Skip to main content
Premium Trial:

Request an Annual Quote

Frontline KRAS G12C Combinations in NSCLC Offer Hope of Improving Upon Monotherapy

lung cancer 1

NEW YORK – Researchers are betting that KRAS G12C inhibitors, when combined with chemotherapy, immunotherapy, or another targeted agent, will yield greater benefits for non-small cell lung cancer patients and eventually become an option in earlier lines of treatment.

At the American Society of Clinical Oncology's annual meeting this weekend, investigators presented data on several combination treatment approaches in NSCLC involving different KRAS G12C inhibitors, including Amgen's Lumakras (sotorasib) with chemotherapy, Eli Lilly's olomorasib with Merck's checkpoint inhibitor Keytruda (pembrolizumab), and GenFleet Therapeutics' fulzerasib with Eli Lilly's EGFR inhibitor Erbitux (cetuximab).

Overall, these combination approaches demonstrated promising efficacy, producing better outcomes in patients than when these KRAS G12C inhibitors are given on their own to NSCLC patients. The data also suggested that next-generation investigational KRAS G12C inhibitors, like olomorasib and fulzerasib, may be more potent and better tolerated than the first-generation Lumakras, said Adrian Sacher, staff medical oncologist in the thoracic and genitourinary groups at Princess Margaret Cancer Center in Toronto, in a discussion of the three combination studies.

"We're increasingly seeing that first-in-class may not be best-in-class [in the KRAS G12C inhibitor setting]," Sacher said. "Existing KRAS G12C inhibitor monotherapy provides modest clinical benefit in the later line setting in KRAS G12C-mutant metastatic NSCLC. However, newer agents may be superior in this setting."

Currently, Lumakras is approved in the US and Europe as a monotherapy for previously treated, locally advanced, or metastatic KRAS G12C-mutant NSCLC. Bristol Myers Squibb's Krazati (adagrasib) is also approved as a monotherapy in this setting in the US and Europe. There are no KRAS G12C inhibitors approved yet in the first-line NSCLC setting.

Sacher likened the race to bring KRAS G12C inhibitors to market to the "Wild West," since in the space of a few years, KRAS has gone from a notoriously undruggable target to one of the most active and competitive areas of drug development.

While at the meeting researchers presented promising data on KRAS combination therapy approaches, with response rates ranging from 65 percent to 81 percent, Sacher still urged the research community to conduct the necessary head-to-head trials that will help oncologists determine the most effective approaches, assess biomarkers for identifying best responders and improving management of toxicities, and find the optimal sequence of these combination treatments that will benefit patients most.

"Optimized KRAS G12C inhibitor monotherapy and combinations will inevitably revolutionize treatment for our patients," he continued. "However, I fear that oncologists and regulators may quickly find themselves struggling to reconcile multiple competing drugs and strategies [in the KRAS space], all with promising nonrandomized data. What we really need in this setting are thoughtful randomized studies and biomarkers."

Enhancing efficacy with chemo

In the Phase Ib CodeBreaK-101 trial, researchers evaluated Lumakras plus carboplatin and pemetrexed in the first-line and second-line setting for KRAS G12C-mutant advanced NSCLC.

Out of 37 patients who received Lumakras plus chemo as a first-line treatment, 65 percent responded, and all patients experienced disease control. The median duration of response was 9.1 months, and median progression-free survival was 10.8 months.

In the 21-patient second-line treatment cohort, the objective response rate was 42 percent, and the disease control rate was 84 percent. Median progression-free survival in this group was 8.3 months, but duration of response was not evaluable due to the small size.

By comparison, in the Phase II trial that supported Lumakras' monotherapy approval in previously treated NSCLC, the response rate was 37 percent and median progression-free survival was 6.8 months.

CodeBreaK-101 is already a biomarker-directed trial in that patients had to have KRAS G12C mutations to be eligible, but researchers also explored the impact of another biomarker: PD-L1 expression. The subgroup of interest were patients with PD-L1-negative tumors, who need more treatment options, according to Bob Li, medical oncologist at Memorial Sloan Kettering Cancer Center who presented the CodeBreaK-101 results. In this group with less than 1 percent of tumor cells with PD-L1 expression, the median progression-free survival in the first-line setting was 11.9 months, slightly higher than what was seen in the overall cohort.

Overall survival data in both the first- and second-line cohorts were immature at the time of the ASCO presentation, Li said. However, he noted that the latest data should spur larger studies of this Lumakras-chemo combination "as a potential new first-line therapy in this patient population."

Toward this end, the Phase III CodeBreaK-202 trial is already open for recruitment, Li said. This trial will evaluate first-line treatment with Lumakras plus doublet chemo followed by maintenance Lumakras plus single-agent chemo and compare that to Keytruda with doublet chemo followed by maintenance Keytruda with single-agent chemo. Researchers will enroll 750 patients with advanced KRAS G12C-mutant, PD-L1-negative NSCLC.

