Telisotuzumab Vedotin Shows Promising Antitumor Activity in Certain Patients with NSCLC

The use of telisotuzumab vedotin (ABBV-399) plus erlotinib (Tarceva) for patients with c-MET protein expressing non–small cell lung cancer (NSCLC) showed promising antitumor activity, according to results published in the Journal of Clinical Oncology.¹

Findings from a phase 1/1b study multicenter, open-label study (NCT02099058) of 42 patients with confirmed c-MET overexpression, MET exon 14 skipping mutations, or MET amplification, in their disease showed that along with promising efficacy results, the combination therapy had an acceptable toxicity profile.

The most common any grade adverse events (AEs) observed by researchers were peripheral sensory neuropathy (43%), dermatitis acneiform (38%), diarrhea (33%), and hypoalbuminemia (33%). Grade 3 or higher AEs occurred in 27 patients with the most common being pulmonary embolism (14%), hypokalemia (10%), diarrhea (7%), malignant neoplasm progression (7%), peripheral sensory neuropathy (7%), and hypophosphatemia (7%).

Any grade treatment-related adverse events (TRAEs) linked to the use of telisotuzumab vedotin were seen in 37 patients, including peripheral sensory neuropathy (36%) and peripheral neuropathy (19%). However, grade 3 or greater TRAEs occurred in 13 patients with the most common also being peripheral sensory neuropathy (7%) and hypophosphatemia (7%).

Other serious AEs related to treatment included decreased appetite, dehydration, hemoptysis, peripheral neuropathy, and pneumonia, among 2% of patients each. Ultimately, the most common AE that led to either dose reductions, interruptions, or discontinuation was peripheral neuropathy at 10%, 21%, and 21%, respectively.

“Although 11 patients [26%] required dose interruption or discontinuation of [telisotuzumab vedotin] because of neuropathy, most of these events were mild-to-moderate, only 12% of grade ≥ 3,” researchers wrote when explaining the acceptable toxicity profile of the drug. “The rate of peripheral sensory neuropathy in this study (43%) was similar to that observed with other approved monomethyl auristatin E [MMAE] antibody drug conjugate-containing drugs.”

Telisotuzumab vedotin is a first-in-class antibody drug conjugate that uses a cleavable linker to combine a recombinant c-Met–targeting humanized monoclonal antibody (ABT-700) and MMAE, which is a potent inhibitor of microtubule polymerization. According to the researchers, by combining this with erlotinib, the treatment allows clinicians to target both c-MET and EGFR mutations in patients with NSCLC.

In this study, all enrolled adult patients had been previously treated with tyrosine kinase inhibitors and given 2.7 mg/kg of telisotuzumab vedotin intravenously once every 3 weeks. In the study cohort, 53% were defined as c-MET high with a confirmed histology score greater than 225, while MET amplification was found in 6 patients. Four patients were positive for EGFR-M, 1 patient had EGFR-wild-type, and 3 patients had a rare/unknown EGFR mutation. Five of the patients with MET amplifications were also classified as c-Met-high. Thirteen patients were also confirmed to have T790M mutations with 6 patients having c-Met-high mutations and 7 with lower c-Met expression in their NSCLC.

The median duration to exposure to treatment lasted at 18.1 weeks (range, 3.1-99.1) with patients receiving a median of 7 treatment cycles (range, 2-34). Median duration of exposure to erlotinib was 20.3 weeks (range, 3.1-110.4) with patients given a median of 5.5 treatment cycles (range, 2-33).

The objective response rate (ORR) was 30.6% (95% CI, 16.3%-48.1%) for all evaluable patients with a disease control rate (DCR) of 86.1% (95% CI, 70.5%-95.3%). Twenty patients had stable disease, 10 had a partial response, 5 patients had progressive disease, and only 1 patient had a complete response with that patient also having c-Met-positive disease and an EGFR-activating mutation.

Looking at patients with EGFR mutation-positive disease, the ORR was 32.1% (95% CI, 15.9%-52.4%) with a DCR of 85.7% (95% CI, 67.3%-96%). When looking at patients with EGFR mutation-positive disease who also had T790M mutations, the ORR was 31% and the DCR was 77%. The median progression-free survival in the entire population was 5.9 months (95% CI, 2.8-not reached [NR]) and the duration of response was NR at the time of data cutoff.

“In conclusion, the combination of telisotuzumab vedotin plus erlotinib showed an acceptable safety profile and encouraging antitumor activity in heavily pretreated patients, especially in [EGFR mutation-positive, c-Met-positive] NSCLC in which previous EGFR TKIs failed,” the researchers wrote. “Although exploratory, targeting c-Met and EGFR showed promising results in this underserved patient population and is worthy of further evaluation in larger studies.”

Reference

Camidge DR, Barlesi F, Goldman JW, et al. Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in Patients With c-Met Protein-Expressing Non-Small-Cell Lung Cancer. J Clin Oncol. 2022 Oct 26:JCO2200739. doi: 10.1200/JCO.22.00739