Telisotuzumab Vedotin With Erlotinib Appears Promising in EGFR-Mutant, c-Met NSCLC

The combination of telisotuzumab vedotin and erlotinib did not lead to any unexpected safety signals and showed encouraging antitumor activity in patients with EGFR-mutated, c-Met protein expressing non–small cell lung cancer.

Telisotuzumab vedotin (ABBV-399) combined with erlotinib (Tarceva) showed promising antitumor activity and an acceptable safety profile in patients with epidermal growth factor receptor (EGFR)-mutated, c-Met protein expressing non–small cell lung cancer (NSCLC) who had been pretreated with an EGFR tyrosine kinase inhibitor (TKI), according to a phase 1b study (NCT02099058).

Among the 36 efficacy-evaluable patients in the trial, neuropathies were the most common of any-grade adverse events (AE) seen in 57% of patients. The median progression-free survival (PFS) for all efficacy-evaluable patients was 5.9 months (95% CI, 2.8-not reached), and the overall response rate (ORR) for EGFR-mutated patients (n = 28) was 32.1%. Among those 28 patients 15 were c-Met high and had an ORR of 52.6%.

Additionally, there were no unexpected safety signals seen when erlotinib was added to telisotuzumab vedotin, and the pharmacokinetic profile was similar to that observed in studies of telisotuzumab vedotin as a monotherapy. Especially in patients with c-Met-high EGFR-mutatedNSCLC, the combination led to promising efficacy.

“The most frequent AE observed in this study was neuropathy [any kind; 57%], a known side effect of MMAE-containing drugs. 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% grade ≥ 3],” wrote the study authors in findings published in the Journal of Clinical Oncology. “The rate of peripheral sensory neuropathy in this study [43%] was like that observed with other approved MMAE ADC-containing drugs. Of note, 86% of patients in this study had received prior chemotherapy and several had prior history of neuropathy, both of which are risk factors for development of subsequent neuropathy.”

Telisotuzumab vedotin is an antibody-drug conjugate which targets c-Met, a receptor tyrosine kinase that is overexpressed in NSCLC tumors. In January 2023, the FDA granted a breakthrough therapy designation to the agent for the treatment of patients with advanced/metastatic EGFR wildtype, nonsquamous NSCLC with high levels of c-Met overexpression whose disease progressed on or after platinum-based therapy.

In the phase 1/2b multicenter, open-label study, the study evaluated telisotuzumab vedotin given at a dose of 2.7 mg/kg once every 21 days plus erlotinib at 150 mg once daily in adult patients with c-Met protein-expressing NSCLC. The trial later added the requirement of the presence of an EGFR-activating mutation and progression on a prior EGFR TKI.

Those enrolled included patients aged 18 years and older with advanced NSCLC not amenable to resection or other approved therapies. Patients must have had archival tumor tissue available for biomarker analysis and confirmation of c-Met overexpression, MET exon 14 skipping mutations, or MET amplification, as determined by a central/local site laboratory, an ECOG performance status of 0-2, and adequate bone marrow, renal, and hepatic function.

The key end points assessed in the study included safety, pharmacokinetics, ORR, and progression-free survival (PFS).

Among evaluable patients, 25 of the 36 (69%) had received 3 or more prior lines of therapy, 36 patients (83%) received a first-/second-generation EGFR TKI across all lines, and 16 (44%) patients were given a third-generation EGFR TKI. A third-generation EGFR TKI was the last prior therapy for 33% of these patients. The median age of all 36 patients enrolled was 65 years (range, 34-80), most patients were female (58%), and most had an ECOG performance status of 1 (72%).

In the c-Met protein expressing efficacy-evaluable population, 53% were c-Met-high, MET amplification was seen in 6 patients (17%), including 4 who were EGFR-mutated, 1 EGFR-wildtype, and one rare/unknown EGFR. Of the 6 patients who were MET-amplified, 5 were c-Met high. Then, 13 patients with confirmed T790M mutations were split between c-Met-high (n = 6) and lower c-Met expression (n = 7).

Findings showed that the median duration of exposure to telisotuzumab vedotin was 18.1 weeks (range, 3.1-99.1). Patients were given a median of 7 treatment cycles (range, 2.0-34.0), and the median duration of exposure to erlotinib was 20.3 weeks (range, 3.1-110.4), while they received a median 5-and-a-half treatment cycles (range, 2.0-33.0).

Among the efficacy evaluable population, the ORR was 30.6% (95% CI, 16.3-48.1), the disease control rate (DCR) was 86.1% (95% CI, 70.5-95.3). At the time of the data cutoff, the duration of response (DOR) was NR.

For the 28 EGFR-mutated patients there was 1 complete response (3.6%) and 8 partial responses (PR; 28.6%). The DCR was 85.7% (95% CI, 67.3-96.0). Then, EGFR-mutated patients who had previously received the third-generation EGFR TKI osimertinib (n = 15), the ORR was 27% and the DCR was 73.3%. For patients who never received osimertinib, the ORR was 39%, and the DCR was 100%. EGFR-wildtype patients (n = 5) had an ORR of40%, including 2 PRs. The DCR for these patients was 80%.

Regarding safety, the most common AEs of any-grade included peripheral sensory neuropathy (43%), dermatitis acneiform (38%), diarrhea (33%), and hypoalbuminemia (33%). Grade 3 or greater AEs were observed in 27 patients (64%), with the most common being pulmonary embolism (14%), hypokalemia (10%), and diarrhea, malignant neoplasm progression, peripheral sensory neuropathy, and hypophosphatemia (7% each).

AEs of any-grade possibly related to telisotuzumab vedotin were seen in 37 patients (88%). The most common was peripheral sensory neuropathy (36%), followed by peripheral neuropathy (19%). Eleven patients (26%) required a dose interruption or discontinued treatment due to neuropathy. However, most events were mild-to-moderate with only 12% being grade ≥ 3.

“Incidence rates of all other ocular toxicities were ≤ 5% for patients treated with Teliso-V plus erlotinib, well below the rates reported for other approved MMAE ADC-containing drugs. Additionally, patients in this study displayed some toxicities associated with targeting c-Met including peripheral edema [12%] and hypoalbuminemia [33%]. However, similar to telisotuzumab vedotin monotherapy, no patients experienced grade ≥ 3 peripheral edema or hypoalbuminemia. Altogether, this suggests that the addition of erlotinib did not exacerbate the safety profile of telisotuzumab vedotin,” concluded the study authors.

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. 2023;41(5):1105-1115. doi:10.1200/JCO.22.00739
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