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Poster session 13

481P - A phase I first-in-human study of XL092 in patients (pts) with locally advanced or metastatic solid tumors: Results from dose-escalation of XL092 alone and in combination with atezolizumab

Date

10 Sep 2022

Session

Poster session 13

Topics

Clinical Research

Tumour Site

Renal Cell Cancer

Presenters

Manish Sharma

Citation

Annals of Oncology (2022) 33 (suppl_7): S197-S224. 10.1016/annonc/annonc1049

Authors

M.R. Sharma1, V. Subbiah2, G. Shapiro3, S.K. Pal4, N. Agarwal5, K. Wentzel6, B. Fang7, N. Zhang8, M. Schwickart9, Z. Wang10, D. Curran11, A. Patnaik12

Author affiliations

  • 1 Medical Oncology Dept., START Midwest, MI 49546 - Grand Rapids/US
  • 2 Department Of Investigational Cancer Therapeutics, Division Of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, 77030 - Houston/US
  • 3 Medical Oncology, Dana Farber Cancer Institute, 02215 - Boston/US
  • 4 Medical Oncology And Therapeutics Research, City of Hope Comprehensive Cancer Center, 91010 - Duarte/US
  • 5 Department Of Clinical Research Innovation, Huntsman Cancer Institute, University of Utah, 84112 - Salt Lake City/US
  • 6 Genitourinary Cancer Clinical Program, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 7 Department Of Clinical Research, Astera Cancer Care, 08816 - East Brunswick/US
  • 8 Department Of Clinical Pharmacology And Nonclinical Development, Exelixis, Inc., 94502 - Alameda/US
  • 9 Department Of Translational Medicine, Exelixis, Inc., 94080-0511 - Alameda/US
  • 10 Department Of Biostatistics And Clinical Data Management, Exelixis, Inc., 94502 - Alameda/US
  • 11 Department Of Clinical Development, Exelixis, Inc., 94502 - Alameda/US
  • 12 Department Of Clinical Research, START San Antonio, 78229 - San Antonio/US
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Abstract 481P

Background

XL092 is a novel multi-targeted inhibitor of receptor tyrosine kinases (RTK) including MET, VEGFR2, AXL, and MER which play roles in tumor growth and immune modulation. XL092 demonstrated antitumor activity alone and in combination with an anti-PD-1 antibody in tumor models. The XL092-001 study (NCT03845166) aimed to define the recommended dose (RD) of XL092 as a single-agent (SA) and in combination with atezolizumab and assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy in pts with solid tumors.

Methods

Pts with advanced solid tumors in which standard of care did not exist or was no longer effective were enrolled. Pts received escalating doses of XL092 (PO QD) as SA or with atezolizumab (Combo) (1200mg IV qQ3W). In dose-escalation, pts were enrolled in a 3 + 3 (SA) or rolling six design (Combo). Study objectives included safety, PK, PD, and preliminary efficacy.

Results

As of 2 Mar 2022, 73 pts (47 SA and 26 Combo) received study treatment. Median age was 61y for SA and 64y for Combo and 62% and 58% pts had an ECOG score of 1. Median number of prior agents across all pts was 5. Pts were dosed from 10–140 mg with SA, and 40–120 mg with Combo. Dose limiting toxicities were hypertension and diarrhea for SA and fatigue, gastritis, and abdominal pain for Combo. Most common treatment-related adverse events were hypertension (43%), nausea (40%), and diarrhea (36%) for SA and fatigue (50%), diarrhea (35%), and hypertension (31%) for Combo. Maximum tolerated dose was 120 mg for both SA and Combo and RD was 100 mg for both. PK showed a half-life of 16–22 hours. PD showed consistent effect of peripheral biomarkers at the RD. Confirmed partial responses were observed for SA (1 renal cell carcinoma, 2 metastatic castration-resistant prostate cancer) and Combo (1 triple-negative breast cancer).

Conclusions

XL092 demonstrated a manageable safety profile with no unexpected AEs based on current RTK inhibitors. PK, PD, and efficacy data support selection of a 100 mg dose for XL092 alone or with atezolizumab for further investigation. Expansion cohorts are ongoing in a number of tumor types.

