Regorafenib Plus Ipilimumab and Nivolumab Shows Intriguing Activity in MSS mCRC

Regorafenib plus ipilimumab and nivolumab led to encouraging survival and responses in approximately half of patients with microsatellite stable, non–liver metastatic colorectal cancer who progressed on prior chemotherapy.

Marwan Fakih, MD

Marwan Fakih, MD

Regorafenib (Stivarga) plus ipilimumab (Yervoy) and nivolumab (Opdivo) led to encouraging survival and responses in approximately half of patients with microsatellite stable (MSS), non–liver metastatic colorectal cancer (mCRC) who progressed on prior chemotherapy, according to findings from a phase 1 trial (NCT04362839).

The triplet was evaluated in patients with MSS mCRC, and its activity was stratified by the presence and absence of liver metastases.

The median progression-free survival (PFS) and overall survival (OS) in the overall population (n = 29) was 4 months and 19.6 months, respectively. In patients without liver metastases (n = 22), the median PFS was 5 months, and the median OS was not reached. Patients with liver metastases (n = 7) had a median PFS and OS of 2 months and 7.3 months, respectively.

“Regorafenib, ipilimumab, [and] nivolumab is a novel regimen with clinical activity in non–liver metastatic MSS CRC,” Marwan Fakih, MD, lead study author and Judy & Bernard Briskin Distinguished Director of Clinical Research at City of Hope in Duarte, California, said.

“These data support further the investigation of this combination in MSS non–liver metastatic CRC.”

Prior research has shown that PD-1 inhibition with or without TKIs elicits clinically meaningful activity in patients with refractory MSS mCRC without liver metastases.

To be eligible for enrollment in the phase 1 study, patients needed to have a diagnosis of MSS mCRC that progressed after treatment with fluoropyrimidine (5-FU), oxaliplatin, irinotecan, and anti-EGFR therapy if RAS and BRAF wild-type with a left-sided primary colon tumor. Additional eligibility criteria stipulated that patients must have adequate hematologic and organ function, an ECOG performance status of 0 or 1, and no prior exposure to regorafenib or anti–PD-(L)1 antibodies.

The trial consisted of a dose-escalation (part 1; n = 9) and dose-expansion (part 2; n = 20) phase. In part 1, patients received 80 mg of regorafenib, with the option to de-escalate to 40 mg once daily plus 240 mg of nivolumab every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks. If no more than 1/6 of patients experienced a dose-limiting toxicity, patients proceeded to receive the same regimen in part 2.

The primary end point included the evaluation of safety and tolerability. Secondary end points included objective response rate (ORR), disease control rate (DCR), PFS per RECIST v1.1 criteria, and OS at the recommended phase 2 dose.

Baseline characteristics indicated that the median patient age was 55 years (range, 36-75). Most patients were White (72.4%; n = 21) and had a left sided primary tumor (69%; n = 20), a RAS mutation (69%; n = 20), and an ECOG performance status of 0 (n = 17).

The median tumor mutational burden was 3 (range, 1-11), and the median tumor proportion score for PD-L1 was 0 (range, 0-10). However, 9 and 19 patients were without TMB and PD-L1 data, respectively.

Regarding prior therapy, the median number of lines was 2 (range, 1-6). All patients had received prior 5-FU, oxaliplatin, and irinotecan. Most patients had received prior bevacizumab ([Avastin] 96.6%; n = 28). Few patients had received prior anti-EGFR therapy or trifluridine/tipiracil ([Lonsurf] 3.4%; n = 1).

Additional findings showed that the ORR among all patients was 31% (n = 9) and consisted entirely of partial responses (PRs). The stable disease rate was 34.5% (n = 10), translating to a DCR of 65.5% (n = 19). Ten patients (34.5%) experienced progressive disease.

In patients with liver metastases, no responses were recorded. Three patients (42.9%) experienced stable disease, and the DCR was 42.9%. Progressive disease occurred in 57.1% of patients (n = 4).

Patients without liver metastases achieved an ORR of 40.9% (n = 9), reflecting a PR rate of 36.4% (n = 8) and a stable disease rate of 31.8% (n = 7). The DCR was 72.7% (n = 16), and 27.3% of patients experienced progressive disease (n = 6).

In terms of safety, immune-related adverse effects (iRAEs) included maculopapular rash (any grade, 65.5%; grade ≥3, 37.9%), increased aspartate/alanine aminotransferase (any grade, 58.6%; grade ≥3, 17.2%), lipase/amylase increase (any grade, 13.8%; grade ≥3, 10.3%), hyperbilirubinemia (any grade, 27.6%; grade ≥3, 3.4%), pruritus (any grade, 27.6%; grade ≥3, 6.9%), colitis (any grade, 10.3%; grade ≥3, 6.9%), sudden death not otherwise specified (any grade, 3.4%; grade ≥3, 3.4%), meningitis (any grade, 3.4%; grade ≥3, 3.4%), myalgia (any grade, 20.7%; grade ≥3, 0), arthralgia (any grade, 24.1%; grade ≥3, 0), xerostomia (any grade, 13.8%; grade ≥3, 0), and hypothyroidism (any grade, 13.8%; grade ≥3, 0).

Grade 3 iRAEs leading to treatment interruption were hepatitis (n = 5) and colitis (n = 2) and resulted in treatment discontinuation in 4 patients.

Non-iRAEs included anemia (any grade, 44.8%; grade ≥3, 13.8%), thrombocytopenia (any grade, 55.2%; grade ≥3, 3.4%), palmar-plantar erythrodysesthesia syndrome (any grade, 17.2%; grade ≥3, 3.4%), fatigue (any grade, 44.8%; grade ≥3, 3.4%), neutropenia (any grade, 10.3%; grade ≥3, 3.4%), abdominal cramping (any grade, 3.4%; grade ≥3, 3.4%), hoarseness (any grade, 44.8%; grade ≥3, 0), proteinuria (any grade, 37.9%; grade ≥3, 0), oral mucositis (any grade, 31%; grade ≥3, 0), nausea (any grade, 27.6%; grade ≥3, 0), dry skin (any grade, 27.6%; grade ≥3, 0), leukopenia (any grade, 20.7%; grade ≥3, 0), anorexia (any grade, 20.7%; grade ≥3, 0), headache (any grade, 20.7%; grade ≥3, 0), and vomiting (any grade, 17.2%; grade ≥3, 0).


Fakih MG, Sandhu J, Lim D, et al. A phase I clinical trial of regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy resistant MSS metastatic colorectal cancer (mCRC). Ann Oncol. 2022;33(suppl 7):S684. doi:10.1016/j.annonc.2022.07.458

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