MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy

Kai He; David Berz; Shirish M. Gadgeel; Wade T. Iams; Debora S. Bruno; Collin M. Blakely; Alexander I. Spira; Manish R. Patel; David M. Waterhouse; Donald A. Richards; Anthony Pham; Robert Jotte; David S. Hong; Edward B. Garon; Anne Traynor; Peter Olson; Lisa Latven; Xiaohong Yan; Ronald Shazer; Ticiana A. Leal

doi:10.1016/j.jtho.2023.02.016

Original Article|Articles in Press

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy

Kai He, MD, PhD
Kai He
Correspondence
Corresponding Author: Dr Kai He, MD, PhD, Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio 43210, USA, , Tel: (+1) 614-366-4139
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Affiliations
Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio 43210, USA
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David Berz, MD ^∗
Author Footnotes
∗ Current affiliation: Valkyrie Clinical Trials, Los Angeles, California 90067, USA
David Berz
Footnotes
∗ Current affiliation: Valkyrie Clinical Trials, Los Angeles, California 90067, USA
Affiliations
Department of Cellular Therapeutics, Beverly Hills Cancer Center, Beverly Hills, California 90211, USA
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Shirish M. Gadgeel, MD
Shirish M. Gadgeel
Affiliations
Henry Ford Cancer Institute, Henry Ford Health System, Detroit, Michigan 48202, USA
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Wade T. Iams, MD
Wade T. Iams
Affiliations
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37212, USA
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Debora S. Bruno, MD, MS
Debora S. Bruno
Affiliations
University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA
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Collin M. Blakely, MD, PhD
Collin M. Blakely
Affiliations
Department of Medicine, University of California San Francisco and Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94158, USA
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Alexander I. Spira, MD, PhD
Alexander I. Spira
Affiliations
Virginia Cancer Specialists, Fairfax, Virginia 22031, USA; US Oncology Network, The Woodlands, Texas 77380, USA
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Manish R. Patel, DO
Manish R. Patel
Affiliations
Division Of Hematology, Oncology and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota 55455, USA
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David M. Waterhouse, MD, MPH ^†
Author Footnotes
† Current affiliation: Dana-Farber/Brigham and Women’s Cancer Center at Milford Regional Medical Center, Milford, Massachusetts 01757, USA
David M. Waterhouse
Footnotes
† Current affiliation: Dana-Farber/Brigham and Women’s Cancer Center at Milford Regional Medical Center, Milford, Massachusetts 01757, USA
Affiliations
Department of Clinical Research, Oncology Hematology Care, Cincinnati, Ohio 45242, USA; US Oncology Network, The Woodlands, Texas 77380, USA
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Donald A. Richards, MD, PhD
Donald A. Richards
Affiliations
Texas Oncology, Tyler, Texas 75702, USA; US Oncology Network, The Woodlands, Texas 77380, USA
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Anthony Pham, MD
Anthony Pham
Affiliations
Northwest Cancer Specialists, Tigard, Oregon 97223, USA
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Robert Jotte, MD, PhD
Robert Jotte
Affiliations
Rocky Mountain Cancer Centers, Denver, Colorado 80218, USA; US Oncology Network, The Woodlands, Texas 77380, USA
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David S. Hong, MD
David S. Hong
Affiliations
MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA
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Edward B. Garon, MD
Edward B. Garon
Affiliations
Department Of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095, USA; Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
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Anne Traynor, MD
Anne Traynor
Affiliations
University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA
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Peter Olson, PhD
Peter Olson
Affiliations
Mirati Therapeutics, Inc., San Diego, California 92122, USA
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Lisa Latven, BA
Lisa Latven
Affiliations
Mirati Therapeutics, Inc., San Diego, California 92122, USA
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Xiaohong Yan, PhD
Xiaohong Yan
Affiliations
Mirati Therapeutics, Inc., San Diego, California 92122, USA
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Ronald Shazer, MD
Ronald Shazer
Affiliations
Mirati Therapeutics, Inc., San Diego, California 92122, USA
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Ticiana A. Leal, MD ^‡
Author Footnotes
‡ Current affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
Ticiana A. Leal
Footnotes
‡ Current affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA
Affiliations
University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, Madison, Wisconsin 53792, USA
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Show footnotesHide footnotes
Author Footnotes
∗ Current affiliation: Valkyrie Clinical Trials, Los Angeles, California 90067, USA
† Current affiliation: Dana-Farber/Brigham and Women’s Cancer Center at Milford Regional Medical Center, Milford, Massachusetts 01757, USA
‡ Current affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA

