SAN DIEGO – A Phase I/II trial of Bristol Myers Squibb's KRAS inhibitor Krazati (adagrasib) plus Eli Lilly's EGFR inhibitor Erbitux (cetuximab) has shown that the combination could be a "potential new standard of care" for previously treated patients with KRAS G12C-mutant metastatic colorectal cancer.
At the American Association for Cancer Research annual meeting on Monday, Scott Kopetz, deputy chair of translational research at MD Anderson Cancer Center's gastrointestinal medical oncology department, presented pooled results from the colorectal cancer cohort of the KRYSTAL-1 study. These data were simultaneously published in Cancer Discovery. In presenting the data at the meeting, Kopetz underscored that the heavily pretreated patients in this trial historically have few therapy options and have poor outcomes on the current standard treatment comprising chemotherapy plus a VEGF inhibitor.
Out of the 94 patients who received the recommended dose of Krazati combined with Erbitux in this pooled analysis, 34 percent responded to the combination. The disease control rate, which includes patients whose tumors shrank and those with stable disease, was 85.1 percent. Median progression-free survival was 6.9 months and median overall survival was 15.9 months. After six months of treatment, 87.8 percent of patients were still alive.
While KRYSTAL-1 did not have a comparator arm, Kopetz noted as a reference point that the current standard treatment of chemotherapy plus a VEGF inhibitor in this setting usually produces progression-free survival between 1.9 months and 5.6 months and overall survival in the range of 6.4 months to 10.8 months.
"There is really a need for more effective treatments [in this patient population]," Kopetz said. "This data supports adagrasib and cetuximab as a new potential standard of care for previously treated metastatic KRAS G12C-mutant colorectal cancer and will hopefully support [this combination] as the new standard of care in a regulatory filing."
According to Kopetz, the Phase III KRYSTAL-10 trial comparing the Krazati-Erbitux combination against chemo in the second-line treatment setting in KRAS G12C-mutant advanced colorectal cancer patients has completed enrollment, and this trial will provide more data that will hopefully advance this combination into the second-line setting.
In February, Bristol Myers Squibb, which acquired Krazati developer Mirati Therapeutics last year, said it has submitted a supplemental new drug application (NDA) to the US Food and Drug Administration seeking approval for Krazati plus Erbutix in this patient population. The FDA is expected to make a decision on this application by June 21.
Krazati is currently approved in the US and UK as a treatment for KRAS G12C-mutant advanced or metastatic non-small cell lung cancer patients who have received at least one systemic therapy. In November, the European Medicine Agency's Committee for Medicinal Products for Human Use recommended that the European Commission also approve this drug in the NSCLC setting.
In the colorectal cancer cohort in KRYSTAL-1, researchers also explored outcomes based on circulating tumor DNA (ctDNA) and reported their findings in the Cancer Discovery paper. In the colorectal cancer cohort, out of 83 patients who provided samples for ctDNA analysis, 15 had samples taken at baseline, four weeks after treatment, and eight weeks after treatment. Researchers found that 80 percent of these patients had at least a 90 percent decrease in KRAS G12C ctDNA levels, and responses were seen in 67 percent.
The researchers also explored acquired genomic alterations within the ctDNA data and found that three-quarters of 34 patients with available ctDNA results had at least one acquired pathogenic alteration between baseline and the end of treatment. Across these patients, the researchers identified 116 acquired alterations, with most patients having acquired multiple alterations.
The latest pooled analysis is an update from an earlier readout within the Phase I portion of the KRYSTAL-1 study, now involving more patients with longer follow-up. Alex Adjei, chief of Cleveland Clinic's Taussig Cancer Institute, in discussing the KRYSTAL-1 data at AACR, noted that the updated colorectal cancer analysis is "very reassuring," since it confirms the earlier Phase I readout and demonstrates an even longer overall survival. In the Phase I portion, data from which were presented in 2022, the median overall survival was 13.4 months, compared to a median overall survival of 15.9 months in the latest readout.
With the caveat that cross-trial comparisons are not ideal, Adjei considered the KRYSTAL-1 data against the activity seen with Amgen's competing KRAS G12C inhibitor Lumakras (sotorasib) plus its EGFR inhibitor Vectibix (panitumumab) in the same patient population. In a readout last year from the CodeBreaK 300 trial, Lumakras plus Vectibix demonstrated a median progression-free survival of 5.6 months and a response rate of 26 percent at the higher Lumakras dose tested. With the lower Lumakras dose, patients had worse outcomes in the study.
Adjei reflected at the meeting that the efficacy of Lumakras-Vectibix and Krazati-Erbitux in these two studies seemed "fairly comparable," despite the limitations of cross-trial comparisons and CodeBreaK 300 involving a smaller cohort. He added that both KRAS-EGFR inhibitor combinations are already listed in the National Comprehensive Cancer Network guidelines as options for previously treated KRAS G12C-mutant metastatic colorectal cancer patients.
Looking to the future of the KRAS inhibitor treatment landscape, Adjei said the response rates for the agents currently on the market, Krazati and Lumakras, are "not as robust as we would like," and the field needs to garner a better understanding of how patients become resistant to these drugs.
He highlighted that newer agents that are KRAS(ON) inhibitors, such as Revolution Medicines' RMC-6236 and BridgeBio's BBO-8520, may surpass first-generation KRAS inhibitors that are KRAS(OFF) inhibitors. KRAS(ON) inhibitors inhibit the active or GTP-bound form of KRAS mutations, while the first-generation KRAS drugs inhibit the inactive form. GTP-bound KRAS can also activate other signaling pathways in the MAPK pathway, which means these drugs could overcome some mechanisms of resistance to KRAS inhibition, Adjei said.
When thinking about all the KRAS inhibitors in development, both Kopetz and Adjei noted that in the absence of head-to-head comparisons of these agents, cross-trial comparisons will become increasingly necessary to help clinicians choose the best option for their patients.
Kopetz cautioned that early-stage trials can sometimes yield better outcomes than late-stage studies, but still noted that Krazati has some features that he believes may be contributing to the "excellent outcomes" seen in the colorectal cancer population and beyond, such as its long half-life and central nervous system penetration.
"This is an area where there's a lot of development being done, both [against] G12C and other [KRAS variants]," Kopetz said. "This work provides a foundation for the next stages."
Although KRAS G12C mutations show up in 3 percent to 4 percent of colorectal cancer patients, KRAS mutations broadly characterize 20 percent of all tumor types and 45 percent of colorectal cancers. "As we explore the next generation of KRAS inhibitors, this type of work [to] really understand how the tumors are adapting to KRAS therapy is critical," Kopetz said.