Amgen may be leading the race to develop a KRAS inhibitor, but its candidate hasn’t logged the same success in colon cancer as it has in lung cancer. Early data out of the annual meeting of the American Association for Cancer Research (AACR) suggest a different route to treating patients with KRAS-mutated colon cancer—including those with mutations thought to be undruggable.
Trovagene’s PLK1 inhibitor, onvansertib, alongside the standard of care, stopped tumors from growing in seven of eight evaluable patients with KRAS-mutated colorectal cancer. It shrank tumors in three of those patients (38%), according to phase 1b data unveiled at the first session of the AACR’s annual meeting.
At the study’s April 1 data cutoff, the combo had kept cancer at bay for a median 6.5 months, and six of the patients who’d responded are still receiving treatment.
The company is testing three dose levels of onvansertib as a second-line treatment in combination with chemo cocktail Folfiri and Roche’s VEGF blocker Avastin—six on the lowest dose, three on the middle dose and three on the highest.
The eight evaluable patients had received the two lower doses. After one of the three patients on the highest dose suffered life-threatening neutropenia—an abnormally low white blood cell count—the investigators are looking for three more patients to test it.
Onvansertib is a “promising therapeutic intervention” for these patients, because PLK1, which occurs at high levels in colorectal cancer, is a synthetic lethal pair with the KRAS mutation, said Afsaneh Barzi, M.D., who presented the study. Thus, blocking PLK1 in cancer cells where KRAS is inactivated by a mutation leads to cell death.
If the data bear out, patients with KRAS-mutant colorectal cancer—who make up about half of all colorectal cancer patients—could end up with their own targeted therapy. Today, they’re treated with chemotherapy and drugs like Avastin, but “prognosis is poor,” Barzi said.
Amgen’s KRAS inhibitor, AMG 510, is designed for patients with a G12C KRAS mutation. Its first clinical data made headlines last year, showing the drug shrank tumors in 90% of patients with non-small cell lung cancer. As the study went on, the drug continued to deliver in lung cancer but served up disappointing results in colorectal cancer, shrinking cancer in just one of 12 patients for an 8% response rate.
Of course, there is no direct comparison between onvansertib and Amgen’s KRAS inhibitor, AMG 510. For starters, Amgen’s drug is specifically for patients with a G12C mutation, while Trovagene’s targets KRAS mutations more broadly.
What’s more, Amgen tested AMG 510 in sicker patients who had tried at least two previous treatments, while Trovagene tested onvansertib in patients who had gone through just one line of treatment. But as Barzi noted, G12C mutations make up only 8% of KRAS mutations in colorectal cancer, suggesting Amgen’s approach may not be the best hope in this type of cancer.