Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.

Pharmacological inhibition of VEGFR2 with tyrosine kinase inhibitors, such as lenvatinib, partially reverted ECM alterations in vitro and in vivo, reducing matrix deposition and modifying its organization. These data identify VEGFR2 as a regulator of tumor ECM dynamics and suggest that its inhibition may restore ECM organization, offering a therapeutic strategy to reprogram the tumor microenvironment and limit cancer progression.

P=N/A, N=364, Not yet recruiting, Tongji Hospital

P2, N=20, Active, not recruiting, Imperial College London | Recruiting --> Active, not recruiting | Trial completion date: Aug 2028 --> Oct 2027 | Trial primary completion date: Mar 2028 --> Oct 2027

P1, N=15, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

P1, N=15, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Common adverse events (AEs) were similar between the two groups, with elevated ALT more frequent in the LEN-RG group. Continuing lenvatinib as second-line therapy after failure may offer sustained survival benefits and demonstrate favorable efficacy and safety in real-world clinical practice.

This case suggests that selpercatinib rechallenge may be effective in difficult-to-treat RET-positive NSCLC patients, including those with uncontrolled CNS disease.

P2, N=96, Completed, Sun Yat-sen University | Initiation date: Aug 2023 --> Feb 2023

The PPP1R15B-ATF4-GPX4 axis is a key determinant of lenvatinib tolerance in HCC by orchestrating redox adaptation and ferroptosis resistance. Targeting PPP1R15B represents a promising therapeutic strategy to eliminate lenvatinib-tolerant persister cells and overcome acquired resistance in HCC.

Participants received a combined regimen of zimberelimab and lenvatinib (immune rechallenge). A population of CD45+CD3+Lyz+dyad cells, composed of T cells and myeloid cells, was correlated with clinical benefit. Our findings proved immune rechallenge could be an effective treatment for patients with advanced cervical cancer who progressed on or after prior ICIs therapy.