Clinical trial identification

NCT03845166.

Editorial acknowledgement

Suvajit Sen, PhD (Exelixis).

Legal entity responsible for the study

Exelixis, Inc.

Funding

Exelixis, Inc.

Disclosure

M.R. Sharma: Financial Interests, Personal, Stocks/Shares: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Incyte, Johnson & Johnson, Eli Lilly, Merck, Moderna, Pfizer, Regeneron, Vertex; Financial Interests, Institutional, Research Grant: AbbVie, Agenus , Alpine, Alexion, Ascentage, Seven and Eight, Bolt, GlaxoSmithKline, ristol Myers Squibb, Celgene, Treadwell, Cullinan, Compugen, Constellation, Coordination, CytomX, Debiopharm, Palleon, eFFECTOR, Genmab, Arrys, Gilead, Helsinn, Innovent, Ikena, InhibRx, Incyte, Macrogenics, Jounce, Kinnate, KSQ, Loxo, Lilly, PureTech, Merck, Alkermes, NGMBio, Onconova, Pfizer, Regeneron, Repare, Symphogen, Seagen, KLUS, Shattuck Labs, Biosplice, Sapience, Syros, Epizyme, Odonate, Theratechnologies, Tempest, Tizona, Exelixis, Mersana. V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/LOXO Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, TAKEDA; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, I receive research funding from NCI: National Cancer Institute, USA. G. Shapiro: Financial Interests, Personal, Advisory Board: Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines; Financial Interests, Institutional, Invited Speaker: Exelixis, Cyteir, Clovis, Samumed, AbbVie, Incyte, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, CanBas, Cyclacel, Aileron, PUMA; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Esperas, Bayer, Lilly, Boehringer Ingelheim, Seattle Genetics, Syros; Other, Patent: Dosage regimen for sapacitabine and seliciclib, issued to Geoffrey Shapiro and Cyclacel Pharmaceuticals: Cyclacel; Other, Pending patent: Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition, with Liam Cornell, PhD (Dana-Farber Cancer Institute): Dana-Farber Cancer Institute. S.K. Pal: Financial Interests, Personal, Other, Consulting/Honoraria: F. Hoffman LaRoche, Eisai, Genentech, Roche, Exelixis, Pfizer. N. Agarwal: Financial Interests, Personal, Advisory Role: Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Jenssen, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, Seattle Genetics; Financial Interests, Institutional, Research Grant: Calithera, Clovis, Celldex, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Jenssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Seattle Genetics, Prometheus, Rexahn, Roche, Sanofi, Takeda, Tracon; Financial Interests, Personal, Invited Speaker: Merck. B. Fang: Financial Interests, Research Grant: Exelixis, Inc. N. Zhang, M. Schwickart, Z. Wang, D. Curran: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc. A. Patnaik: Financial Interests, Personal, Other, Honoraria: Texas Society of Clinical Oncology (TxSCO); Financial Interests, Personal, Advisory Role: Genentech, Merck, Bristol-Myers Squibb, Bayer, Novartis, Seattle Genetics, Silverback Therapeutics, Shenzhen IONOVA Life Sciences Co., Ltd., Gilead, Daiichi Sankyo, Inc., HalioDx; Financial Interests, Institutional, Research Grant: Merck, Pfizer, Lilly, Plexxikon, Corvus Pharmaceuticals, Tesaro, AbbVie, Forty Seven, Five Prime Therapeutics, Infinity Pharmaceuticals, Pieris Pharmaceuticals, Surface Oncology, Livzon, Vigeo Therapeutics, Astellas Pharma, Klus Pharma, Symphogen, Syndax, Arcus, Fochon, Upsher-Smith, Exelixis, Inc., Seattle Genetics, Bolt, Ionova, Daiichi Sankyo, Sanofi, Seagen Inc., Pionyr Immunotherapeutics, Inc., Loxo Oncology, Inc., on behalf of Eli Lilly and Company, Nektar Therapeutics, KSQ Therapeutics, Alpine Immune Sciences, Amgen, Institut de Recherches Internationales Servier (I.R.I.S). All other authors have declared no conflicts of interest.

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