An evaluation of telisotuzumab vedotin for the treatment of non-squamous non-small cell lung cancer

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate that delivers a cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) payload to c-Met-expressing tumor cells. It received accelerated approval from the US FDA for the treatment of adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression (≥ 50% of tumor cells with strong [3+] staining) at a dose of 1.9 mg/kg every 2 weeks (Q2W; maximum 190 mg for patients ≥ 100 kg) as an intravenous infusion. Population pharmacokinetic (PK) modeling used pooled data from a phase 1 (N = 35) and phase 2 study (N = 269) to describe the Teliso-V conjugate and unconjugated MMAE PK and evaluate the impact of intrinsic and extrinsic factors on exposures in patients with solid tumors. Body weight, race, albumin, and anti-drug antibody status were identified as significant covariates on Teliso-V conjugate clearance, but did not result in clinically meaningful changes in exposure. The exposure-response evaluations for efficacy (based on the pivotal phase 2 study) showed significant correlations between conjugate exposure and overall response rates. Higher conjugate exposures were also correlated with improved progression-free survival and overall survival, demonstrating meaningful clinical benefit with the 1.9 mg/kg Q2W dosing regimen. Exposure-safety evaluations showed significant relationships between conjugate exposures and grade ≥ 2 and grade ≥ 3 peripheral neuropathy, and grade ≥ 2 corneal epitheliopathy. Unconjugated MMAE payload exposures were correlated with a greater probability of grade ≥ 3 treatment-emergent adverse events. The 1.9 mg/kg Q2W dose maximized efficacy while balancing adverse events in patients with c-Met overexpressing NSCLC.

Telisotuzumab vedotin (telisotuzumab vedotin-tllv; EMRELIS™), an antibody-drug conjugate (ADC) directed against c-mesenchymal-epithelial transition factor (c-MET) protein, is being developed by AbbVie for the treatment of solid tumours. On 14 May 2025, telisotuzumab vedotin received accelerated approval in the USA for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with high c-Met protein overexpression, as determined by an FDA-approved test, who have received a prior systemic therapy. This article summarizes the milestones in the development of telisotuzumab vedotin leading to this first approval for NSCLC.

BackgroundPembrolizumab combined with chemotherapy is now first-line standard of care in advanced non-small cell lung cancer. This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer.MethodsCAP29 is a retrospective, observational, multicenter real-life study conducted in 6 French centers. We evaluated efficacy of first-line setting chemotherapy plus pembrolizumab (November 2019 to September 2020) in advanced (stage III-IV) non-squamous non-small cell lung cancer patients without targetable alterations. Primary endpoint was progression-free survival. Secondary endpoints were overall survival, objective response rate and safety.ResultsWith a median follow-up of 4.5 months (0 to 22 months), a total of 121 patients were included. Baseline characteristics were: median age of 59.8 years with 7.4% ≥75 years, 58.7% of males, 91.8% PS 0-1, 87.6% of stage IV with ≥3 metastatic sites in 62% of cases. Patients had brain and liver metastases in 24% and 15.7% of cases, respectively. PD-L1 was <1% (44.6%), 1–49% (28.1%) and ≥50% (21.5%). Median progression-free survival and overall survival achieved 9 and 20.6 months, respectively. Objective response rate was 63.7% with 7 prolonged complete responses. Survival benefit seemed to be correlated with PD-L1 expression. Brain and liver metastases were not statistically associated with decreased overall survival. Most common adverse events were asthenia (76%), anemia (61.2%), nausea (53.7%), decreased appetite (37.2%) and liver cytolysis (34.7%). Renal and hepatic disorders were the main causes of pemetrexed discontinuation. Grade 3–4 adverse events concerned 17.5% of patients. Two treatment-related deaths were reported.ConclusionsFirst-line pembrolizumab plus chemotherapy confirmed real-life efficacy for patients with advanced non-squamous non-small cell lung cancer. With median progression-free survival and overall survival of 9.0 and 20.6 months, respectively and no new safety signal, our real-life data are very close to results provided by clinical trials, confirming the benefit and the manageable toxicity profile of this combination.

Results from a phase Ib study of telisotuzumab vedotin in combination with osimertinib in patients with c-Met protein-overexpressing, EGFR-mutated locally advanced/metastatic non-small-cell lung cancer (NSCLC) after progression on prior osimertinib.

TPS8658 Background: c-Met protein (also known as MET protein) overexpression is observed in ∼25% of patients with non-squamous EGFR wildtype (WT) non-small cell lung cancer (NSCLC) and is associated with poor prognosis. Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate consisting of the monoclonal antibody telisotuzumab and the cytotoxic payload monomethyl auristatin E. The primary analysis of the phase 2 LUMINOSTY trial (NCT03539536) demonstrated that Teliso-V at 1.9 mg/kg once every 2 weeks (Q2W) was associated with durable responses in patients with previously treated c-Met protein–overexpressing (OE) advanced/metastatic (a/m) non-squamous EGFR WT NSCLC, and adverse events (AEs) were generally manageable. The overall response rate was 28.6% among all patients with c-Met protein overexpression and 34.6% among those with c-Met high protein overexpression (Camidge et al. JCO 2024;42:3000-11). Methods: This global, multicenter, open-label, randomized phase 2 study (NCT06568939) evaluates the safety and efficacy of Teliso-V monotherapy at 1.6 mg/kg Q2W and 1.9 mg/kg Q2W in patients with previously treated c-Met protein OE, a/m non-squamous EGFR WT NSCLC. Eligible patients are ≥18 years old with c-Met protein OE (≥25% tumor cells at 3+ intensity by immunohistochemistry assay [investigational use only assay for MET (SP44) (Roche)]), a/m non-squamous EGFR WT NSCLC. Patients must have measurable disease according to RECIST v1.1, ECOG PS 0–1, and documented disease progression on ≥1 prior lines of therapy (≤1 line of prior chemotherapy) in the a/m setting. Approximately 100 patients will be randomized 1:1 to receive Teliso-V monotherapy at either 1.6 mg/kg or 1.9 mg/kg Q2W until disease progression or other protocol-specified discontinuation criteria are met. The primary safety endpoints are treatment-emergent AEs (TEAEs; any grade and grade ≥2), interstitial lung disease (any grade and grade ≥2), peripheral neuropathy (any grade and grade ≥2), ocular surface disorders (any grade and grade ≥2), TEAEs leading to discontinuation, and grade 5 TEAEs. The primary efficacy endpoint is objective response based on RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints are pharmacokinetics, patient-reported outcomes, duration of response by BICR, progression-free survival by BICR, and overall survival. Clinical trial information: NCT06568939 .