Open AccessPublished:February 24, 2023DOI:https://doi.org/10.1016/j.jtho.2023.02.016

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ABSTRACT

Introduction

Sitravatinib, a receptor tyrosine kinase inhibitor targeting TAM receptors and VEGFR2, can shift the tumor microenvironment towards an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPI) may augment antitumor activity.

Methods

The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2/4 weeks) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) who progressed on/after prior CPI (CPI-experienced) or chemotherapy (CPI-naïve). CPI-experienced patients had prior clinical benefit (PCB; complete/partial response or stable disease for ≥12 weeks then disease progression) or no PCB (NPCB) from CPI. Primary endpoint was objective response rate (ORR); secondary objectives included safety and secondary efficacy endpoints.

Results

Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naïve patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naïve. Median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naïve, respectively; median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naïve patients; median follow-up 20.4 months). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naïve patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction/interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action.

Conclusions

Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination demonstrated antitumor activity and encouraging survival in CPI-experienced patients with non-squamous NSCLC.

Keywords

Article info

Publication history

Accepted: February 21, 2023

Received in revised form: February 16, 2023

Received: December 7, 2022

Publication stage

In Press Journal Pre-Proof

Footnotes

CRediT author statement

Kai He: Conceptualization, Formal analysis, Investigation, Resources, Data curation, Writing – Reviewing and Editing, Visualization, Supervision, Project administration; David Berz: Investigation, Resources, Writing – Reviewing and Editing, Supervision; Shirish M. Gadgeel: Investigation, Resources, Writing – Reviewing and Editing; Wade T. Iams: Investigation, Resources, Writing – Reviewing and Editing; Debora S. Bruno: Investigation, Resources, Data curation, Writing – Reviewing and Editing; Collin M. Blakely: Investigation, Writing – Reviewing and Editing; Alexander I. Spira: Formal analysis, Investigation, Resources, Data curation, Writing – Original draft, Writing – Reviewing and Editing, Supervision, Funding acquisition; Manish R. Patel: Resources, Writing – Reviewing and Editing; David M. Waterhouse: Validation, Formal analysis, Investigation, Resources, Writing – Original draft, Writing – Reviewing and Editing, Supervision, Project administration; Donald A. Richards: Investigation, Writing – Reviewing and Editing; Anthony Pham: Investigation; Robert Jotte: Data curation, Writing – Reviewing and Editing, Supervision; David S. Hong: Investigation, Resources, Data curation, Writing – Reviewing and Editing, Supervision; Edward B. Garon: Investigation, Resources, Writing – Reviewing and Editing; Anne Traynor: Investigation, Resources, Writing – Reviewing and Editing; Peter Olson: Conceptualization, Formal analysis, Investigation, Data curation, Writing – Original draft, Writing – Reviewing and Editing, Supervision, Project administration; Lisa Latven: Writing – Reviewing and Editing, Supervision, Project administration; Xiaohong Yan: Formal analysis, Writing – Reviewing and Editing, Visualization; Ronald Shazer: Validation, Data curation, Writing – Reviewing and Editing, Supervision, Project administration; Ticiana A. Leal: Investigation, Resources, Writing – Original draft, Writing – Reviewing and Editing, Visualization, Supervision, Project administration

Previous presentations: Presented in part at the European Society Medical Oncology annual meeting 2021.

