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A novel antibody-drug conjugate (ADC) yielded responses in about a fourth of patients with heavily pretreated, MET-positive non-small cell lung cancer (NSCLC), a multicenter phase II trial showed.

The highest objective response rate with telisotuzumab vedotin was in the group with non-squamous NSCLC and EGFR wild-type disease, in which 35.1% of patients responded per central review, with a median response duration of 6.9 months (95% CI 3.8 to not reached), reported D. Ross Camidge, MD, PhD, of the University of Colorado Cancer Center in Aurora, at the World Conference on Lung Cancer (WCLC).

Among this cohort, those with high MET expression were twice as likely to respond compared with those with intermediate levels of expression (53.8% vs 25%, respectively).

Overall, telisotuzumab vedotin appeared tolerable, said Camidge, and adverse events were consistent with its cytotoxic payload and MET-directed mechanism of action.

Responses were more limited in those with non-squamous NSCLC and EGFR mutations (13.3% per central review), and in those with squamous NSCLC (14.3%) where the median duration of response was 4.4 months (95% CI 3.0 to not reached). There were no complete responses across the three groups, said Camidge.

The level of response in the non-squamous EGFR wild-type cohort will activate an expansion (stage 2) of the trial for this cohort, while activity in the EGFR-mutant cohort continues to be observed until the next interim analysis. The response rate in the squamous cohort "was too low to proceed, per the study plan," he said.

Camidge explained that telisotuzumab vedotin is a first-in-class MET-directed ADC that drives "internalization and degradation of the MET protein" and facilitates delivery of a cytotoxic payload -- the microtubule inhibitor monomethyl auristatin E.

WCLC-designated discussant Federico Cappuzzo, MD, of Istituto Nazionale Tumori Regina Elena in Rome, called the response rate in the non-squamous histology group with high MET expression "remarkable."

"These data are of great interest," he said, adding that the results raise the question of whether immunohistochemistry (IHC) staining could have broader use for treatment decision-making in lung cancer beyond PD-L1 assessment.

For safety, 72% of patients in the study experienced a treatment-emergent adverse event (TEAE) deemed related to the study drug, and common low-grade events included nausea, blurred vision, anemia, and peripheral neuropathy. Grade ≥3 TEAEs occurred in 44%, with the most frequent being malignant neoplasm progression in 5%. Across the cohorts, 21-36% of patients stopped treatment due to TEAEs.

Common serious TEAEs included pneumonia in 5% and pneumonitis in 4%, which might be a class toxicity, said Camidge. There were also three deaths on trial that were "possibly attributable" to the study drug (one case each of sudden death, dyspnea, and pneumonitis).

Study Details

Stage 1 of the phase II trial tested telisotuzumab vedotin at a dose of 1.9 mg/kg every 2 weeks in 90 patients with locally advanced or metastatic NSCLC. Patients were separated by histology (22 squamous, 68 non-squamous), EGFR mutation status (non-squamous: 37 wild-type, 31 mutant), and MET expression level as determined by H-scoring on IHC assay on available archival tumor tissue. Across the three cohorts, patients had a median age of 58-67 years, and 68-86% had an Eastern Cooperative Oncology Group performance status of 1.

A total of 841 patients were screened for inclusion, with MET expression in 25% of those with EGFR wild-type non-squamous tumors, 37% of those with EGFR-mutant non-squamous tumors, and 39% of those with squamous NSCLC.

Across study arms, patients had a median of two prior lines of systemic therapy (up to four), including platinum-based chemotherapy in 84-96% of patients. Prior immunotherapy was more common in the squamous (93%) and EGFR wild-type non-squamous (71%) cohorts, while prior tyrosine kinase inhibitors were nearly exclusive to the EGFR-mutant non-squamous cohort (97%).

For the non-squamous cohort, the cutpoint for MET-high expression was ≥50% membrane staining on IHC at 3-plus intensity, while intermediate expression was 25% to <50% membrane staining at 3-plus intensity. For the EGFR wild-type group, 35% of patients had high MET expression and 65% had intermediate levels. In the EGFR-mutant group, 71% had high expression and the remaining had intermediate MET expression.

For the squamous cohort, MET expression was defined simply as staining on ≥75% of tumor cells on IHC at 1-plus intensity.

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