Researchers find 'highly synergistic' combo featuring Mirati's Krazati in pancreatic cancer models

New therapies for cancers with once-tough-to-target mutations in the KRAS G12C gene are starting to emerge from the clinic, but like all oncology drugs, they come with the risk of resistance. That’s led some scientists to explore combo treatments that could potentially block resistance before it starts.

A new study from researchers at the University of California San Diego School of Medicine has found one potentially beneficial combo for pancreatic cancer: Mirati Therapeutics' KRAS inhibitor adagrasib, known as Krazati, and Boehringer Ingelheim’s ERBB gene inhibitor afatinib, trade name Gilotrif. In an article published June 28 in Cancer Research, the team showed that the combo not only reduced resistance and improved survival in mouse models of the disease, but was also more effective at clearing tumors than either drug alone.

“The synergy between [adagrasib] and afatinib was remarkable, and we strongly encourage the clinical testing of this drug combination for patients with pancreatic cancer,” co-senior author Andrew Lowy, M.D., said in a press release.

Krazati made headlines last year when Mirati revealed a 50% response in patients with pancreatic cancer during a phase 1/2 clinical trial. The therapy is currently approved for KRAS G12C-mutated lung cancer. While it has the potential to be a “game changer” in pancreatic cancer, co-senior author Herve Tiriac, Ph.D., told Fierce Biotech Research in an interview, the trial only tested the drug as a single agent—and resistance is always just around the corner.

“The preclinical data is very encouraging that [adagrasib] is going to have a profound effect in patients, but we know that pancreas cancer, like a few other gastrointestinal cancers, is very resilient,” he said. “No one had addressed the resistance question yet, so we wanted to see what we could do with clinically available compounds today to prevent those resistance mechanisms from being an issue.”

Tiriac’s team knew from earlier research that one of cancer’s many pathways to KRAS drug resistance involved ERBB genes. ERBB receptors communicate with KRAS inhibitors to send signals. Typically, the interaction between ERBB and KRAS is a negative feedback loop—activating KRAS inhibits further ERBB protein. But when KRAS is turned off, those proteins accumulate, Tiriac explained.

“It’s like a traffic jam upstream of KRAS,” he said. When the drug runs out, leaving the KRAS receptor uninhibited, the floodgates open: ERBB proteins stimulate the KRAS receptor en masse, driving up KRAS expression once again. In addition the new study showed exposure to the KRAS inhibitor changes how some genes are regulated in a way that ultimately increases the number of KRAS receptors.

“That makes the problem of this feedback mechanism worse because there are more receptors now,” Tiriac said.

To see if they could counter this by improving the efficacy of adagrasib, the researchers conducted a screening assay on small molecules, then tested the results on pancreatic cancer cell lines and 3D organoids grown from human and mouse cells. Though the researchers tried several combinations, none was more synergistic than afatinib. This was likely because afatinib forms a permanent bond with the ERBB receptor, which causes the receptor to completely shut down—theoretically blocking off that particular pathway to drug resistance.

“It’s a very potent drug,” Tiriac said. “It’s basically broad-spectrum inhibition, and it’s non-reversible.”

The researchers then moved into live mice, testing tumor cells that were resistant and nonresistant to adagrasib. In all cases, the cancer was very aggressive: Without any intervention, the mice would die within a couple weeks of being grafted with the tumor cells, Tiriac said.

The researchers found that for models where the mice’s tumors didn’t yet have resistance to adagrasib, the afatinib duo not only prevented it from developing but also shrunk their tumors more effectively than either agent alone, including a high dose of adagrasib. That suggests that using the two drugs at the same time improved the initial response.

“In identifying this mechanism, we show that you don’t have to wait for resistance to consider choosing this combination—using it up front is very effective,” Tiriac said. “It was highly synergistic in every model that we tested.”

For the already resistant models, the combination stalled tumor growth while treatment with afatinib alone did not. This suggested that it was giving the drugs together that offered the benefits.

The combo conferred a statistically significant survival benefit in all the models. Mice who received the dual treatment outlived those who received only one agent. Some of the mice in the dual treatment group lived as long as 60 days; in contrast, the mice in the other groups died before day 40. That said, all of the mice did ultimately die, including the ones who received the dual therapy, Tiriac noted.

“There are no cures, even with this combination,” he said. “This is important to state.”