Telisotuzumab Vedotin Plus Osimertinib Shows Promise in TKI-Resistant NSCLC with c-MET Overexpression
核心洞察
The combination of telisotuzumab vedotin and osimertinib demonstrated a 50% objective response rate in patients with EGFR (搜索)-mutant NSCLC (搜索) who had progressed after prior osimertinib treatment.
All patients experienced at least one treatment-emergent adverse event, with peripheral sensory neuropathy (50%) and peripheral edema (32%) being most common, though no dose-limiting toxicities were reported.
The promising efficacy data, including a median progression-free survival of 7.4 months, suggests this combination could address an unmet medical need in patients with c-MET (搜索) protein overexpression-mediated resistance to EGFR (搜索) TKIs.
Results from a phase 1/1b clinical trial show that combining telisotuzumab vedotin (Teliso-V; Emrelis (搜索)) with osimertinib (Tagrisso) demonstrates significant clinical activity and acceptable tolerability in patients with EGFR (搜索)-mutant non-small cell lung cancer (搜索) (NSCLC (搜索)) who have developed resistance to prior osimertinib therapy.
The study, published in Annals of Oncology, specifically evaluated patients with c-MET (搜索) protein overexpression, a known mechanism of resistance to EGFR (搜索) tyrosine kinase inhibitors (TKIs).
Promising Efficacy Results
After a median follow-up of 7.4 months, the objective response rate (ORR) reached 50.0% (95% CI, 33.4%-66.6%) according to independent central review and 52.6% (95% CI, 35.8%-69.0%) per investigator assessment. All responses were confirmed partial responses.
The median duration of response was not reached per independent review and was 8.0 months according to investigator assessment. Median progression-free survival (PFS) was 7.4 months (95% CI 5.4-not reached) and 6.8 months (95% CI, 5.3-9.2) per independent review and investigator assessment, respectively.
"This combination has the potential to address an unmet medical need in this population," noted corresponding author Jonathan Goldman, MD, and colleagues in their publication.
Safety and Tolerability Profile
The safety analysis revealed that while all patients experienced at least one treatment-emergent adverse event (TEAE), no dose-limiting toxicities were reported. Thirty-seven patients experienced one or more TEAEs possibly related to telisotuzumab vedotin.
The most frequent adverse events included:
- Peripheral sensory neuropathy (50%)
- Peripheral edema (32%)
- Nausea (24%)
- Anemia (21%)
- Fatigue (21%)
Grade 3/4 TEAEs occurred in 19% of patients, while serious TEAEs were reported in 11%. Treatment discontinuation due to adverse events occurred in 24% of patients, with 16% of these cases considered possibly related to telisotuzumab vedotin. Dose interruptions and reductions were required in 58% and 37% of patients, respectively.
Study Design and Patient Characteristics
The analysis included 38 patients who received telisotuzumab vedotin (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18, every 2 weeks) plus osimertinib (80 mg once daily). The antibody-drug conjugate was initially evaluated at 1.6 mg/kg in a safety lead-in phase before escalation to 1.9 mg/kg.
Patient demographics revealed that 66% were female, 55% were Asian, and 61% were never smokers. The median age was 60 years (range, 40-79), and seven patients had central nervous system involvement at baseline. High c-Met (搜索) protein overexpression was reported in 64% of evaluable patients, with the remaining 36% showing intermediate c-Met protein overexpression.
In the dose-expansion cohorts, patients had received a maximum of two previous lines of therapy, with the requirement that one must have contained osimertinib, and no more than one may have contained chemotherapy.
Context Within the Treatment Landscape
The development of resistance to EGFR (搜索) TKIs remains a significant challenge in the treatment of EGFR-mutant NSCLC (搜索). c-MET (搜索) protein overexpression has been identified as one of the key mechanisms driving this resistance.
This study builds on previous research combining telisotuzumab vedotin with erlotinib (Tarceva) in c-MET (搜索)-positive NSCLC (搜索), which showed a median PFS of 5.9 months and an ORR of 32.1% in EGFR (搜索)-mutated positive patients. Among patients with high c-MET expression in that earlier study, the ORR was 52.6%.
Notably, telisotuzumab vedotin received accelerated approval from the FDA on May 14, 2025, for use in NSCLC (搜索) with high c-Met (搜索) overexpression based on data from the phase 2 LUMINOSITY trial.
Future Implications
The positive results from this combination therapy suggest a potential new treatment option for patients with EGFR (搜索)-mutant NSCLC (搜索) who develop resistance to osimertinib through c-MET (搜索) overexpression. The study highlights the importance of targeting specific resistance mechanisms to extend the benefit of targeted therapies in lung cancer.
Further research with longer follow-up will be needed to determine the durability of responses and the long-term safety profile of this combination. Additional studies may also explore biomarkers to better identify patients most likely to benefit from this approach.