Trial registry: https://clinicaltrials.gov/ct2/show/NCT02954991

Funding

This study was sponsored by Mirati Therapeutics, Inc.

Author Disclosures

K. He: Financial Interests, Personal, Advisory Board: Mirati Therapeutics, Inc., Perthera, Bristol Myers Squibb, Iovance Biotherapeutics, Lyell, AstraZeneca.

D. Berz: Financial Interests, Personal, Advisory Board: Biocept, Prelude Dx; Financial Interests, Personal, Speaker’s Bureau: Caris Life Sciences, Tempus, Natera, Biocept, Boehringer Ingelheim, Genentech, Novartis, AstraZeneca, Sun, Oncocyte.

S.M. Gadgeel: Advisory Board: Genentech/Roche, AstraZeneca, Eli Lilly, Takeda, Bristol Myers Squibb, Pfizer, Janssen, Novartis, Daiichi Sankyo, Blueprint Medicines, Mirati Therapeutics, Inc.; DSMB: AstraZeneca.

W.T. Iams: Financial Interests, Personal, Advisory Board: Genentech, Defined Health, Outcomes Insights, Jazz Pharmaceuticals, GI Therapeutics, Curio Science, AstraZeneca, Janssen, Bristol Myers Squibb, Mirati Therapeutics, Inc., NovoCure, Regeneron.

D.S. Bruno: Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Mirati Therapeutics, Inc., Bristol Myers Squibb, Daiichi Sankyo, Tempus Lab, AstraZeneca; Research funding: AstraZeneca.

C.M. Blakely: Financial Interests, Personal, Advisory Board: Foundation Medicine, Amgen, Blueprint Medicines, Bayer, Oncocyte; Financial Interests, Institutional, Research Grant: Novartis, Ignyta, Mirati Therapeutics, Inc., MedImmune, AstraZeneca, Roche/Genentech, Takeda, Spectrum.

A.I. Spira: Financial Interests, Personal, Research Funding: LAM Therapeutics, Regeneron; Financial Interests, Institutional, Research Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, Abbvie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Inc., Rubius, Synthekine, Mersana, Blueprint Medicines, Alkermes, Revolution Medicines; Financial Interests, Personal, Consulting Fees: Incyte, Amgen, Novartis, Mirati Therapeutics, Inc., Gritstone, Jazz Pharmaceuticals, Takeda, Janssen, Mersana, Daiichi Sankyo/AstraZeneca, Regeneron; Financial Interests, Institutional, Consulting Fees: Array Biopharma, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Blueprint Medicines; Financial Interests, Personal, Lectures, Presentations, Speakers Bureaus, Manuscript Writing or Educational Events: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer; Financial, Institutional, Leadership or fiduciary role in other board, society, committee or advocacy group: NEXT Oncology Virginia; Financial, Personal, Stock or stock options: Eli Lilly.

M.R. Patel: Financial Interests, Personal, Advisory Board: Sanofi, Juice Pharma Worldwide; Research funding: Merck Sharp & Dohme, AstraZeneca, Fate Therapeutics.

D.M. Waterhouse: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, AZ Therapies, AbbVie, Amgen, Janssen, McGivney Global Advisors, Seattle Genetics, Jazz Pharmaceutical, Exelixis, Eisai, EMD Serono, Mirati Therapeutics, Inc., Pfizer, Merck, Regeneron/Sanofi; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck, Janssen, AstraZeneca; Financial Interests, Personal, Consulting Fees: Amgen, Janssen, Fresenius Kabi.

D.A. Richards: Financial Interests, Personal, Advisory Board: Ipsen, Taiho, Seattle Genetics/Astellas, Mirati Therapeutics, Inc.

A. Pham: Dr Pham reports no disclosures.

R. Jotte: Financial Interests, Personal, Advisory Board: Mirati Therapeutics, Inc.

D.S. Hong: Financial Interests, Personal, Stocks/Shares: Molecular Match, OncoResponse; Financial Interests, Personal, Advisory Board: Telperian; Financial interests, Personal, Consulting, