Regorafenib/Pembrolizumab Combo Suggests Provocative OS Despite Missing PFS End Point in MSSCRC


Results from a large trial evaluating the combination of pembrolizumab and regorafenib showed durable results for patients with microsatellite stable colorectal cancer.

Findings from the largest trial (NCT03657641) evaluating the combination of pembrolizumab (Keytruda) and regorafenib (Stivarga) in patients with microsatellite stable colorectal cancer (MSSCRC) demonstrated a significant median overall survival (OS) and duration of disease control, despite missing the trial’s prespecified progression-free survival (PFS) end point, according to Afsaneh Barzi, MD, PhD, during the 2022 Gastrointestinal Cancers Symposium.1

With a median follow-up of 8.1 months, the median PFS was 2.0 months (95% CI, 1.8-3.5). This did not meet the prespecified PFS of 2.85 months; however, investigators reported that the median OS was 9.6 months (95% CI, 4.5-15.0).

“Although we did not have any patients who responded to therapy, 49% of the patients had stable disease, with a median duration of stable disease of 2.9 months [95% CI, 0.2-18.8],” said Barzi, associate professor, Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California.

Despite the presence of a hostile immune microenvironment in CRC, data from preclinical and clinical studies suggest that antiangiogenic therapy can result in immune reconstitution in the tumor microenvironment.2,3 The combination of regorafenib and pembrolizumab is a reasonable approach in treating patients with MSSCRC.

The single arm, open label study consisted of 2 parts: phase I and phase II. Phase I used a standard 3 × 3 design with regorafenib given in 80 mg, 120 mg, and 160 mg doses for 14 out of 21 days. Pembrolizumab was given at 200 mg every 3 weeks. The phase II portion delivered regorafenib at 80 mg for 14 out of 21 days and pembrolizumab at 200 mg every 3 weeks.

The primary end point in phase I was identifying the recommended phase II dose of regorafenib. In phase II, the primary end point was PFS. Secondary end points for both phases were OS and objective response rate (ORR). The study was powered to show an improvement in PFS from 1.9 months to 2.85 months. Eligible patients were naïve to regorafenib and immune checkpoint inhibitors and had to have an ECOG performance status of 0 to 1.

Patient accrual was completed in July 2021, and at the time of analysis, 74 patients were enrolled, of whom 73 patients were eligible. As of December 2021, 9 patients were still on treatment, said Barzi.

There were 70 patients in the recommended phase II dose population (RP2D). The median age was 54 years (range, 23-81) and 51% were female. The majority (53%) of patients were White and 21% were Asian, 12% were Black, and 11% were Hispanic. Seventy-one percent had a RAS mutation and the median lines of therapy were 2 (range, 1-5). Eighty-two percent had undergone surgery, and 32% received radiotherapy. Barzi also noted that patients had a heavy burden of disease, with more than 75% of patients having disease in more than 2 organs.

Regarding safety, 44% of patients experienced grade 3 and 4 toxicities, and the most common adverse events (AEs) of any grade affecting the skin were hand-foot syndrome (23 patients), rash (12 patients), and pruritus (11 patients). There were no unexpected safety signals in this population.

Post hoc subgroup analysis revealed that patients with no liver metastases and those treated with prior radiotherapy achieved longer PFS. “Although the lack of liver metastases as a predictor of better PFS in this population has been previously reported,” Barzi said, “prior radiotherapy has stood out to be something unique that we observed.”

In the population of patients who received prior radiotherapy, the median PFS was 4.4 months as compared with 1.8 months in the patients who did not receive prior radiotherapy. Similarly, the median OS in this subgroup was not reached compared with 5.6 months in patients who did not receive prior radiotherapy.

“It is important to assert that these are post hoc analyses and the results should be looked at with the caveat that it may not be accurate,” Barzi cautioned.

Ongoing studies are looking at biomarkers in this patient population to identify the subgroup of patients who can potentially benefit from these treatments.


1. Barzi A, Azad NS, Yang Y, et al. Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC). J Clin Oncol. 2022;40(suppl 4):15-15. doi: 10.1200/JCO.2022.40.4_suppl.015

2. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res. 2007;13(5):1472-1479. doi:10.1158/1078-0432.CCR-06-2073

3. Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109(43):17561-17566. doi:10.1073/pnas.1215397109

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