NEW YORK – Up to 40 percent of patients with KRAS G12C mutations driving their colorectal and pancreatic cancer also have tumor alterations associated with primary resistance to KRAS G12C inhibitors, a recent study has shown. The findings have shed light on why these targeted treatments have shown modest efficacy in clinical trials.
The study, published in Clinical Cancer Research on Monday, may help oncologists better select which advanced colorectal and pancreatic cancer patients should receive KRAS G12C inhibitors and suggests potential combination strategies to overcome primary KRAS G12C inhibitor resistance.
The researchers, led by Hao Xie, a gastrointestinal medical oncologist at Mayo Clinic, aimed to better characterize primary resistance due to mutations patients had before they even receive KRAS inhibitors because this is less understood and studied than acquired resistance to these drugs due to mutations that emerge after initial response, Xie said.
"When we treat patients with targeted therapy, often we emphasize acquired resistance," Xie said. "As oncologists or cancer researchers, we typically pay less attention to what we call primary resistance, meaning when we treat patients with drugs, some of the patients don't respond, so their cancers will continue grow."
Xie believes the field needs to focus more on studying patients with primary resistance in order to improve precision administration of existing therapies and develop better drugs.
Studies of acquired resistance to KRAS G12C inhibitors have found that these tumors use escape mechanisms in the RAS-MAPK pathway, such as alterations in BRAF, NRAS, MEK, and EGFR to resist KRAS G12C inhibition. The pharma companies developing KRAS G12C inhibitors are already exploring combination regimens to address this resistance. For instance, after Amgen's Lumakras (sotorasib) demonstrated only a 9.7 percent response rate as a monotherapy in a Phase II trial in colorectal cancer, the firm pivoted to combination strategies with EGFR inhibitors in this setting.
Currently, two KRAS G12C inhibitors are approved in the US for KRAS G12C-mutant, previously treated advanced colorectal cancer: Amgen's Lumakras (sotorasib) combined with its EGFR inhibitor Vectibix (panitumumab) and Bristol Myers Squibb's Krazati (adagrasib) plus Eli Lilly's EGFR inhibitor Erbitux (cetuximab). There are currently no approved KRAS inhibitors for pancreatic cancer, but both Amgen and BMS are exploring their drugs in this setting and both drugs are already included in National Comprehensive Cancer Network guidelines as an option for KRAS G12C-mutant advanced pancreatic cancer.
The researchers analyzed two datasets to evaluate the genetic landscape of candidate primary resistance alterations to KRAS G12C inhibition, including Guardant Health's national cohort of comprehensive genomic profiling results from patients who have been evaluated on its Guardant360 liquid biopsy assay and a cohort of patients from the Mayo Clinic who were also tested with the Guardant360 assay.
The Guardant Health cohort included 13,603 patients with colorectal cancer and 5,016 patients with pancreatic cancer. In the colorectal cancer group, 3.3 percent of patients had only KRAS G12C mutations, while 2.8 percent had KRAS G12C mutations alongside primary resistance mutations. The pancreatic cancer group had a lower rate of resistance alterations, with 3.4 percent harboring just a KRAS G12C mutation compared to 0.7 percent harboring a KRAS G12C mutation and a primary resistance alteration.
The most frequently co-occurring resistance mutations in the KRAS G12C-mutant colorectal cancer group were other KRAS alterations in 35.4 percent, EGFR amplifications in 22.2 percent, PIK3CA alterations in 11.3 percent, and BRAF alterations in 9.7 percent of patients.
The researchers found similar co-occurring resistance alterations in the KRAS G12C-mutant pancreatic cancer group. About half, 52.6 percent, of patients harbored other KRAS alterations, 17.5 percent had co-occurring PIK3CA alterations, and 10.5 percent had co-occurring EGFR amplifications.
This proportion of baseline resistance alterations may explain the lower efficacy of single-agent KRAS G12C inhibitors relative to other targeted therapies. With response rates around 30 percent in colorectal cancer trials of Lumakras and Krazati and primary resistance mutations occurring in up to 40 percent of KRAS-mutant patients in this study, the researchers concluded in their paper that "non-responders in these trials may, in part, be explained by the potential presence of these [primary resistance] alterations at baseline."
"We found that up to 40 percent of patients, before they even receive the KRAS G12C inhibitors, already have acquired the resistant molecular aberrations," Xie said. "If they already have resistant genetic aberrations in their cancer before they even receive the drug, then we might want to be very careful about who we treat with the drug or maybe consider some alternative drugs that they can benefit from more."
The Mayo Clinic cohort, which included 741 patients with colorectal cancer and 422 patients with pancreatic cancer, demonstrated similar rates to the Guardant cohort of co-occurring candidate resistance alterations in KRAS, EGFR, and BRAF in both groups. The Mayo Clinic cohort also contained a subset of patients with MYC amplifications, and researchers flagged this as a candidate resistance alteration in the KRAS G12C-mutant colorectal and pancreatic cohorts, occurring in 8.1 percent and 25 percent of these patients, respectively.
The Mayo Clinic cohort also included treatment and outcomes data, which the researchers analyzed to evaluate whether the resistance mutations had an effect on treatment efficacy.
Across all treatments, overall survival was worse in the group of pancreatic cancer patients with a KRAS G12C mutation and another primary resistance mutation than those with just a KRAS G12C mutation. The group with co-occurring resistance mutations had a median overall survival of 4 months compared to 22 months for those with a KRAS G12C mutation alone. Among patients without a KRAS G12C mutation, median overall survival was 25 months.
In the colorectal cancer group, median overall survival for those with only a KRAS G12C mutation was 21.9 months compared to 30 months for those with co-occurring alterations. Those without KRAS G12C mutations, again, fared best, with a median overall survival of 48.8 months.
Only eight KRAS G12C-mutant colorectal and pancreatic cancer patients in the Mayo Clinic dataset received a KRAS G12C inhibitor due to the time period selected for analysis, between January 2016 and June 2023, occurring before any KRAS G12C inhibitor was approved in these settings. Six of those patients were evaluable for response, five of whom had a confirmed response to KRAS G12C targeted therapy. The one patient who did not respond to the treatment had co-occurring mutations in PIK3CA and BRAF at baseline, which suggests potential primary resistance to the KRAS G12C inhibitor.
Xie noted that this research can help biopharma sponsors refine drug development strategies with potential targets for combination regimens with KRAS G12C inhibitors. He also said it supports the need for improved patient selection for these treatments.
"All the potential resistance aberrations are already part of the [Guardant360] panel [used at the Mayo Clinic]," Xie said. "We do routine liquid biopsy on patients with metastatic pancreas and colorectal cancer, and we potentially repeat the testing at the time of cancer progression. Therefore, I would encourage other community oncologists to do the same because that will help with matching patients to these treatments, to clinical trials, and potentially to better therapies in the future."
Xie and his colleagues hope to continue exploring and validating this research. He said his team has already begun validating these findings in tumor models and is aiming to identify novel therapies or combination strategies with KRAS G12C inhibitors for future clinical trials.