Raising the Bar for KRAS G12C+ Colorectal Cancer Treatment

“I just want to see my youngest daughter graduate.”

This is the first thing my patient told me when we met to discuss her diagnosis of recurrent colon cancer. She had just celebrated her 10th year being cancer-free after being treated for oligometastatic disease to the liver. Now, cruelly, the cancer was back with diffuse involvement in her lungs and mesenteric lymph nodes.

When discussing a treatment plan we noted that next-generation sequencing harbored a KRAS G12C mutation. Historically, this molecular marker has portended a worse prognosis and an aggressive disease course.¹ Now, with 2 KRAS G12C inhibitors showing encouraging results in combination with anti-EGFR agents, there is a ray of hope for this population–a treatment that may offer patients such as mine the chance to make it to important milestones.

Forty percent of patients with metastatic colorectal cancer (CRC) have mutated KRAS, with KRAS G12C occurring in 2% to 4% of this group.² KRAS G12C–mutated patients have shorter overall survival by as much as 6 months in some studies^3,4 and reduced response to standard first-line therapies.⁴ These patients are also less likely to receive second- or third-line therapies.⁵

Adagrasib (Krazati) and sotorasib (Lumakras) are both irreversible inhibitors of mutant KRAS G12C that trap KRAS in the inactive GDP-bound state via binding the switch II pocket region, thus decreasing signaling through downstream pathways.^6,7 Both agents are FDA approved for the treatment of patients with KRAS G12C–mutated non-small cell lung cancer. Preclinical data have indicated that combining KRAS G12C inhibitors with anti-EGFR antibodies can improve antitumor activity in metastatic colorectal adenocarcinoma by mitigating RAS-MAPK activation that occurs via upregulation of EGFR activity.^8,9

The combinations of adagrasib and cetuximab (Erbitux) and sotorasib and panitumumab (Vectibix) show promising results in initial studies of small groups of heavily pretreated patients. In a cohort of the KRYSTAL-1 study, 32 patients with CRC were treated with adagrasib plus cetuximab, with 46% achieving a partial response (95% CI, 28%-66%) and 54% achieving stable disease (SD).¹⁰ Median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.1), and median overall survival was 13.4 months (95% CI, 9.5-20.1). Stating these data differently, no patients had progressive disease as their best overall response, which is quite remarkable. This is especially impressive when considered in context of traditional third-line therapies, regorafenib (Stivarga) and trifluridine-tipiracil (TAS-102; Lonsurf), which historically provide ORR of approximately 1%.^11,12 Based on these data, adagrasib in combination with cetuximab has received FDA breakthrough therapy designation in December 2022.

In an expansion cohort of the CodeBreaK 101 study, similarly positive results were seen. Forty refractory patients were treated with sotorasib and panitumumab, with an ORR of 30%.¹³ Sixty-three percent of patients had stable disease. Median PFS was 5.7 months, and median overall survival has not been reached with a median follow-up of 8.8 months.

Regarding toxicity, patients experienced the expected acneiform dermatitis with both cetuximab and panitumumab. Rates of grade 3/4 treatment-related adverse events were 16% with adagrasib and cetuximab and 23% with sotorasib and panitumumab, whereas 100% of patients experienced any-grade toxicities with adagrasib and cetuximab and 93% with sotorasib and panitumumab. Frequent toxicities of any-grade experienced with both combinations included nausea (62% with adagrasib/cetuximab and 33% with sotorasib/panitumumab), diarrhea (56% with adagrasib/cetuximab and 25% with sotorasib/panitumumab), and fatigue (47% and 15%, respectively). No patients on either study required discontinuation of the KRAS G12C inhibitor due to toxicities, although 5 patients discontinued cetuximab primarily due to infusion-related reactions.

It is tempting to compare these 2 combination regimens, despite inherent limitations in doing so. A key pharmacokinetic difference is adagrasib’s long half-life of 23 hours, compared to the 5.5-hour half-life of sotorasib. Whether this is related to the numerically higher ORRs and rates of certain toxicities with adagrasib and cetuximab is impossible to say. More data from ongoing studies will undoubtedly add to the discussion. The difference in anti-EGFR combination partner warrants mention as well—most notably that panitumumab is associated with a decreased risk of infusion-related reactions compared to cetuximab (which is particularly important for patient populations in regions of the country with high prevalence of alpha-gal antibodies, such as the Southeast).

However, the similarities between the 2 combinations are more important than the differences. KRYSTAL-1 and CodeBreaK 101 showed remarkable disease control rates of 100% and 93%, respectively, with the combinations in refractory populations, with median PFS data that surpass other options currently available.

Given these encouraging data, there are ongoing studies to further assess both combinations. We await results of trials such as CodeBreaK 300 (NCT05198934), which is evaluating sotorasib and panitumumab vs investigator’s choice of regorafenib or TAS-102 and KRYSTAL-10 (NCT 04793958) of adagrasib and cetuximab vs chemotherapy to guide when and how we employ these regimens in our treatment armamentarium.

I am thrilled that there are upcoming options for patients with KRAS G12C–mutated CRC that can produce better outcomes. In my practice at Sarah Cannon Research Institute at Tennessee Oncology, I will be prioritizing clinical trial enrollment for these patients early in their treatment course. In doing so, I hope that more patients, such as mine, can be there for those important life milestones.

Meredith Pelster, MD, MSCI, is assistant director of Gastrointestinal Research for Sarah Cannon Research Institute at Tennessee Oncology.

References

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