Table 1.
Representative clinical research findings on MSS CRC in recent years.
| • Year/study | • Treatment | • Population | • Important findings |
|---|---|---|---|
| 2020/REGONIVO, EPOC1603 (an open-label, dose-escalation, and dose-expansion phase Ib trial) (62) | Regorafenib+Nivolumab | • N=50. (25 each with GC and CRC) • MSI-H: 1 CRC; MSS/pMMR: 49. |
• ORR: 40% (20/50); 44% (11/25) in GC; 36% (9/25) in CRC. • mPFS: 5.6 months (95% CI, 2.7-10.4) inGC; 7.9 months (95% CI, 2.9-NR) in CRC. |
| 2021/REGOMUNE (a single-arm, open-label, phase II trial) (63) | Avelumab + Regorafenib | • N=48. • MSS advanced or mCRC patients and received at least one previous line of systemic treatment. • Among them, 43 assessable for efficacy. |
• ORR: 0%; SD 53.5% (23/43); PD 39.5% (17/43). • mPFS: 3.6 months [95% CI, 1.8-5.4]; • mOS:10.8 months (95% CI, 5.9-NA). • High baseline infiltration by TAM was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). • Patients with increased infiltration by CD8+ T cell at cycle 2 Day 1 compared to baseline had significantly better PFS (3.7 vs 2.3 months, P =0.035) and OS (NR vs 4.3 months, P =0.03). |
| 2021/ EPOC1704 (an open-label, dose-finding, and expansion phase Ib trial) (64) | Nivolumab+TAS-116 (an Oral HSP90 Inhibitor) | • N=44. • advanced or metastatic solid tumors refractory to or intolerant of standard chemotherapy. • MSI-H: 1 CRC; MSS/pMMR: 36 (28 CRC+8 GC). |
• ORR: 16% (95% CI, 5–36) in MSS CRC without prior anti–PD-1/PD-L1 Ab. • The median duration of response was 8.6 months (95% CI, 2.9-NR) in 4 MSS CRC. • mPFS: 3.2 months (95% CI, 2.8-4.4) in MSS CRC without prior anti–PD-1/PD-L1 Ab. The PFS rate at 4 months or 6 months was 36.0% or 24.0% in MSS CRC without prior anti–PD-1/PD-L1 Ab. • mOS: 13.5 months (95% CI, 8.2–15.1) in MSS CRC without prior anti–PD-1/PD-L1 Ab. |
| 2021/LEAP-005 (a phase II multicohort study) (65) | Pembrolizumab (anti-PD-1)+Lenvatinib | • N=32. • metastatic and/or unresectable CRC, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy |
• ORR(CR+PR): 22% (95%CI, 9-40), DCR(CR+PR+SD) : 47% (95%CI, 29-65); • mPF: 2.3 months (95%CI, 2.0-5.2); • mOS: 7.5 months (95%CI, 3.9-NR) |
| 2022/ PICCASSO (a phase I trial) (66) | Pembrolizumab+CCR5 inhibitor | • N=20. • refractory pMMR CRC. |
• Of the 20 patients, 1 not evaluable, 1 PR, 18 PD. • mPFS was only 9 weeks. • mOS was 9 months. |
| 2022/AtezoTRIBE (a multicentre, open-label, randomised, controlled, phase II trial) (67) | Control group: FOLFOXIRI+Bevacizumab; N=73; Atezolizumab group: FOLFOXIRI+Bevacizumab+Atezolizumab (anti-PD-L1); N=145; |
• N=218. • unresectable, previously untreated mCRC. • Tumor MMR status was successfully tested in 212 (97%) of 218 patients, and dMMR was detected in 13 (6%) patients (eight in the atezolizumab group and five in the control group). |
• Compared with chemotherapy and targeted therapy, the addition of immunotherapy significantly improved mPFS (11.5 vs. 13.1 months, HR 0.69, 95% CI 0.56-0.85, P=0.012). • After excluding dMMR patients, the analysis of the pMMR subgroup also showed an improvement trend in mPFS (11.4 vs. 12.9 months, HR 0.78, 95% CI 0.62-0.97, P=0.071). |
| 2022/ A real-world study (68) | RS group: Regorafenib+ Sintilimab; N=42 FS group: Fruquintinib+ Sintilimab; N=30; third-line or above therapy |
• N=72. • Patients with MSS mCRC who have failed from prior treatment. |
