Telisotuzumab Vedotin Receives Breakthrough Therapy Status From FDA for Select NSCLC


The FDA granted a breakthrough therapy designation to telisotuzumab vedotin for use in patients with advanced or metastatic EGFR wild-type, nonsquamous non–small cell lung cancer who have high levels of c-Met overexpression and whose disease has progressed on, or after, platinum-based chemotherapy.

Mohamed Zaki, MD, PhD

Mohamed Zaki, MD, PhD

The FDA has granted a breakthrough therapy designation to telisotuzumab vedotin (ABBV-399; teliso-V) for use in patients with advanced or metastatic EGFR wild-type, nonsquamous non–small cell lung cancer (NSCLC) who have high levels of c-Met overexpression and whose disease has progressed on, or after, platinum-based chemotherapy.1

The decision is supported by findings from the ongoing phase 2 LUMINOSITY trial (Study M14-239; NCT03539536), which found that treatment with the investigational antibody-drug conjugate as a monotherapy in the second- or third-line setting elicited an overall response rate (ORR) of 53.8% in patients with EGFR wild-type, nonsquamous NSCLC and high c-Met expression; the ORR was 25.0% in the subset of patients with intermediate c-Met expression.

Additional data on telisotuzumab vedotin will be shared at upcoming medical meetings, according to AbbVie, the drug developer.

“Patients with NSCLC have a high unmet need and telisotuzumab vedotin has the potential to provide them with an additional treatment option to manage their disease,” Mohamed Zaki, MD, PhD, vice president and global head of oncology clinical development at AbbVie, stated in a press release. “Today’s announcement marks an important step in our mission to advance new oncology treatments across tumor types to improve standards of care for patients with cancer.”

A cell-surface receptor kinase that is encoded by the MET proto-oncogene, c-Met binds hepatocyte growth factor (HGF).2 Aberrant activation of the c-Met/HGF axis through MET amplification, transcription, and constitutive activation has been reported in several cancers and is associated with poor outcomes.

Overexpression of c-Met has been observed in 30% to 50% of patients with NSCLC, with activation noted in 4% of primary tumors. This activation is thought to be the primary driver of high levels of MET amplification or MET exon 14 skipping mutations in some cases of NSCLC.

Additionally, high levels of MET amplification have also been reported in those who have NSCLC and tumors that harbor EGFR-activating mutations, who have experienced disease progression on EGFR TKIs. As such, it is hypothesized that MET amplification may drive acquired resistance to such TKIs.

Telisotuzumab vedotin is a humanized monoclonal antibody that targets c-Met and is conjugated to monomethyl auristatin E (MMAE). The ADC is internalized and has been shown to release MMAE, which binds to tubulin and causes cell death through the inhibition of mitosis. Previously, the agent has demonstrated antitumor activity in both MET-amplified and c-Met–overexpressing tumor models.

The key eligibility criteria for the LUMINOSITY trial includes having histologically confirmed, nonsquamous NSCLC with known EGFR status and locally advanced or metastatic disease with c-Met positivity.3 Moreover, patients must have received no more than 2 prior lines of systemic treatment and have an ECOG performance status of 0 or 1.

If patients previously received c-Met–targeted, antibody-based therapies, have adenosquamous histology, clinically significant conditions, unresolved clinically significant toxicities from previous therapies, underwent major surgery within 21 days before their first dose of the study drug, or received live vaccine within 30 days of the first ADC dose, they were excluded. Patients with central nervous system (CNS) metastases are only eligible if they had received definitive therapy, such as surgery or radiotherapy.

The primary end point of the trial is ORR, and key secondary end points include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival.

Stage 1 of the trial will examine the ADC as second- and third-line treatment in this population, and then investigators will expand the groups to further assess the efficacy of the agent in select patient populations.

Previously, the ADC was evaluated in combination with erlotinib (Tarceva) or nivolumab (Opdivo) in patients with c-Met–positive NSCLC, as part of a phase 1/1b trial (NCT02099058).2 The multicenter, open-label trial enrolled patients with advanced NSCLC not amenable to resection or other approved options who had c-Met overexpression and a documented MET exon 14 skipping mutation or MET amplification.

To be eligible, patients needed to be at least 18 years of age, have an ECOG performance status ranging from 0 to 2, measurable disease per RECIST v1.1 criteria, and acceptable bone marrow, renal, and hepatic function.

To participate in the erlotinib arm specifically, patients needed to have an EGFR activating mutation and have progressed on a prior EGFR TKI.

