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ESMO Studies Investigate KRAS-Mutated Cancers in Targeted Combination Rx, Chemo Trials


NEW YORK – The race to bring new therapies for KRAS-mutated cancers continues to intensify, as demonstrated at the European Society for Medical Oncology Congress this week, where drugmakers and researchers explored the value of combination treatment strategies to mitigate resistance and discussed efforts to understand how patients with these mutations fare on chemotherapy regimens.

With Amgen's sotorasib (Lumakras) already first to market for KRAS-mutated NSCLC and other KRAS-targeted drugs close behind, the data presented at the meeting suggests that researchers are already thinking about how to best combine these new KRAS inhibitors with other drugs to improve outcomes in patients who have stopped responding to other targeted agents. Given the unmet need in this setting and how recalcitrant KRAS-mutated tumors are to treatment, investigators are also working to better characterize patients' responses to chemotherapy-based regimens already in their armamentarium.

Researchers at the meeting presented results from several studies involving KRAS-mutated cancer patients, including one evaluating Mirati Therapeutics' adagrasib with or without cetuximab (Eli Lilly's Erbitux) in previously treated colorectal cancer patients with a KRAS G12C mutation and another investigating two chemotherapy-based regimens in advanced KRAS-mutated non-small cell lung cancer.

Targeted combinations

In the Phase I/II trial of adagrasib, called KRYSTAL-1, researchers are studying colorectal cancer patients with RAS or RAF mutations who have become resistant to the EGFR inhibitor cetuximab and exploring whether rechallenging patients with cetuximab plus the KRAS inhibitor adagrasib could make patients respond again.

"KRAS G12C mutations occur in approximately 3 percent or 4 percent of colorectal cancer, act as oncogenic drivers, and are strong negative predictors of cetuximab efficacy," study investigator Jared Weiss, an associate professor of medicine at the University of North Carolina, said at the meeting. "We hypothesized that combining adagrasib with cetuximab, an EGFR inhibitor, may enhance inhibition of KRAS-dependent signaling or overcome adaptive feedback to improve clinical outcomes."

In fact, analysis of a prospective Phase II study of cetuximab and chemotherapy maintenance treatment in colorectal cancer patients presented on Saturday demonstrated that resistance. In that trial, patients with mutations in MAPK pathway genes, such as RAS, RAF, MEK, and ERK, had significantly lower median progression-free survival when treated with cetuximab and chemo compared to those without MAPK mutations, 2.3 months versus 3.7 months, respectively. That study concluded that patients with these mutations were not good candidates for cetuximab maintenance treatment.

Weiss noted in his presentation that preclinical models have shown the combination of EGFR and KRAS inhibitors leads to deeper and more durable tumor regressions. "Preclinical data show EGFR signaling is the dominant mechanism of colorectal cancer resistance to KRAS G12C inhibitors," he explained. "Further, in vitro data show that combined EGFR and KRAS G12C inhibition result in greater modulation of phosphorylated ERK signaling." ERK is also part of the MAPK pathway, which was identified as an indicator of resistance to cetuximab by the prospective study.

Meanwhile, the KRYSTAL-1 results showed that 22 percent of advanced KRAS G12C-mutated colorectal cancer patients responded to treatment with adagrasib as a monotherapy. However, in the combination arm with adagrasib and cetuximab, the response rate was nearly doubled at 43 percent in this population. The patients were heavily pretreated with a median of three prior lines of treatment.

In the combination arm, which had 28 patients evaluable for response, the disease control rate was 100 percent, while the adagrasib monotherapy arm had a disease control rate of 87 percent among 45 evaluable patients. The monotherapy group had a median progression-free survival of 5.6 months and a median duration of response of 4.2 months. In the combo arm, the median progression-free survival or duration of response analyses were not mature.

In light of the KRYSTAL-1 results in colorectal cancer, Mirati has begun a Phase III trial, called KRYSTAL-10, further investigating the adagrasib-cetuximab combination as a second-line treatment for advanced or metastatic KRAS G12C-mutated colorectal cancer.

The company will also begin discussions with the US Food and Drug Administration before the end of 2021 about the KRYSTAL-1 data and "clarify the potential pathway for accelerated approval in late-line colorectal cancer for adagrasib as a monotherapy and in combination with cetuximab," said Charles Baum, head of research and development at Mirati, in a call with investors on Monday.

Based on the agency's input, the company will enroll additional patients in either the combination or monotherapy arm to confirm the KRYSTAL-1 results and generate enough data to apply for accelerated approval, said Mirati CEO David Meek on the investor call.

Separately at the ESMO Congress, Amgen reported early trial data from a small cohort of KRAS-mutated colorectal cancer patients who received a similar KRAS and EGFR inhibitor combination treatment. That trial, which only included 18 patients with KRAS-mutated colorectal cancer, also saw early promising results.

The patients were treated with Amgen's sotorasib and its EGFR inhibitor panitumumab (Vectibix). In those early results, the overall response rate was 33 percent, with three confirmed partial responses and three unconfirmed partial responses.

Federica di Nicolantonio, a researcher at the University of Torino in Italy who was not involved with the KRYSTAL-1 or sotorasib trials, supported combining KRAS-EGFR inhibitor combos in KRAS-mutated colorectal cancer. "KRAS inhibitors as monotherapy yield relatively low response rates in colorectal cancer, but when you combine them with an EGFR inhibitor the response rate is nearly doubled."

"We're also eager to see what other combinations of KRAS G12C inhibitors will look like in colorectal cancer, in particular those with SHP2 inhibitors that have very solid preclinical data," she added.

KRAS and chemo

Researchers are also trying to improve their understanding of how NSCLC patients with KRAS mutations respond to chemotherapy-based regimens. In a Phase III study, investigators led by Anne-Marie Dingemans, chair of the lung cancer group at Erasmus Medical Center in the Netherlands, compared two chemo regimens, cisplatin-pemetrexed (cis-pem) and carboplatin-paclitaxel-bevacizumab (CPB), in chemotherapy-naïve patients with advanced KRAS-mutated NSCLC.

The investigator-sponsored trial, called NVALT22, was designed based on the findings from a retrospective study that showed patients with KRAS-mutated NSCLC treated with a taxane-based regimen, like CPB, had improved outcomes compared to treatment with pemetrexed or gemcitabine. In that study, patients who received bevacizumab (Genentech's Avastin) also had the best overall response rate of 63 percent. That led Dingemans and colleagues to compare cis-pem and CPB in the NVALT22 trial.

"Based on the retrospective data, we thought that the difference [between the two regimens] would be huge," Dingemans said. However, her team found no such difference between the two treatment arms in KRAS-mutated NSCLC patients. The median progression-free survival for the CPB group was 5.2 months compared to 4.7 months for the cis-pem group.

The researchers are continuing to analyze data in this trial, which stopped recruiting early due to enrollment issues from the COVID-19 pandemic and a change in treatment strategies for first-line patients.

In an analysis of 92 patients with KRAS G12C mutations, which made up nearly half of the study population, they found that median progression-free survival was not significantly different between the arms, but that the hazard ratio favored the taxanes group, Dingemans said.

The researchers will also continue to analyze subgroups from this trial to better understand these findings, including subgroups with different KRAS mutations and those who received different prior treatments like immunotherapy.

"We have a large translational program in this study, so we collected blood samples and tissue, and we hope we will learn more from this study," she said.