A drug in early clinical development has demonstrated an ability to indirectly target a mutation in colorectal cancer that has so far evaded other drugs.
San Diego-based Trovagene said Monday that data from a Phase Ib/II trial of the drug onvasertib, combined with Roche’s Avastin (bevacizumab) and the chemotherapy combination FOLFIRI – had shown clinical responses in patients with second-line metastatic colorectal cancer (mCRC) with mutations of a gene known as KRAS. The data were presented last weekend at the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium in San Francisco.
According to the data, all five patients who were evaluable for efficacy saw “significant” reduction in KRAS mutational burden, and three saw a greater than 25% shrinkage in their tumors, with one becoming eligible for curative surgery.
Strictly speaking, onvasertib is not a KRAS inhibitor, but a PLK1 inhibitor. However, it exhibits a property known as synthetic lethality, whereby tumors with KRAS mutations have a higher sensitivity to PLK1 inhibition than those in which KRAS is not mutated. The drug is also being developed for other cancers, like prostate and acute myeloid leukemia.
In a phone interview, Mark Erlander, the company’s chief scientific officer, said there is precedent for such a mechanism of action.
“The BRCA-PARP story is the poster child for this,” he said, referring to drugs called PARP inhibitors that treat tumors with BRCA mutations, such as AstraZeneca’s Lynparza (olaparib). It is hoped that new technologies like CRISPR/Cas9 gene editing will also aid the discovery of synthetic lethality in other targets.
It’s thanks to that synthetic lethality that onvasertib has had more luck in treating KRAS-mutated mCRC than drugs that target KRAS directly. Long thought an “undruggable” target, KRAS has drawn significant attention due to its widespread expression across a range of cancers. One of the biggest breakthroughs came last year, when Amgen presented data on AMG 510, a KRAS G12C inhibitor, showing clinical activity in solid tumors, especially non-small cell lung cancer (NSCLC). Another company, Mirati Therapeutics, is also developing a KRAS G12C inhibitor.
Although the KRAS inhibitors have shown efficacy in mCRC, it hasn’t been as dramatic as that observed in NSCLC. In October, Amgen said AMG 510 had produced partial responses in seven of 13 evaluable patients with NSCLC, but only one response out of 12 patients with mCRC, in those patients receiving the target dose of 960mg. Mirati’s MRTX849 produced partial responses in three of six NSCLC patients, but only one of four mCRC patients across all dose levels.
Erlander explained that the higher efficacy in NSCLC compared with mCRC despite both tumors harboring KRAS G12C mutations indicates that cellular context matters, and the mCRC cells are simply not as susceptible to KRAS G12C targeting as their NSCLC counterparts. “Synthetic lethality allows you go to further downstream, connecting the dots,” he said.
Photo: nopparit, Getty Images