If patients received anticancer therapy within 21 days before first study dose, had uncontrolled CNS metastases, or underwent a major surgical procedure within 21 days before first study dose, they were excluded.

In the phase 1, dose-expansion portion of the trial, single-agent telisotuzumab vedotin was examined at escalating intravenous doses, going from 0.15 mg/kg every 3 weeks to 0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg, 1.8 mg/kg, 2.4 mg/kg, 3.0 mg/kg, up to 3.3 mg/kg in patients with c-Met–positive NSCLC. The recommended phase 2 dose of the ADC was established to be 2.7 mg/kg, given every 3 weeks.

In the phase 1b portion, telisotuzumab vedotin was evaluated in combination with erlotinib in this patient population. Here, the ADC was given intravenously at a dose of 2.7 mg/kg every 3 weeks and erlotinib was administered orally at a daily dose of 150 mg.

As of December 2018, a total of 42 patients were enrolled to the expansion cohort of the trial, which was examining the doublet. Of these patients, 37 had c-Met positivity, and 36 were determined to be evaluable. Thirty-five patients had an H-score of 150 or higher, and 1 patient had MET amplification.

The median age among all 36 patients was 65 years (range, 34-83), 61% were female, and 69% had an ECOG performance status of 1. Most participants (97%) had nonsquamous histology and 3% had squamous histology. Eighty-one percent of patients had EGFR-sensitizing mutations such as del19 (39%) and L858R (36%).

Moreover, 11% had 1 prior line of treatment, 17% had 2 prior lines, 31% had 3 prior lines, and 39% had 4 or more prior lines. Previous anticancer therapies included platinum-based treatment (67%), checkpoint inhibitors (28%), docetaxel (17%), c-Met inhibitor (67%), and an EGFR TKI (83%). Forty-four percent of patients previously received a third-generation EGFR TKI and 58% received an EGFR TKI prior to study enrollment.

The median time from initial diagnosis was 26 months (range, 3-116), and the median duration of the last line of anticancer treatment received was 8 months (range, 1-112).

Of the 36 patients who were efficacy evaluable, 29 had tumors that harbored EGFR mutations and 7 did not harbor such mutations. The doublet elicited an ORR of 34.5% (95% CI, 17.9%-54.3%) in those with EGFR positivity vs 28.6% (95% CI, 3.7%-71.0%) in those without those mutations. The DCRs with the combination in these subsets were 86.2% (95% CI, 68.3%-96.1%) and 85.7% (95% CI, 42.1%-99.6%), respectively.

The median duration of response had not yet been reached (NR) in both those harboring EGFR mutations (95% CI, 2.8–not evaluable [NE]) and those who did not (NR–NE). Among those with EGFR-mutant disease, the median PFS had not yet been reached (95% CI, 2.8–NE) vs 5.9 months (95% CI, 1.2–NE) in those without those mutations.

The median duration of treatment with the ADC was comparable in those who harbored an EGFR mutation vs those who did not. The duration of treatment with erlotinib was found to be longer in those with EGFR-mutant disease vs those without that mutation.

Regarding safety, all patients examined reported a treatment-emergent adverse effect (TEAE), the most common of which included dermatitis acneiform (all grade, 38%; grade 3 or higher, 5%), diarrhea (36%; 7%), peripheral sensory neuropathy (36%; 2%), dyspnea (31%; 5%), fatigue (31%; 2%), hypoalbuminemia (31%; 0%), decreased appetite (24%; 2%), and nausea (24%; 0%), among others.

Sixty-two percent of patients reported grade 3 or higher TEAEs, the most frequent of which being pulmonary embolism (14%).

A total of 3 patients experienced a TEAE that resulted in death; 2 of these patients experienced progressive disease and 1 died from hemoptysis.

Telisotuzumab vedotin will also be examined as a single agent in patients with previously treated, c-Met–overexpressing NSCLC as part of the randomized phase 3 TeliMET NSCLC trial (Study M18-868).


  1. AbbVie announces US FDA granted breakthrough therapy designation (BTD) to telisotuzumab vedotin (teliso-V) for previously treated non-small cell lung cancer. News release. AbbVie; January 4, 2022. Accessed January 5, 2022.
  2. Camidge DR, Barlesi F, Goldman JW, et al. Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status. J Clin Oncol. 2019;37(suppl 15):3011. doi:10.1200/JCO.2019.37.15_suppl.3011
  3. Study of telisotuzumab vedotin (ABBV-399) in participants with previously treated c-Met+ non-small cell lung cancer. Updated December 27, 2021. Accessed January 5, 2022.
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