• In the general population, the ORR and DCR were 13.9% and 70.8%, and the mPFS and mOS was 4.2(95% CI, 2.9-5.5) and 10.5 (95% CI,8.6-12.4) months, respectively. • There were no statistically significant differences between RS and FS group in PFS (3.5(2.2-4.8) vs. 5.5(3.5-7.5) months, P=0.434) and OS (11.0(7.0-15.0) vs. 10.5(3.8-17.2) months, P=0.486). • Subgroup analysis suggested that patients without liver metastasis responded well to this combination regimen (ORR: 21.4% vs. 9.1%) and obtained better OS (26(8.8-43.2) vs. 10.0(7.4-12.6) months, P=0.016). |
| 2023/ NEST-1 (investigator-initiated trial, NCT05571293) (69) | Botensilimab (anti-CTLA-4)+Balstilimab (anti-PD-1) | • N=70. • locally advanced pMMR CRC. |
• The ORR was 23%, and 11/16 were still being followed up at the time of reporting. • Remission was observed in all patients without liver metastasis. Importantly, 81% of patients without liver metastasis were alive at 12 months. |
| 2023/ MEDITREME (a phase Ib/II trial) (70) | Durvalumab (anti-PD-L1)+Tremelimumab (anti-CTLA-4)+FOLFOX | • N=57. • RAS-mutant untreated and unresectable mCRC. • MSI: 3; MSS: 48. • Only the 48 MSS tumors were included in the eligible population for efficacy analyses. |
• ORR: 64.5% (31/48); PR: 52% (25/48); CR: 12.5% (6/48). DCR (CR+PR+SD): 93.7%. • 3-month PFS: 90.7% (95% confidence interval (CI): 79.2–96%). Six-month, 12-month and 24-month PFS was, respectively, 60.4% (95% CI, 45.2–72.6%), 26.9% (95% CI, 15.3–39.9%) and 6.7% (95% CI, 1.8–16.5 %). mPFS was 8.2 months (95% CI, 5.9–8.6). • OS at 6 months, 12 months and 24 months, was respectively, 95.8% (95% CI, 84.3–98.9%), 81.1% (95% CI, 66.8–89.7%) and 57.6% (95% CI, 42.3–70.2%). mOS was not reached. |
| 2023/VOLTAGE-A (Investigator-initiated clinical trial, phase Ib/II study) (71) | Preoperative chemoradiotherapy+ Nivolumab+ radical surgery | • N=42. • 37 resectable MSS mCRC. |
• With a median follow-up of 44.8 months (range, 25.7-58.9), the 3-year RFS and 3-year OS rates were respectively 79.5% and 97.4% in MSS, and 100% in MSI-H. • Of the MSS, those with pCR, cCR according to the MSKCC criteria, high PD-L1 expression (TPS ≥1%), and CD8/eTreg ratios of ≥2.5 had a trend of better 3-year RFS and OS than those without. |
| 2023/BBCAPX (a randomized, open-label, multicentric study) (72) | CAPEOX+Bevacizumab; CAPEOX+ Bevacizumab +Sintilimab (anti-PD-1) |
• N=25. • patients with untreated, RAS-mutant, MSS, unresectable mCRC. |
• CR: 8.0% (2/25); PR: 76.0% (19/25); SD: 16.0% (4/25). • Patients with liver or lung metastasis had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). • DCR (CR+PR+SD): 100%. • mPFS has not reached. |
| 2023/ NCT03903705 (phase Ib/II, open-label, multi-centre, multi-cohort dose-escalation and dose-expansion study) (73) | Fruquintinib+Sintilimab | • N=44. • Among 44, 37 patients with mCRC in the dose-expansion phase, 25 (67.6%) were identified as pMMR, and MMR status was not available for the other 12 (32.4%) patients. |
• In pooled mCRC analysis, the ORR was 23.8% (95% CI, 8.2–47.2), mPFS was 6.9 months (95% CI,5.4–8.3), and mOS was 14.8 months (95% CI 8.8–NR); • In mCRC patients with pMMR, mPFS and mOS were 20.0% (95% CI, 4.3–48.1), 6.9 months (95% CI, 4.8–10.1), and 20.0 months (95% CI 8.1–NR), respectively. |
95% CI, 95% confidence interval; Ab, antibody; cCRclinical complete response; CR, complete response; DCR, disease control rate; dMMR, deficient mismatch repair; GC, gastric cancer; mCRC, metastatic colorectal cancer; mOS, median overall survival; mPFS, median progression-free survival; MSI-H, microsatellite instability-high; MSKCC, Memorial Sloan Kettering Cancer Center; MSS microsatellite stability; NR, not reached; ORR, objective response rate; pCR, pathological complete response; pMMR, proficient mismatch repair; PR, partial response; RFS, relapse-free survival; SD, stable disease; TAM, tumor-associated macrophages; TPS, tumor proportion score.