Phase 1 study of telisotuzumab vedotin in Japanese patients with advanced solid tumors

Yutaka Fujiwara, Hirotsugu Kenmotsu, Noboru Yamamoto, Toshio Shimizu, Kan Yonemori, Christopher Ocampo, Apurvasena Parikh, Sumiko Okubo, Kazuteru Fukasawa, Haruyasu Murakami, Yutaka Fujiwara, Hirotsugu Kenmotsu, Noboru Yamamoto, Toshio Shimizu, Kan Yonemori, Christopher Ocampo, Apurvasena Parikh, Sumiko Okubo, Kazuteru Fukasawa, Haruyasu Murakami

Abstract

Telisotuzumab vedotin (formerly ABBV-399) is an antibody-drug conjugate targeting c-Met-overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open-label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose-limiting toxicity events were observed. The most common treatment-emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment-emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non-Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%-99.7%]). Median progression-free survival was 7.1 months (95% confidence interval: 1.2-10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477.

Keywords: Antibody-drug conjugate; Cancer; Clinical trial; Japanese patients; c-Met.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Preliminary PK profiles for (A) teliso‐v and (B) MMAE. PK profiles (mean +standard deviation) after IV infusion (2.4 mg/kg and 2.7 mg/kg) in cycle 1 on a Q3 W dosage schedule. Log‐linear scales. IV, intravenous; MMAE, monomethyl auristatin E; PK, pharmacokinetic; Q3 W, every 3 weeks; teliso‐v, telisotuzumab vedotin
FIGURE 2
FIGURE 2
Best overall response per patient and duration of treatment. Duration of treatment with overall responses is shown in different types of solid tumors. Two patients had PR, six patients had SD, and one patient had PD. BR, breast cancer; ES, esophageal cancer; LI, liposarcoma; NS, non‐small cell lung cancer; OV, ovarian cancer; PA, pancreatic cancer; PD, progressive disease; PR, partial response; SD, stable disease; TH, thymic cancer; UR, urothelial carcinoma

References

    1. Tong JH, Yeung SF, Chan AWH, et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non‐small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22(12):3048‐3056.
    1. Ma PC, Maulik G, Christensen J, Salgia R. c‐Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22(4):309‐325.
    1. Strickler JH, Weekes CD, Nemunaitis J, et al. First‐in‐human phase I, dose‐escalation and ‐expansion study of telisotuzumab vedotin, an antibody‐drug conjugate targeting c‐Met, in patients with advanced solid tumors. J Clin Oncol. 2018;36(33):3298‐3306.
    1. Benedettini E, Sholl LM, Peyton M, et al. Met activation in non‐small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol. 2010;177(1):415‐423.
    1. Spigel DR, Ervin TJ, Ramlau RA, et al. Randomized phase II trial of onartuzumab in combination with erlotinib in patients with advanced non‐small‐cell lung cancer. J Clin Oncol. 2013;31(32):4105‐4114.
    1. Kim HJ, Yoon A, Ryu JY, et al. c‐MET as a potential therapeutic target in ovarian clear cell carcinoma. Sci Rep. 2016;6:38502.
    1. Sawada K, Radjabi AR, Shinomiya N, et al. c‐Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Can Res. 2007;67:1670‐1679.
    1. Ho‐Yen CM, Jones JL, Kermorgant S. The clinical and functional significance of c‐Met in breast cancer: a review. Breast Cancer Res. 2015;17(1):52.
    1. Varkaris A, Corn PG, Gaur S, Dayyani F, Logothetis CJ, Gallick GE. The role of HGF/c‐Met signaling in prostate cancer progression and c‐Met inhibitors in clinical trials. Expert Opin Investig Drugs. 2011;20(12):1677‐1684.
    1. Safaie Qamsari E, Safaei Ghaderi S, Zarei B, et al. The c‐Met receptor: implication for targeted therapies in colorectal cancer. Tumour Biol. 2017;39(5):1010428317699118.
    1. Lee HE, Kim MA, Lee HS, et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer. 2012;107(2):325‐333.
    1. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17(1):77‐88.
    1. Lennerz JK, Kwak EL, Ackerman A, et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011;29(36):4803‐4810.
    1. Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti‐EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658‐673.
    1. Resnick MB, Routhier J, Konkin T, Sabo E, Pricolo VE. Epidermal growth factor receptor, c‐MET, beta‐catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clin Cancer Res. 2004;10(9):3069‐3075.
    1. Papadimitrakopoulou VA, Wu Y, Han J, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 2018;29(suppl 8):abstract 5121.
    1. Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first‐line osimertinib: preliminary data from the phase III FLAURA study. Ann Oncol. 2018;29(suppl 8):abstract 5005.
    1. BioSpace . Exelixis announces partner Takeda receives approval in Japan for CABOMETYX® (cabozantinib) tablets for the treatment of curatively unresectable or metastatic renal cell carcinoma. 2020. . Accessed September 21, 2020.
    1. BioSpace . OxOnc announces that co‐development partner has received approval in Japan and Taiwan for crizotinib (Xalkori) as a first‐line treatment for patients with ROS1‐positive non‐small cell lung cancer. 2017. . Accessed December 17, 2020.
    1. Wu YL, Soo RA, Locatelli G, Stammberger U, Scagliotti G, Park K. Does c‐Met remain a rational target for therapy in patients with EGFR TKI‐resistant non‐small cell lung cancer? Cancer Treat Rev. 2017;61:70‐81.
    1. Rimassa L, Assenat E, Peck‐Radosavljevic PM, et al. Tivantinib for second‐line treatment of MET‐high, advanced hepatocellular carcinoma (METIV‐HCC): a final analysis of a phase 3, randomised, placebo‐controlled study. Lancet Oncol. 2018;19(5):682‐693.
    1. Shah MA, Bang YJ, Lordick F, et al. Effect of fluorouracil, leucovorin, and oxaliplatin with or without onartuzumab in HER2‐negative, MET‐positive gastroesophageal adenocarcinoma: the METGastric randomized clinical trial. JAMA Oncology. 2017;3(5):620‐627.
    1. Yoshioka H, Azuma K, Yamamoto N, et al. A randomized, double‐blind, placebo‐controlled, phase III trial of erlotinib with or without a c‐Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall‐cell lung cancer harboring wild‐type epidermal growth factor receptor (ATTENTION study). Ann Oncol. 2015;26(10):2066‐2072.
    1. Engstrom LD, Aranda R, Lee M, et al. Glesatinib exhibits antitumor activity in lung cancer models and patients harboring MET exon 14 mutations and overcomes mutation‐mediated resistance to type I MET inhibitors in nonclinical models. Clin Cancer Res. 2017;23(21):6661‐6672.
    1. Paik PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol. 2019;37(suppl 15):abstract 9005.
    1. Wolf J, Seto T, Han JY, et al. Capmatinib (INC280) in METDex14‐mutated advanced non‐small cell lung cancer (NSCLC): efficacy data from the phase II GEOMETRY mono‐1 study. J Clin Oncol. 2019;37(suppl 15):abstract 9004.
    1. Vaidya KS, Oleksijew A, Tucker LA, et al. A "prozone‐like" effect influences the efficacy of the monoclonal antibody ABT‐700 against the hepatocyte growth factor receptor. Pharmacology. 2017;100(5–6):229‐242.
    1. Wang J, Anderson MG, Oleksijew A, et al. ABBV‐399, a c‐Met antibody‐drug conjugate that targets both MET‐amplified and c‐Met‐overexpressing tumors, irrespective of MET pathway dependence. Clin Cancer Res. 2017;23(4):992‐1000.
    1. National Institutes of Health. US National Library of Medicine . . A study to evaluate the safety and pharmacokinetics ABBV‐399 in Japanese participants with solid tumors. 2020. . Accessed September 21, 2020.
    1. Moosavi F, Giovannetti E, Saso L, Firuzi O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit Rev Clin Lab Sci. 2019;56(8):533‐566.
    1. Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non‐small‐cell lung cancer are associated with advanced age and stage‐dependent MET genomic amplification and c‐Met overexpression. J Clin Oncol. 2016;34(7):721‐730.
    1. Camidge DR, Otterson GA, Clark JW, et al. Crizotinib in patients (pts) with MET‐amplified non‐small cell lung cancer (NSCLC): updated safety and efficacy findings from a phase 1 trial. J Clin Oncol. 2018;36(suppl 15):abstract 9062.
    1. Vuong HG, Ho ATN, Altibi AMA, Nakazawa T, Katoh R, Kondo T. Kondo T Clinicopathological implications of MET exon 14 mutations in non‐small cell lung cancer ‐ a systematic review and meta‐analysis. Lung Cancer. 2018;123:76‐82.
    1. Ogura M, Tobinai K, Hatake K, et al. Phase I/II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30‐positive Hodgkin's lymphoma or systemic anaplastic large‐cell lymphoma. Cancer Sci. 2014;105(7):840‐846.

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