To explore the therapeutic effects of pembrolizumab combined with paclitaxel and cisplatin chemotherapy on advanced non-squamous non-small cell lung cancer and its influencing factors is the main objective. A total of 87 patients with advanced non-squamous non-small cell lung cancer treated in our hospital from October 2016 to May 2018 were enrolled and allocated into control group and observation group according to their disease conditions and willingness. Paclitaxel and cisplatin chemotherapy regimen was employed for control group, based on which pembrolizumab was used for observation group. Cellular immunity indices, cytokine indices, short-term efficacy, adverse reactions, and long-term prognosis were compared, and the factors affecting short-term efficacy and long-term prognosis were analyzed. After treatment, observation group exhibited increased cluster of differentiation 3+ T lymphocytes, cluster of differentiation 4+ T lymphocytes, and cluster of differentiation 4+/cluster of differentiation 8+ ratio and decreased cluster of differentiation 8+ T lymphocytes compared with control group (p<0.05). After treatment, the levels of interleukin-6 and tumor necrosis factor-alpha in observation group were lower than those in control group (p<0.05). The short-term efficacy and long-term prognosis in observation group were better than those in control group (p<0.05), but statistically no significant difference in the incidence rate of adverse reactions was found between the two groups (p>0.05). Decreased cluster of differentiation 4+/cluster of differentiation 8+ ratio increased tumor necrosis factor-alpha level and chemotherapy were risk factors for the poor short-term efficacy and long-term prognosis in patients with advanced non-squamous nonsmall cell lung cancer (p<0.05), and clinical stage IV was a risk factor for the unfavorable long-term prognosis as well (p<0.05). Pembrolizumab combined with paclitaxel and cisplatin chemotherapy regimen can relieve the cellular immune suppression and alleviate inflammatory responses to improve the shortterm efficacy and long-term prognosis, without raising the incidence rate of severe adverse reactions in the treatment of advanced non-squamous non-small cell lung cancer

First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: A randomised, phase 3 trial

Telisotuzumab vedotin represents a clinically important antibody-drug conjugate (ADC) that received accelerated approval from the US Food and Drug Administration in May 2025, establishing it as the first-in-class targeted therapy for adult patients with immunohistochemistry (IHC)-confirmed high-c-Met, EGFR wild-type, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Its mechanism of action relies on precise targeting of the c-Met protein receptor, followed by internalization and release of the potent cytotoxic payload monomethyl auristatin E (MMAE) to eradicate tumor cells. The pivotal phase II LUMINOSITY trial demonstrated that the high c-Met overexpressing group had an overall response rate (ORR) of 34.6%. This therapeutic agent addresses a critical unmet need within a molecularly defined NSCLC subpopulation, marking a substantial advancement in c-Met-targeted oncology. The regulatory authorization and clinical use of telisotuzumab vedotin may significantly advance precision medicine for NSCLC, though an ongoing phase III trial will further confirm its efficacy and safety and determine its eligibility for full regulatory approval in the future.

To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. Bevacizumab concomitant with chemotherapy is effective and the related toxicity can be well tolerated in Chinese patients with NSNSCLC.

Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP+BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3+3 dose escalation design was applied. In stage 1, 140, 260, or 340mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340mg/day of pictilisib was administered in combination with CP+BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340mg once daily. For combination with CP+BEV, tolerability up to 260mg/day was confirmed.

P0066 A randomised phase 3 study comparing first-line pemetrexed plus cisplatin followed by gefitinib as maintenance with gefitinib monotherapy in east Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer

BackgroundBevacizumab with platinum doublet therapy including paclitaxel + carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel + carboplatin led to Grade > 3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination in a Japanese population.MethodsChemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4–6 cycles of carboplatin (area under the concentration–time curve = 6 on Day 1) + nanoparticle albumin-bound paclitaxel (100 mg/m2 on Days 1, 8 and 15) + bevacizumab (15 mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel + bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial.ResultsThe overall response rate was 56.5% (90% confidence interval: 44.5–68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42 months, the median overall survival was 18.9 (range: 10.5–32.4) months. The most frequently observed Grade ≥ 3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%).ConclusionsAll adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

BackgroundAfter the approval of nivolumab some time ago it is necessary to analyse if the results of the randomised clinical trials are correlated with usual clinical practice.PurposeIn this study we...

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein Overexpressing, Nonsquamous, EGFR Wild-type Advanced NSCLC: Updated Analysis of the LUMINOSITY Trial.