Sacher, who was not involved with the CodeBreaK-101 study, found the response rate and progression-free survival results encouraging. "We do need a confirmatory study of this regimen, though there is significant potential for this approach as a first-line treatment in groups that do not benefit from PD-1 and PD-L1 inhibitors, including PD-L1-negative patients … and other patients with unfavorable co-mutations such as [in] STK11 or KEAP1," Sacher said.

Encouraging toxicity profile with immunotherapy

In the Phase I/II LOXO-RAS-20001 trial, Eli Lilly is evaluating the activity of its second-generation KRAS G12C inhibitor olomorasib on its own and in combination with other drugs in different solid tumor and across various lines of treatment.

At ASCO, researchers presented data from two cohorts in this trial involving patients with KRAS G12C-mutant advanced NSCLC, who received olomorasib and the immunotherapy Keytruda in either the first-line setting or in the second- or later-line. The efficacy results included data from 60 patients, 17 of whom were receiving the combination as their first-line treatment for metastatic disease.

In the first-line treatment cohort, the objective response rate was 77 percent, and the disease control rate was 88 percent on olomorasib-Keytruda. Timothy Burns, associate professor of medicine at the University of Pittsburgh School of Medicine, said while presenting the results at the meeting that these responses occurred in tumors with different PD-L1 expression thresholds, including in PD-L1-negative tumors.

Median progression-free survival in the first-line setting was not reached at a median follow-up of 5.5 months. The six-month progression-free survival rate was 72.8 percent.

Previously treated patients who received olomorasib with Keytruda in the second-line or later settings had a response rate of 40 percent and a disease control rate of 81 percent. Again, responses were seen across PD-L1 expression levels.

In previously treated patients, Burns specifically highlighted the incidence of treatment-related liver toxicity with olomorasib-Keytruda. This toxicity, measured by increases in the liver enzymes AST and ALT, has been seen with KRAS G12C inhibitor and checkpoint inhibitor combinations. Specifically, in one study of Lumakras plus Keytruda, 88 percent of patients who received the regimen within six weeks of each other experienced grade 3 hepatotoxicity.

In the olomorasib-Keytruda trial, however, only 6 percent of patients had grade 3 ALT increase and 8 percent experienced grade 3 AST increase. Burns added that these liver enzyme increases lasted a short time, and the patients were able to continue on the trial with a dose modification or the addition of corticosteroids.

Sacher was also encouraged to see that the hepatotoxicity rates appeared manageable. "Combination strategies really do represent an attractive approach to attempt to enhance benefit," Sacher said. "However, toxicity has been a key stumbling block here, especially with respect to PD-1 and KRAS G12C inhibitor combinations."

He noted that prior attempts to combine Lumakras with Keytruda resulted in patients experiencing intolerable hepatotoxicity early in the course of treatment. "In contrast, a similar combination of olomorasib and pembrolizumab did not encounter the same degree of hepatotoxicity," he noted.

Dual targeted approach

In a third study, the Phase II KROCUS trial, researchers evaluated yet another KRAS combination strategy in first-line NSCLC: GenFleet's second-generation KRAS G12C inhibitor fulzerasib with the EGFR inhibitor Erbitux.

The KROCUS trial enrolled 40 treatment-naïve patients with KRAS G12C-mutant advanced NSCLC. Of 33 patients evaluable for response, 81.8 percent responded to the fulzerasib-Erbitux combo, with one patient having a complete response. Among 13 patients with brain metastases, 70 percent responded. All patients in the trial experienced disease control, Vanesa Gregorc, director of the medical oncology department at Candiolo Cancer Institute in Italy, said while presenting the results at the meeting.

"In the majority of patients, there were very deep responses, with more than 50 percent reduction in tumor size," Gregorc added.

In a biomarker analysis within this study, researchers observed responses in patients regardless of their baseline PD-L1 and EGFR expression levels. Although STK11 and KEAP1 mutations are common resistance biomarkers in patients treated with KRAS G12C inhibitors, in 20 patients with these mutations, responses did differ compared to patients who didn't have these mutations, Gregorc noted, adding that no resistance mechanisms to this combination regimen have been identified yet.

Sacher noted that this study "diverged sharply" from the standard first-line approach in this setting by not including either chemo or immunotherapy. While this trial yielded positive data, he cautioned that testing a treatment without the standard of care can harm patients.

Gregorc explained that the rationale behind testing the fulzerasib-Erbitux combo in the first-line was based on both preclinical data of these two drugs and evidence from studies in later lines of treatment combining other KRAS G12C and EGFR inhibitors. Gregorc noted that downregulation of the MIG6 gene due to KRAS inhibitors can lead to upregulation in the EGFR pathway. Inhibiting both targets was thought to lead to greater efficacy, which the preclinical models of fulzerasib-Erbitux confirmed. She added that GenFleet is planning a Phase III trial to confirm these findings in a larger population.

"A randomized first-line study with careful attention to PD-1, PD-L1 refractory subsets, like PD-L1-negative and KEAP1 and STK11 co-mutation patients, will be important," Sacher said, adding that this combination regimen may also work in later lines and in patients with acquired resistance to KRAS G12C inhibitors.