KRAS G12C–Targeted Therapies May Move Earlier in the mCRC Treatment Sequence

Rona Yaeger, MD

The second-line safety and efficacy of the KRAS G12C inhibitor sotorasib (Lumakras) in combination with panitumumab (Vectibix) in patients with metastatic colorectal cancer (mCRC) underscores the importance of further exploring KRAS G12C–inhibitors in earlier lines of therapy, according to Rona Yaeger, MD.

Initial findings from a cohort study of the phase 1/2 CodeBreaK 101 trial (NCT04185883) demonstrated that sotorasib plus panitumumab, when administered as second-line therapy, elicited an overall response rate (ORR) of 30% (95% CI, 11.9%-54.3%), which is similar to that previously observed with the combination in a more chemorefractory KRAS G12C–mutated CRC population. At a median follow-up of 16.4 months (95% CI, 7.2-not evaluable), the median progression-free survival (PFS) was 11.0 months (95% CI, 4.3-14.3) with the second-line combination.¹

Moreover, the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Colon Cancer version 1.2024 recommend the use of sotorasib or adagrasib (Krazati) plus cetuximab (Erbitux) or panitumumab for patients with KRAS G12C–mutated disease in the second line and beyond.²

“It’s exciting that we’re seeing several KRAS G12C inhibitor combinations moving forward in CRC as new treatments that can [lead to tumor regression] in many patients and as a treatment that, in patients who received chemotherapy, is in many ways easier to tolerate,” Yaeger said in an interview with OncLive® during the 2024 Gastrointestinal Cancers Symposium.

In the interview, Yaeger, an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, discussed the rationale for investigating second-line sotorasib plus panitumumab in patients with KRAS G12C–mutated CRC, highlighted the implications of the findings from this trial, and noted how the expanding CRC treatment paradigm reveals remaining questions regarding treatment sequencing in this patient population.

OncLive: What was the rationale for the trial evaluating sotorasib in combination with panitumumab in patients with KRAS G12C–mutated CRC?

Yaeger: This is an expansion cohort [study] that builds off the activity seen in the phase 1b [CodeBreaK 101 trial] of the combination of sotorasib and panitumumab. This study is investigating the activity [of the combination] in the defined second-line setting [in] 20 patients.

There’s a lot of interest to bring these targeted therapies to earlier lines. It’s important to have these expansion [studies] where we can see the activity [of the agents] and [evaluate them in] a second-line population—[especially since] many of the patients treated in the phase 1b trial were heavily treated [with] later lines [of therapy].

What was the key objective of the study, and what patient population was included?

The patients in the study were meant to all be second-line patients. [Most] had received [no more than] 1 prior treatment for metastatic disease. [This trial enrolled those with] KRAS G12C–mutated mCRC. [We asked:] What is the safety and activity of the combination of sotorasib and panitumumab?

What efficacy and safety findings with the combination did this study reveal?

The combination was overall well tolerated. Among the 20 patients treated, the ORR was 30%, and [all 6 responders] had a PR. The median PFS was 11.0 months. The drugs were both well tolerated. [Some] patients needed dose reductions of panitumumab, but no patients needed to discontinue treatment. The adverse effects [(AEs) associated with the combination that we saw in this study] were in line with the AEs seen in prior studies of both agents.

These targeted therapy combinations are overall well tolerated. Most of the toxicities seen in these studies have been related to the EGFR antibody. We have experienced [those AEs as] a community treating patients with CRC, and [we know] how to modulate [those toxicities]. Some patients in the study received prophylaxis for skin rash, and [they] were advised, for example, to avoid the sun and do other behavioral changes to try to minimize rash and help with toxicity.

What does the future look like for KRAS G12C inhibition in mCRC?

At the end of 2023, KRAS G12C–targeted therapy was added to the NCCN guidelines for CRC. The NCCN guidelines include sotorasib and panitumumab, as well as adagrasib and cetuximab. I’m hopeful, as we look to the future, that these drugs will move forward, and hopefully we’ll have an approval.

Other new KRAS G12C inhibitors are also moving forward with encouraging data that may allow for another treatment option [in the CRC treatment paradigm]. The area of targeting KRAS is quite active. Many drugs are being tested, and there’s a potential for using these drugs in a smart way. We don’t know yet whether there’s a way to sequence them, so this is just the beginning of targeting KRAS.

What are the future implications of this research?

One of the most exciting findings in the study was that the median PFS was so long. That may be because the patients treated were in the second-line setting. As we treat patients earlier, we might be able to identify those who can respond longer before the tumor adapts to these multiple chemotherapies and multiple treatments and can become resistant quickly. There’s a hope that even if the [second-line] response rate [with sotorasib/panitumumab] is similar [to that in the third and later lines], patients will benefit longer [from receiving the combination earlier in the treatment sequence].

What biomarker testing barriers exist for patients with GI cancers?

Every patient with mCRC should have biomarker sequencing. At a minimum, there are markers we should check. All patients should be tested for either microsatellite instability or mismatch-repair deficiency, any RAS hotspot mutations, BRAF V600E, and HER2 amplification. We do this at Memorial Sloan Kettering Cancer Center with a single next-generation sequencing panel; I have seen that done in the community, as well. However, sometimes patients are tested with individual tests that are staggered, which is also fine.

It’s important to look for these markers, and especially as we’re starting to have matched therapies, it’s important for patients to know the molecular status of their tumors. It can be hard to get the results in time for early treatment decisions.

This is a second-line study. Most [CRC] drugs have been developed in the advanced setting [in patients who have received] multiple prior lines of therapy. However, studies are now [investigating therapies] in the first-line setting. It’s a little bit of a barrier to [not] have the molecular results early. Hopefully, if there’s a big turnaround time with the assay being used, there will be other ways, even circulating tumor DNA testing, to get a quick look at the molecular status of the tumor.

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

References

1. Yaeger R, Langer CJ, Ruffinelli JC, et al. A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer. J Clin Oncol. 2024;42(suppl 3):128. doi:10.1200/JCO.2024.42.3_suppl.128
2. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 1.2024. Accessed January 30, 2024. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf