Christine Parseghian, MD, Examines Anti-EGFR Rechallenge With Panitumumab Plus/Minus Trametinib in Metastatic CRC

Results from a phase 2 study (NCT03087071) of anti-EFGR rechallenge therapy of panitumumab (Vectibix) with or without trametinib (Mekinist) in advanced RAS/BRAF wild-type colorectal cancer (CRC) were recently presented in a poster at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and showed that circulating tumor DNA–guided strategies lead to objective responses in 18% of patients without acquired resistance mutations.

Christine M. Parseghian, MD, assistant professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston and lead investigator of this study, spoke with CancerNetwork^® about each of the treatment arms examined in the study and how the selected regimens fared in terms of efficacy.

Results showed concurrent rechallenge with EGFR inhibition plus MEK inhibition was ineffective at overcoming anti-EGFR resistance mechanisms in advanced CRC. However, the results supported the efficacy of anti-EFGR rechallenge with panitumumab alone in those without resistance mutations, with response rates exceeding those seen with current third-line standard options.

CancerNetwork^®: What was the rationale for combining panitumumab with trametinib in advanced CRC?

Parseghian: This study looked at patients with CRC who had RAS/RAF wild-type status in their tissue and were previously treated with anti-EGFR therapy in the first- or second-line setting with a period of response prior to progression. We know that patients who progress on anti-EGFR do so [through] a mechanism by which they acquire RAS/RAF, MAP2K1, or EGFR ectodomain mutations. We know often this occurs through an upregulation of the MAPK pathway, and MEK is part of that MAPK pathway. The point of this study was to improve on findings from other studies, like CRICKET (NCT02296203) and CHRONOS (NCT03227926), that have shown anti-EGFR rechallenge alone can be successful with concurrent MEK inhibition.

How did you find this combination worked versus thesingle agent?

We looked at 3 cohorts. The first [Arm A] looked only at EGFR ectodomain mutations in the acquired setting. The second [Arm B] looked at patients with several different acquired mutations which we know are relevant in this population, those being KRAS, NRAS, BRAF, and MAP2K1. In that cohort, we gave them upfront the MEK inhibitor [trametinib] in combination with anti-EGFR therapy. The third [Arm C] were patients with no acquired mutations of interest, and those patients received panitumumab as a single agent, with the option to crossover to a MEK combination at rechallenge. The patients in Arm B who received the combination and who had the anti-EGFR resistant mechanisms did not overcome their resistance with the MEK combination. But we did see an almost 20% response rate in Arm C, which [comprised] those patients who did not have any acquired resistance mutations of interest. We did not see any improvement in outcomes with the addition of MEK inhibition upon progression, so our conclusion is that we likely need to shift gears away from MEK inhibition to potentially targeting EGFR and that MAPK pathway through other mechanisms, such as ERK inhibition in combination with anti-EGFR therapy.

Do you think this might be achieved by adding additional agents to this regimen or by examining a new regimen entirely?

Anti-EGFR therapy should be continued as multiple studies have now shown that rechallenge is successful in a subset of patients. That MAPK pathway can still be targeted, but we’re looking more downstream now at ERK inhibition, and combination regimens with ERK and EGFR targeted therapy. We have a few studies in that area to see if we can overcome that resistance.

Was there anything notable regarding the safety profile of these treatments among the 3 cohorts of patients?

In the trametinib and anti-EGFR cohort, or those patients who got the combination at any time, data showed that it was very toxic in terms of a rash; grade 3 acneiform eruptions were not uncommon. Thankfully, we do have a close collaboration with our dermatology colleagues and we were able to address those in a timely manner. But still, we were unable to maximize the dosing of the trametinib [due to these] skin toxicities. We are not seeing as much skin toxicity with some of our trials looking at ERK inhibitor combinations, so hopefully we will be able to bypass that.

Reference

Parseghian CM, Sanchez EV, Sun R, et al. Phase 2 study of anti-EGFR rechallenge therapy with panitumumab with or without trametinib in advanced colorectal cancer. J Clin Oncol. 2022;40(16) 3520. doi: 10.1200/JCO.2022.40.16_suppl.3520