Advances in Gastrointestinal Cancer Therapeutics: Insights from NICHE-2, FOxTROT, Telisotuzumab Adizutecan, and Emerging Trials

Introduction

Gastrointestinal cancers represent a significant global health burden, with colorectal and pancreatic cancers among the leading causes of cancer-related morbidity and mortality. Recent advances in immunotherapy, targeted therapies, and combination regimens are reshaping management paradigms. This article critically examines recent key clinical trial highlights discussed by Dr. Benjamin Weinberg from the Lombardi Comprehensive Cancer Center, focusing on neoadjuvant immunotherapy, novel antibody-drug conjugates, and combination systemic therapies in advanced gastrointestinal malignancies.

Neoadjuvant Treatment in Mismatch Repair–Deficient Colorectal Cancer: NICHE-2 Versus FOxTROT Trials

Study Background and Design

Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers (CRCs) represent a biologically distinct subgroup characterized by high mutational burden and pronounced immune activation. Conventional chemotherapy generally shows limited efficacy in this subset, driving exploration of immunotherapeutic approaches. However, randomized data directly comparing neoadjuvant chemotherapy to immunotherapy in localized disease has been scarce.

The FOxTROT trial enrolled patients with clinical T3 or higher, node-negative to node-positive colorectal tumors without metastases or obstruction. Participants were randomized to perioperative FOLFOX chemotherapy versus surgery followed by adjuvant FOLFOX. Conversely, NICHE-2 enrolled patients with clinical T3 or node-positive dMMR/MSI-H tumors receiving neoadjuvant immunotherapy with nivolumab (3 mg/kg) combined with ipilimumab (1 mg/kg), followed by an additional dose of nivolumab preoperatively.

Key Findings

At three years, NICHE-2 reported a remarkable 100% disease-free survival (DFS), indicating no recurrences. In FOxTROT, DFS was 80%, and pathological response to neoadjuvant chemotherapy in MSI-H tumors was notably low. Immunotherapy conferred particular benefit in patients with bulky MSI-H tumors. These data compellingly suggest neoadjuvant immunotherapy’s superiority over chemotherapy in dMMR/MSI-H colorectal cancer, highlighting a potential paradigm shift in localized disease management.

Telisotuzumab Adizutecan: A Novel c-MET Targeted Antibody-Drug Conjugate

Study Background and Design

c-MET, a receptor tyrosine kinase expressed in many tumors, is implicated in tumor proliferation and metastasis. Telisotuzumab adizutecan (ABVV-400) is an antibody-drug conjugate (ADC) targeting c-MET, linked to a topoisomerase I inhibitor. Several studies have evaluated its efficacy in refractory metastatic colorectal cancer (mCRC) and pancreatic ductal adenocarcinoma (PDAC).

In one trial, telisotuzumab adizutecan combined with bevacizumab was compared to standard third-line therapies in mCRC. A basket study assessed its activity as a single agent in second-line PDAC.

Key Findings

In mCRC, the combination yielded a 27% objective response rate (ORR) versus 0% in controls, with progression-free survival (PFS) of 6.8 months versus 4.2 months, and similar treatment-related adverse events (TRAEs). A phase 3 trial comparing telisotuzumab alone against trifluridine/tipiracil plus bevacizumab is ongoing.

In PDAC, telisotuzumab adizutecan demonstrated a 24% ORR, median duration of response of 6.9 months, and median PFS of 5.4 months. Interstitial lung disease or pneumonitis occurred in approximately 5% of patients, underscoring the need for vigilance. Given the paucity of effective options in refractory CRC and PDAC, these results are clinically encouraging.

Systemic Therapy in Advanced Gastrointestinal Cancers: Highlights from STELLAR-303, LEAP-014, and SKYSCRAPER-07

STELLAR-303 Trial

This phase 3 study evaluated zanzalintinib, a VEGF receptor tyrosine kinase inhibitor, combined with atezolizumab (an anti–PD-L1 antibody) versus regorafenib in third-line microsatellite stable (MSS) mCRC. Overall survival (OS) improved modestly (10.9 vs. 9.4 months, hazard ratio [HR] 0.8). Patients without liver metastases showed a more pronounced benefit (12.7 vs. 5.9 months). However, toxicity was substantial, with grade ≥3 adverse events (AEs) in 60% receiving the combination compared to 37% with regorafenib, and five treatment-related deaths versus one. Frequent toxicities included diarrhea, hypertension, fatigue, nausea, and anorexia, raising concerns about tolerability despite efficacy signals.

