Abstract 341P
Background
Trop2 and Nectin4 are two transmembrane proteins overexpressed in many solid tumors with minimal levels in adult somatic tissues, thus emerging as appealing therapeutic targets. Indeed, sacituzumab govitecan, an anti-Trop2 antibody–drug conjugate (ADC), and enfortumab vedotin, an anti-Nectin4 ADC, were recently approved for the treatment of triple-negative breast cancer and urothelial carcinoma, respectively. In metastatic colorectal cancer (mCRC), the role of Trop2 and Nectin4 has been poorly investigated.
Methods
Tumor samples of patients (pts) randomized in the phase III TRIBE2 study comparing upfront FOLFOXIRI/bevacizumab (bev) vs FOLFOX/bev, were assessed for Trop2 and Nectin4 expression (exp). Immunohistochemistry exp levels were categorized based on a histochemical score.
Results
Out of 679 pts enrolled in the TRIBE2 study, 386 tumors were assessed for Trop2 exp. Overall, 90 (23%), 115 (30%) and 181 (47%) were classified as high, medium and low, respectively. High Trop2 tumors were more frequently BRAF mutated (p=0.005) and right-sided (p=0.03) compared to medium and low ones. Pts with low Trop2 tumors achieved longer PFS (12 vs 9.9 months, HR: 0.81, 95%CI: 0.66-1.00, p=0.05) and OS (27.3 vs 21.3 months, HR: 0.76, 95%CI: 0.60-0.95, p=0.01) than those with high/medium Trop2 tumors. The prognostic value of Trop2 was confirmed in the multivariate analysis in terms of both PFS (p=0.02) and OS (p=0.03). An interaction effect was shown between Trop2 and treatment intensification with higher benefit from FOLFOXIRI/bev in the medium/high Trop2 cohort (pinteraction=0.04). Overall, 251 tumors were assessed for Nectin4 exp and 14 (5%), 67 (27%) and 170 (68%) were classified as high, medium and low, respectively. High Nectin4 tumors were more frequently left-sided (p=0.01). No prognostic impact was observed based on Nectin4 exp and no interaction effect was reported between Nectin4 exp groups and treatment arm.
Conclusions
In mCRC, exp levels of Trop2 and Nectin4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin4 ADCs. Medium/high Trop2 exp is associated with worse prognosis and higher benefit from chemotherapy intensification.
Clinical trial identification
NCT02339116.
Editorial acknowledgement
Legal entity responsible for the study
GONO foundation.
Funding
Has not received any funding.
Disclosure
C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD; Financial Interests, Personal, Invited Speaker: Bayer, Servier; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche, Bayer, Servier, Merck. All other authors have declared no conflicts of interest.