Rona Yaeger, MD, is an associate attending physician, gastrointestinal medical oncologist, and early drug development specialist at the Memorial Sloan Kettering Cancer Center in New York.

Rona Yaeger, MD, details the efficacy of adagrasib/cetuximab in heavily pretreated patients with KRAS G12C–mutant mCRC.

Dr Yaeger on the Efficacy of Adagrasib/Cetuximab in KRAS G12C+ mCRC

“The combined population [was] 94 patients, and the objective response rate by blinded independent [central] review was 34% and by investigator review was 43%—the responses were durable.”

Rona Yaeger, MD, associate attending physician, gastrointestinal medical oncologist, early drug development specialist, Memorial Sloan Kettering Cancer Center, details the efficacy of adagrasib (Krazati) plus cetuximab (Erbitux) in heavily pretreated patients with 

G12C–mutant metastatic colorectal cancer (mCRC).

 showed that among patients from the subgroup analysis treated with adagrasib/cetuximab (n = 94), the overall response rate (ORR) was 34% (95% CI, 25%-45%) per blinded independent central review (BICR) and 43% (95% CI, 32%-53%) per investigator assessment.

accelerated approval to adagrasib plus cetuximab

G12C–mutant locally advanced or mCRC who received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

In the open-label, nonrandomized, multi-cohort KRYSTAL-1 study, the best overall response per BICR and investigator review included complete response (0%; 0%), partial response (34%; 43%), stable disease (51%; 44%), progressive disease (6%; 5%), and not evaluable (9%; 9%). Of note, the disease control rate was 85% (95% CI, 76%-92%) and 86% (95% CI, 78%-92%) per BICR and investigator review, respectively. The median duration of response was 5.8 months (95% CI, 4.2-8.5) and 5.9 (95% CI, 5.5-7.6) per BICR and investigator review, respectively. In the subgroup analysis of ORR per BICR, which included patients from the overall adagrasib/cetuximab cohort, the ORR was 37% (95% CI, 25%-50%) in patients 65 years of age or younger vs 29% (95% CI, 14%-48%) in patients 65 years of age or older. 

The median progression-free survival (PFS) was 6.9 months (95% CI, 5.6-7.4; 95% CI, 5.9-7.4) per both BICR and investigator review, respectively. Specifically, the 6- and 12-month PFS rates were 57% and 19%, respectively, per BICR; these rates were 61% and 19% per investigator review. The median overall survival (OS) in the population was 16 months (95% CI, 13.3-18.8), of which the 6- and 12-month OS rates per BlCR and investigator review were 88% and 66%, respectively.

Videos

Rona Yaeger, MD, discusses the implications of data with second-line sotorasib plus panitumumab in KRAS G12C–mutated metastatic colorectal cancer.

Dr Yaeger on the Implications of Data With Second-Line Sotorasib Plus Panitumumab in mCRC

Rona Yaeger, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, discusses the future implications of findings from an expansion cohort study of sotorasib (Lumakras) plus panitumumab (Vectibix) in the second-line setting patients with 

 G12C–mutated metastatic colorectal cancer (mCRC).

The expansion cohort study was based on findings from the phase 1b/2 CodeBreaK 101 trial (NCT04185883), in which sotorasib plus panitumumab elicited an overall response rate (ORR) of 30% when administered as second-line therapy.

 showed that the combination elicited an observed ORR of 30% (n = 20; 95% CI, 11.9%-54.3%), comprised entirely of partial responses. Moreover, the regimen's adverse effect profile in this cohort study was comparable to safety data from prior studies of these agents.

Yaegar states that one of the most exciting findings in the study was the extended median progression-free survival (PFS) of 8.3 months (95% CI, 4.3-14.1), which may be attributed to the fact that patients were treated in the second-line setting. This finding indicates that initiating treatment earlier in the disease course could lead to longer-lasting responses before the tumor develops resistance to multiple therapies, even if response rates in the second-line setting are similar to those observed in later lines of therapy, Yaeger explains.

As of the end of 2023, KRAS G12C–targeted therapy has been incorporated into the National Comprehensive Cancer Network guidelines for CRC, Yaeger continues. The guidelines now include sotorasib, panitumumab, adagrasib (Krazati), and cetuximab (Erbitux) as recommended treatment options. There is hope that these drugs will receive regulatory approval in this indication, further expanding the therapeutic options available in CRC, she states.

Several new KRAS G12C inhibitors are also progressing through clinical development with promising data, offering the potential for additional treatment choices within the CRC treatment paradigm, Yaeger adds. However, the optimal sequencing of these agents remains unknown, highlighting the need for further research to determine the most effective treatment strategies for targeting 

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing

referapatient@mskcc.org, or by calling 833-315-2722.

Rona Yaeger, MD, discusses the rationale for launching an expansion cohort study based on findings from the CodeBreaK 101 study.

Dr Yaeger on Outcomes of the CodeBreaK 101 Trial in mCRC

Rona Yaeger, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, discusses the rationale for launching an expansion cohort study based on findings from the phase 1b/2 CodeBreaK 101 trial (NCT04185883) of sotorasib (Lumakras) plus panitumumab (Vectibix) in patients with metastatic colorectal cancer (mCRC), highlights the characteristics of the specific patient population that was evaluated, 

This expansion cohort study extends the findings from the CodeBreaK 101 trial, which demonstrated promising activity with the combination of sotorasib and panitumumab in patients with mCRC, Yaeger begins. Focused on a defined second-line setting, the study enrolled 20 patients and assessed the safety and activity of this combination in a population that had not been heavily treated with later lines of therapy, she says. Most patients in this study had received no more than 1 prior treatment for metastatic disease, and the study focused on those with 

 G12C–mutated mCRC, Yaeger explains. The combination elicited an observed overall response rate of 30% (95% CI, 11.9%-54.3%). All 6 responders achieved a partial response, she notes.

The median progression-free survival reached 11.0 months (95% CI, 4.3-14.3), and the safety profile was favorable, Yaeger expands. Although some patients required dose reductions of panitumumab, none had to discontinue treatment. The adverse effects associated with the combination in this cohort study aligned with those reported in prior studies of both agents, she highlights.

The study's emphasis on second-line patients provides valuable insights into the safety and efficacy of the sotorasib and panitumumab combination in a specific clinical setting, Yaeger continues. The overall tolerability of these targeted therapy combinations is encouraging, and the observed toxicities, primarily related to the EGFR antibody, are manageable with established strategies, such as prophylaxis for skin rash, as well as behavioral modifications, she explains. This study contributes to the ongoing exploration of targeted therapies in CRC, laying the groundwork for potential advancements in treatment strategies, Yaeger concludes.

Clinicians referring a patient to MSK can do so by visiting 

, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Rona Yaeger, MD

Articles

Dr Yaeger on the Efficacy of Adagrasib/Cetuximab in KRAS G12C+ mCRC

Dr Yaeger on the Implications of Data With Second-Line Sotorasib Plus Panitumumab in mCRC

Dr Yaeger on the Background of the CodeBreaK 101 Trial in mCRC