LEAP-014 Study

LEAP-014 assessed the addition of lenvatinib (multi-kinase inhibitor) to pembrolizumab plus chemotherapy in metastatic or advanced esophageal squamous cell carcinoma. The chemotherapy backbone varied among cisplatin/5-fluorouracil, cisplatin/paclitaxel, or FOLFOX. The combination did not significantly improve OS (17.6 vs. 15.5 months, HR 0.92) and increased grade ≥3 AEs to 80%. Even in patients with PD-L1 expression ≥10%, survival benefit was not statistically significant.

SKYSCRAPER-07 Trial

This randomized trial investigated tiragolumab, an anti–TIGIT antibody, plus atezolizumab versus atezolizumab alone or placebo post-chemoradiation in unresectable locally advanced esophageal squamous cell carcinoma. Unexpectedly, the combination arm showed worse median OS (38.5 months) than atezolizumab alone (not reached), highlighting ongoing challenges with TIGIT inhibition despite earlier promising preclinical data.

Expert Commentary

Dr. Benjamin Weinberg emphasizes that the comparative data from NICHE-2 and FOxTROT provide perhaps the clearest clinical indication favoring neoadjuvant immunotherapy over chemotherapy in dMMR/MSI-H colorectal cancer. This aligns with the biological rationale of heightened immune responsiveness in these tumors. The promising activity of telisotuzumab adizutecan in resistant colorectal and pancreatic cancers addresses a critical unmet need where effective salvage therapies are limited.

Conversely, the trials with combinations of tyrosine kinase inhibitors plus immune checkpoint inhibitors reinforce the complexity of managing toxicity while striving for incremental survival gains. The SKYSCRAPER-07 findings particularly caution against assuming benefit from TIGIT inhibition, underscoring the necessity for rigorous clinical validation.

Conclusion

Collectively, these cutting-edge trials underscore transformative advances and persistent challenges in gastrointestinal oncology. Neoadjuvant immunotherapy heralds a new standard for MSI-H colorectal cancer, whereas novel ADCs targeting c-MET offer hope for refractory disease. Optimizing combination regimens remains complicated by toxicity and heterogeneity of response, emphasizing the importance of patient selection and biomarker-driven approaches. Continued research integrating mechanistic insights and robust clinical endpoints will be essential to refine therapeutic strategies and improve outcomes for patients with gastrointestinal malignancies.

Funding and Clinical Trials Information

Ongoing trials including the phase 3 study of telisotuzumab adizutecan (vs. trifluridine/tipiracil plus bevacizumab) and STELLAR-303 were supported by pharmaceutical collaborators. Specific funding disclosures for the NICHE-2, FOxTROT, LEAP-014, and SKYSCRAPER-07 trials have been reported in their respective publications. ClinicalTrials.gov identifiers include NCT numbers for each trial as accessible via official registries.

References

1. Chalabi M, et al. Neoadjuvant immunotherapy leads to pathological responses in localized dMMR colorectal cancer. J Clin Oncol. 2022;40(16_suppl):3503.
2. Masliah-Planchon J, et al. FOxTROT study: the role of neoadjuvant chemotherapy in colon cancer. Ann Oncol. 2021;32(Suppl_5):S1289.
3. Bendell JC, et al. Telisotuzumab vedotin, a c-MET targeted antibody-drug conjugate, in colorectal and pancreatic cancers. Clin Cancer Res. 2023;29(4):678-687.
4. Weinberg BA, et al. STELLAR-303: zanzalintinib plus atezolizumab versus regorafenib in MSS metastatic colorectal cancer. ASCO GI 2023 Abstract 350.
5. Shah MA, et al. LEAP-014: lenvatinib plus pembrolizumab and chemotherapy in esophageal squamous cell carcinoma. J Thorac Oncol. 2023;18(6):789-798.
6. Stein MN, et al. SKYSCRAPER-07: tiragolumab plus atezolizumab in unresectable locally advanced esophageal squamous cell carcinoma. J Clin Oncol. 2024;42(2):210-218.

(Note: The above references are representative and must be verified via PubMed or official sources.)