Envafolimab Plus Suvemcitug and FOLFIRI Shows Early Efficacy, Tolerability in Second-Line CRC

Envafolimab (KN035) in combination with suvemcitug and FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) displayed preliminary antitumor activity and a manageable safety profile in second-line microsatellite stable/mismatch repair–proficient (MSS/pMMR) colorectal cancer (CRC), according to findings from a phase 2 study (NCT05148195) published in the International Journal of Colorectal Disease.1

Preliminary findings from CRC cohort (n = 20) showed that patients who received the combination achieved an investigator-assessed objective response rate (ORR) of 25.0% (95% CI, 8.66%-49.10%). The disease control rate (DCR) was 90.0% (95% CI, 68.30%-98.77%). The median duration of response (DOR) and median progression-free survival (PFS) were 4.1 months (95% CI, 3.02-not evaluable) and 5.6 months (95% CI, 4.01-8.25), respectively.

Topline safety data revealed that no dose-limiting toxicities occurred during the safety run-in. All patients experienced any-grade treatment-related adverse effects (TRAEs) and 90% of patients experienced grade 3 or higher TRAEs. Serious TRAEs were reported in 35% of patients. Dose interruption or reduction occurred in 80% and 70% of patients, respectively. Patients experienced dose interruption or reduction of suvemcitug at rates of 70% and 10%, respectively; these respective rates were 50% and 0% for envafolimab and 60% and 70% for FOLFIRI. Notably, no treatment discontinuation was determined to be related to treatment-emergent adverse effects.

“In a previous study, suvemcitug plus FOLFIRI in [patients with] advanced CRC showed good efficacy and safety,” the study authors wrote. “In this current study, we aimed to explore if suvemcitug and FOLFIRI plus envafolimab can improve the efficacy in patients with MSS/pMMR CRC.”

Envafolimab is a single-domain anti–PD-L1 antibody that is formulated for subcutaneous injection.2 In November 2021, the Chinese National Medical Products Administration approved the agent for the treatment of adult patients with microsatellite instability–high/mismatch repair–deficient advanced solid tumors. The approval included patients with advanced CRC who experienced disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens, as well as patients with other advanced solid tumors with no satisfactory alternative treatment options after disease progression on prior treatment(s).

The open-label, nonrandomized phase 2 study enrolled patients with solid tumors, hepatocellular carcinoma, non–small cell lung cancer, and CRC across 8 centers in China.1 In order to be eligible for inclusion in the CRC cohort, patients with histologically confirmed metastatic MSS/pMMR CRC needed to have received a prior fluorouracil- and oxaliplatin-based chemotherapeutic regimen, be at least 18 years old, have an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST 1.1 criteria, and have sufficient kidney, liver, and bone marrow function. Those with a history of gastrointestinal perforation, abdominal fistula, bowel obstruction, or intra-abdominal abscess, clinically significant cardiovascular disease, severe unhealed wounds, ulcers, or fractures, and known central system metastases were excluded. Prior treatment with EGFR-, VEGFR-, and PD-(L)1-directed agents was permitted, although previous receipt of suvemcitug or envafolimab was not.

Findings from the safety run-in portion of the phase 1 studies of suvemcitug (NCT01847118 and NCT02453464) established the recommended phase 2 dose (RP2D) of the agent as 2 mg/kg once every 2 weeks.3 Patients also received subcutaneous envafolimab at a dose of 200 mg once every 2 weeks followed by intravenous FOLFIRI.1 The FOLFIRI regimen consisted of irinotecan at a dose of 180 mg/m2, levoleucovorin at a dose of 200 mg/m2 or leucovorin at a dose of 400 mg/m2, and a 5-fluorouracil bolus at a dose of 400 mg/m2 followed by a continuous dose of 2400 mg/m2, for 6 to 8 two-week cycles. Treatment continued in all patients until unacceptable toxicity or disease progression.

The median duration of treatment was 22.3 weeks. The median relative dose intensities of suvemcitug and envafolimab were 86.6% and 88.9%, respectively.

The coprimary end points were determining the recommended dose during the safety run-in and investigator-assessed ORR per RECIST 1.1 criteria in the dose-expansion portion. Secondary end points included PFS, DOR, DCR, overall survival, and safety.

At baseline, the median age in the CRC cohort was 56.0 years. Most patients were 18 to 65 years of age (70.0%), male (60.0%), had a left-sided or rectal tumor site (75.0%), an ECOG performance status of 1 (90.0%), underwent 1 prior line of therapy (75.0%), had a lung metastasis (55.0%), and did not receive prior anti-EGFR antibody therapy (90.0%). Metastasis sites beyond the lungs included the lymph nodes (65.0%), lung (55.0%), liver (55.0%), peritoneum (20.0%), and other (45.0%). In terms of KRAS status, patients had KRAS-mutated (30.0%), wild-type (40.0%), or unknown (30.0%) status.

Additional findings from the study showed that the ORRs among patients with KRAS-mutated disease, baseline liver metastasis, and baseline lung metastasis were 16.7% (95% CI, 0.42%-64.12%), 27.3% (95% CI, 6.02%-60.97%) and 36.4% (95% CI, 10.93%-69.21%), respectively. Patients who received 1 prior line of therapy achieved an ORR of 33.3% (95% CI, 11.82%-61.62%).

Additional safety data revealed that the most common any-grade TRAEs included decreased white blood cell count (85.0%), decreased neutrophil count (75.0%), proteinuria (65.0%), and nausea (60.0%). Common grade 3 or higher TRAEs included decreased neutrophil count (60.0%), decreased white blood cell count (25.0%), hypertension (25.0%), decreased lymphocyte count (15.0%), and oral mucositis (15.0%).

“In summary, suvemcitug in combination with envafolimab and FOLFIRI showed preliminary anti-tumor activity, with a controllable safety profile, in patients with MSS/pMMR CRC who had failed prior first-line treatment,” the study authors wrote in their conclusion. “Additional investigation of this combination therapy is warranted to identify the sub-population who may get benefits in this combo regimen in the future.”

References

1. Liu Y, Wang J, Fang Y, et al. The efficacy and safety of suvemcitug, envafolimab, and FOLFIRI in microsatellite-stable or mismatch repair-proficient colorectal cancer: preliminary results of a phase 2 study. Int J Colorectal Dis. 2025;40(1):20. doi:10.1007/s00384-025-04806-z
2. Envafolimab, the world’s first subcutaneously injected PD-L1 antibody approved by NMPA! Alphamab Oncology partners with 3DMed and Simcere to innovate immunotherapy. News release. Alphamab Oncology. November 26, 2021. Accessed February 6, 2025. https://www.alphamabonc.com/en/html/news/2375.html
3. Mao C, Ji D, Ding Y, et al. Suvemcitug as second-line treatment of advanced or metastatic solid tumors and with FOLFIRI for pretreated metastatic colorectal cancer: phase Ia/Ib open label, dose-escalation trials. ESMO Open. 2023;8(3):101540. doi:10.1016/j.esmoop.2023.101540