The IMHOTEP trial recently showcased significant advancements in treating localized colorectal cancer (CRC) with a specific molecular signature. This study explored the role of perioperative pembrolizumab in patients presenting with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). These tumors are known for generating highly immunogenic neoantigens, making them ideal targets for immunotherapy. Consequently, researchers investigated if using pembrolizumab before and after surgery could improve clinical outcomes.

Efficacy of Perioperative Pembrolizumab

The primary goal of the IMHOTEP trial was to assess the pathologic complete response (pCR) rate. Among the 72 evaluable patients, 52.7% achieved a pCR. Furthermore, the researchers observed a notable trend regarding the number of treatment cycles. For instance, the pCR rate rose from 46% after a single cycle to 68.2% after two cycles. This finding suggests that a longer neoadjuvant phase might yield better pathological outcomes. Therefore, clinicians might consider individualizing the duration of therapy based on early response markers.

Safety remained a crucial secondary objective throughout the trial. Most patients tolerated the regimen well. However, 15.7% experienced grade 3 or higher immune-related toxicities. One patient unfortunately suffered a grade 5 myasthenia event. In contrast, the majority of adverse events were manageable. Despite these risks, the study confirms that neoadjuvant immunotherapy is a feasible approach for localized dMMR/MSI CRC.

Clinical Implications for Oncology

This prospective study is pioneering because it demonstrates the safety and feasibility of a perioperative approach. In the past, surgery was the primary standard of care. Now, the introduction of neoadjuvant immunotherapy offers a chance to eliminate the tumor before the surgeon even operates. Additionally, the high pCR rates might eventually lead to organ-sparing strategies for certain patients.

Frequently Asked Questions

What is the pCR rate seen in the IMHOTEP trial?

The trial reported a pathologic complete response (pCR) rate of 52.7% in the efficacy population of patients with localized dMMR/MSI colorectal cancer.

How did the number of pembrolizumab cycles affect the results?

A post hoc analysis showed that the pCR rate increased significantly from 46% after one cycle to 68.2% after two cycles of neoadjuvant therapy.

What were the main safety concerns identified?

Grade 3 or higher immune-related toxicities occurred in 15.7% of participants, including one case of fatal myasthenia.

Disclaimer: This content is for informational and educational purposes only. It does not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified healthcare provider with any questions you may have regarding a medical condition. Refer to the latest local and national guidelines for clinical practice.

References

de la Fouchardière C et al. Efficacy of Perioperative Pembrolizumab in Mismatch Repair Deficient/Microsatellite Unstable Localized Colorectal Cancers: Results of the Phase II Trial IMHOTEP. J Clin Oncol. 2026 Apr 14. doi: 10.1200/JCO-25-02169. PMID: 41980235.

de la Fouchardière C et al. Assessment of pathologic response in the colorectal cancer cohort of the IMHOTEP phase II trial of neoadjuvant pembrolizumab in dMMR/MSI tumors. J Clin Oncol. 2025 Jan 27;43(3_suppl):241-241. doi: 10.1200/JCO.2025.43.3_suppl.241.