK inhibitor. Taken together, the combination could lead to maximal RAS pathway inhibition, while also preventing parallel signaling of the FAK pathway. In other words, the drugs are targeting proteins that the cancer needs, while also helping to overcome resistance.

Initial studies showed promising results, and now the drugs are being tested alongside the standard-of-care gemcitabine and nab-paclitaxel chemotherapy regimen.

The Current Trial

The phase I/II RAMP 205 study is assessing the safety and efficacy of the drug combination in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have been previously untreated. It demonstrated favorable tolerability in the first patients, leading to an expansion of the trial to allow more patients to be treated.

The drug’s developers are hoping that such customized RAS-targeted combinations could expand the number of effective treatment options for subsets of pancreatic cancer patients who have limited options today, and that the convenient oral dosing regimen may help those patients stay on therapy longer.

What Researchers Are Looking For

Despina Siolas, M.D., Ph.D., who is leading the multi-institutional trial’s Weill Cornell Medicine (New York) cohort, is optimistic about the combination of traditional and novel targeted therapies. 

“We have to alter our approach. When it comes to pancreatic cancer, we can’t just keep doing the same things. We need new and different therapies,” Siolas says. “This is an exciting trial, with promising early results, prompting the enrollment of more and more patients.”

An additional benefit to the trial is that it could help expand our understanding of how the drugs are acting on each patient’s pancreatic cancer. Researchers will be studying tumor DNA secreted in blood and other molecular markers among responders and non-responders.

“We know that cancer is a personal disease and we need to take targeted approaches for each patient. We want to know who might benefit the most from these therapies, and why,” Siolas explains. “Cutting-edge trials like these provide great opportunities for patients and institutions to try new therapies, and also for society as a whole, who get to benefit if things go well,” she adds.

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