Is dual immunotherapy needed in first-line treatment of microsatellite instability (MSI)-high metastatic colorectal cancer?

In microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient metastatic colorectal cancer (CRC), first-line treatment with immunotherapy with pembrolizumab is now the standard of care (1). Pembrolizumab, a programmed death 1 (PD-1) inhibitor, versus chemotherapy demonstrated a median progression-free survival (PFS) of 16.5 months versus 8.2 months, respectively (P=0.0002), and the median overall survival (OS) with pembrolizumab was not reached (1). Despite improved survival, more patients had progressive disease as best response with pembrolizumab (29.4%) than with chemotherapy (12.3%), suggesting resistance in a subset of patients (1). The mechanism of resistance in the cohort of patients who did not have a response to single-agent PD-1 blockade is not clear, however, it is possible that combinations with chemotherapy or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors to PD-1 blockade may result in improved responses by overcoming resistance, and thus, survival. There is promise that dual checkpoint blockade with the addition of CTLA-4 inhibitor to anti-programmed death ligand-1 (PD-L1)/PD-1 inhibitor may result in improved survival, however, at what cost to toxicity and quality of life?

In CheckMate 142 Study, Lenz et al. present the efficacy and safety of first-line dual immunotherapy with nivolumab (PD-1 inhibitor) plus low-dose ipilimumab (CTLA-4 inhibitor) in MSI-high/MMR-deficient metastatic CRC (2). This phase 2, multi-cohort study included patients who were untreated and previously treated (2). In this study, those enrolled onto the first-line cohort received nivolumab 3 mg/kg once every 2 weeks and low-dose ipilimumab 1 mg/kg once every 6 weeks (2). Of the 45 patients, median age was 66 (range, 21–85) years (2). BRAF mutations were in 38%, and KRAS mutations were in 22% of patients (2). Thirty patients discontinued treatments (2). Disease progression (18%) was the most common cause of discontinuation, followed by maximum clinical benefit (13%), adverse events (AEs) related to study drug (11%), patient request to discontinuation (9%), and lost to follow-up (2%) (2). Eleven patients went on to receive subsequent therapies, whereas 19 patients did not receive subsequent therapies (2).

The primary endpoint was objective response rate (ORR). ORR was 69% (75% in patients with BRAF mutations and 80% in patients with KRAS mutations) (2). Other RAS mutations or HER2 aberrations were not reported. Complete response (CR) rate was 13% (2). Median time to response was 2.7 months; median duration of response (DOR) was not reached (2). Median OS was not reached, and the 12-month OS rate was 84.1% [95% confidence interval (CI): 69.5 to 92.1], 18-month OS rate was 81.7% (95% CI: 66.8 to 90.4), and 24-month was OS rate: 79.4% (95% CI: 64.1 to 88.7) (2). Eighty percent patients had AEs, of which 22% were grade 3 or higher AEs (2). Additionally, quality of life remained stable over the treatment period based on EORTC QLQ-C30 and EQ-5D questionnaires (2). Although this study enrolled a smaller cohort of patients compared to the pivotal KEYNOTE-177 trial, which led to FDA-approval of front-line pembrolizumab in MSI-high metastatic CRC, similar toxicity outcomes, percentage of total AEs and grade 3 or higher AEs, were reported with pembrolizumab monotherapy (1).

The outcomes of the study demonstrate that dual immunotherapy shows promise, especially in regard to the CR, survival, and disease control rates (Table 1). Further, in subgroups of BRAF and KRAS mutations, which have traditionally poor outcomes to chemotherapy, the median PFS was not reached. ORR (69%) were higher with ipilimumab/nivolumab than those reported with pembrolizumab (11.1%) and chemotherapy (3.9%), which may be attributable to the resistance to anti-PD-1 monotherapy that is overcome by CTLA-4 inhibition (1,2). However, the limitations of this study include that it was a single cohort study without a comparator arm with a small sample size, which may have less impressive outcomes in a larger, randomized controlled study. In the previously treated cohort, patients who had received prior treatment with a PD-1 inhibitor, a PD-L1/PD-L2 inhibitor, a CTLA-4 inhibitor, or any other agents targeting the T-cell co-stimulation or immune checkpoint pathways were excluded (4). This cohort had ORR was 65%, and 48-month rates of PFS and OS were 53% and 71%, respectively, suggesting that dual checkpoint blockade has efficacy in later lines after chemotherapy, but the efficacy of dual checkpoint inhibition after progression on first-line PD-1 inhibitors is not clear (4).

Historically, there has been clinical concern about increased toxicity with the addition of anti-CTLA-4 inhibitors. Therefore, the investigators chose to study less frequent, lower dose of ipilimumab, which showed better tolerability. The combination was tolerated in the first-line setting versus the second-line setting (grade 3/4 treatment-related AEs were 22% versus 32%, respectively) (2). Further, the grade 3/4 AEs appear to be similar to that seen with single agent immunotherapy in Keynote-177 (pembrolizumab 22% versus chemotherapy 66%) (1). Additionally, nivolumab with low-dose ipilimumab show stability of quality of life during treatment, which is challenging to interpret in a single-arm study (2). Pembrolizumab resulted in a clinically meaningful improvement in EORTC QLQ-C30 global health status/quality of life versus chemotherapy (3).

In summary, dual immunotherapy with nivolumab and low-dose ipilimumab showed clinical benefit with a manageable safety profile and sustained quality of life in the first-line setting to treat MSI-high metastatic CRC. We still need long-term survival data and confirming efficacy of dual checkpoint blockade in a randomized controlled trial, which is underway (NCT04008030). There are numerous studies evaluating novel immunotherapeutic agents in mCRC (5), including several phase 2 and 3 studies currently enrolling (Table 2). Further, the future landscape of dual checkpoint inhibition especially in the neoadjuvant setting of locally advanced CRC and metastatic CRC is exciting given the ORR, the tolerability, and the ability to downstage metastatic CRC or convert metastatic CRC to resectability, and therefore, ultimately cure.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1426/coif). SPA reports that she is on the speaker’s bureau for Exelixis, Bayer, Bristol-Meyers Squibb, and advisory board for Seagen, AstraZeneca, QED Therapeutics and Exelixis, and she serves as an unpaid board member of Young SIOG and Support New India and unpaid editorial board member of Annals of Palliative Medicine from June 2022 to May 2024. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

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