Chemoimmunotherapy Advances in Anal and Colorectal Cancers Show Promise in First-Line Treatment

The frontline treatment of advanced squamous cell carcinoma of the anal canal (SCAC) is increasingly shifting toward chemoimmunotherapy to maximize durability and response rates, as evidenced by the introduction of retifanlimab-dlwr (Zynyz) plus carboplatin/paclitaxel into the treatment paradigm as a new gold standard.

The May 2025 FDA approval of retifanlimab plus carboplatin/paclitaxel for the first-line treatment of adult patients with inoperable locally recurrent or metastatic SCAC was supported by data from the phase 3 POD1UM-303/InterAACT2 trial (NCT04472429). This study met its primary progression-free survival (PFS) end point with the chemoimmunotherapy combination reducing the risk of disease progression or death by 37% compared with placebo plus carboplatin/paclitaxel (HR, 0.63; 95% CI, 0.47-0.84; P = .0006).

Prior to the May 2025 FDA approval of retifanlimab plus carboplatin and paclitaxel, carboplatin and paclitaxel was considered the standard of care based on the phase 2 InterAACT trial (NCT02051868). In the PODIUM-303 study, approximately 75% of evaluable patients were p16-positive, but it is unclear if that is a predictive biomarker for response to immunotherapy.

In colorectal cancer, onvansertib combined with standard-of-care chemotherapy and bevacizumab (Avastin) regimens improved outcomes in patients with treatment-naive RAS-mutated metastatic colorectal cancer (CRC), according to findings from the randomized phase 2 CRDF-004 trial (NCT06106308). The findings potentially address a significant unmet need in the RAS-mutated population, which accounts for approximately half of all metastatic CRC cases and has seen limited therapeutic advancement in the first line setting for more than 2 decades.

In an intent-to-treat analysis with a data cut-off of January 22, 2026, onvansertib at 30 mg plus FOLFIRI and bevacizumab achieved a confirmed overall response rate (ORR) of 72.2%. This represented a substantial improvement over the 43.2% ORR observed in the combined standard of care arms—FOLFIRI plus bevacizumab and FOLFOX plus bevacizumab—and the 42.1% ORR in the FOLFIRI plus bevacizumab control arm alone. When onvansertib was administered at 20 mg in combination with FOLFIRI and bevacizumab, the ORR was 44.4%.

Additionally, the 30-mg onvansertib plus FOLFIRI and bevacizumab arm achieved statistical significance for progression-free survival (PFS) compared with standard of care, demonstrating a hazard ratio of 0.37 (95% CI, 0.13-1.02; P = .048). While the median PFS had not yet been reached for the onvansertib arms at the time of the analysis, the standard of care regimens demonstrated a median PFS of 10.97 months (95% CI, 6.53-15.44). The 6-month PFS rate was 94.1% (95% CI, 83.6%-100.0%) with 30 mg onvansertib plus FOLFIRI and bevacizumab, 88.1% (95% CI, 73.9%-100.0%) with 20 mg ovansertib plus FOLFIRI and bevacizumab, 79.5% (95% CI, 61.1%-100.0%) with FOLFIRI and bevacizumab, and 88.8% (95% CI, 77.4%-100.0%) with standard of care.

Participants in the CRDF-004 trial were randomly assigned to receive 20 mg of onvansertib plus standard of care, 30 mg of onvansertib plus standard of care, or standard of care alone. In the experimental arms, onvansertib was administered orally as a capsule once daily on days 1 through 5 and days 15 through 19 of each 28-day cycle. Eligibility criteria required patients to have histologically confirmed metastatic CRC with a documented KRAS or NRAS mutation and unresectable disease. Patients must have been treatment-naive in the metastatic setting and possessed an ECOG performance status of 0 or 1. The primary end point of the trial was ORR per RECIST v1.1, with secondary endpoints including PFS, duration of response, and safety.

The addition of onvansertib to standard chemotherapy did not result in major or unexpected toxicities or significant additive adverse effects (AEs). Neutropenia was identified as the most common treatment-emergent AE across the treatment arms, though investigators characterized it as manageable.

The global oncology market is on track to nearly triple in value over the next decade, growing from $279.98 billion in 2026 to an estimated $748.17 billion by 2035. Cancer drug revenues alone are projected to reach $335.2 billion by 2033, driven by a surge in targeted therapies and immunotherapy adoption. The immuno-oncology segment specifically is forecast to expand from $65.22 billion in 2025 to $170.19 billion by 2032, representing a compound annual growth rate of 14.9%.