Sintilimab Triplet Demonstrates Efficacy With Acceptable Safety in pMMR/MSS CRC

The triplet combination of sintilimab (Tyvyt), chidamide, and bevacizumab (Avastin) resulted in a high 18-week progression-free survival (PFS) rate with a favorable toxicity profile in patients with microsatellite stable (MSS) or mismatch repair–proficient (pMMR) metastatic colorectal cancer (mCRC), according to data from the phase 2 CAPability-01 trial (NCT04724239).¹

The findings, which were shared at the 2023 ESMO Congress, showed that sintilimab plus chidamide with or without bevacizumab resulted in a 18-week PFS rate of 42.6%. These rates were 66.7% in those who received the triplet (n = 25) and 17.4% in those given the doublet (n = 23; P = .0012). The median PFS was 7.3 months with the triplet regimen vs 1.5 months with the doublet (HR, 0.43; 95% CI, 0.23-0.81; P = .008).

Moreover, sintilimab plus chidamide and bevacizumab elicited an objective response rate (ORR) of 44.0% vs 13.0% with sintilimab plus chidamide (P = .027). The disease control rates (DCRs) in these groups were 72.0% vs 39.1% (P = .041).

“These data support the exploration of the triplet combination in [the] phase 3 CAPability-02 trial,” Feng Wang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, said in a presentation of the data.

It is known that patients with CRC and MSS/pMMR phenotype do not achieve strong responses to single-agent immune checkpoint inhibitors. Pairing PD-1 or PD-L1 antibodies with antiangiogenic therapy have also demonstrated unsatisfactory efficacy. Although combinations comprised of histone deacetylase (HDAC) inhibitors and PD-1 or PD-L1 antibodies have been found to have efficacy in patients with lymphoma, this approach has had limited success in other solid tumors. Preclinical data have suggested that regimens that include a HDAC inhibitor, VEGF(R) antibody, and a PD-1 antibody have synergistic activity.

The open-label, multicenter, randomized CAPability-01 trial enrolled patients with MSS/pMMR mCRC whose disease has progressed beyond or was intolerable to at least 2 lines of systemic treatment. Patients were required to have an ECOG performance status of 0 or 1 and acceptable organ and bone marrow function. Patients could not have prior exposure to a HDAC inhibitor or a PD-1/PD-L1 antibody.

Participants were randomly assigned in a 1:1 fashion to receive sintilimab at 200 mg every 3 weeks plus chidamide at 30 mg twice weekly or sintilimab at 200 mg every 3 weeks, chidamide at 30 mg twice weekly, and bevacizumab at 7.5 mg/kg every 3 weeks.

In addition to 18-week PFS rate serving as the trial’s primary end point, key secondary end points included overall survival, PFS, ORR, DCR, duration of response, and safety.

The median age in both arms was 55 years (range, 21-73). In the doublet arm, 43.5% of patients were female vs 24.0% of those in the triplet arm. Most patients had an ECOG performance status of 1 (78.3% vs 76.0%) and a left-sided primary site (69.6% vs 76.0%). In the doublet arm, 52.2% of patients had metastatic lesions in the liver, 69.6% had them in the lung, and 56.5% had them in the lymph node; these rates were 56.0%, 68.0%, and 52.0%, respectively, in the triplet arm. Regarding RAS/BRAF V600E mutational status in the doublet arm, 52.2% had wild-type disease, 39.1% had RAS-mutated disease, 4.3% had BRAF V600E–mutated disease, and 4.3% had unknown status; in the triplet arm, these rates were 48.0%, 44.0%, 0%, and 8.0%, respectively.

In the doublet arm, all patients experienced any-grade adverse effects (AEs) and 30.4% experienced grade 3 or higher AEs. The most common any-grade AEs included proteinuria (60.9%), thrombocytopenia (43.5%), anemia (29.1%), neutropenia (26.1%), hematuria (21.7%), leukopenia (17.4%), diarrhea (13.0%), and increased blood thyroid-stimulating hormone (13.0%). Three patients experienced grade 3 or higher AEs in the form of thrombocytopenia (n = 2) and anemia (n = 1).

In the triplet arm, 96.0% of patients had any-grade AEs and 52.0% experienced grade 3 or higher AEs. The most common any-grade AEs in this group were thrombocytopenia (72.0%) and proteinuria (72.0%), followed by neutropenia (60.0%), leukopenia (44.0%), diarrhea (44.0%), anemia (40.0%), increased blood thyroid-stimulating hormone (36.0%), and hematuria (28.0%). Fourteen patients experienced grade 3 or higher AEs in the form of neutropenia (n = 6), thrombocytopenia (n = 4), proteinuria (n = 1), leukopenia (n = 1), diarrhea (n = 1), and anemia (n = 1).

“The combination of chidamide and sintilimab with or without bevacizumab had an acceptable safety profile,” Wang concluded.

Editor’s Note: Dr Wang did not disclose any conflicts of interests.

Reference

Wang F, Jin Y, Luo H-Y, et al. 556MO a phase II clinical trial of sintilimab plus chidamide combined with or without bevacizumab in patients with MSS/pMMR metastatic colorectal cancer. Ann Oncol. 2023;34(suppl 2):S414-S415. doi:10.1016/j.annonc.2023.09.1747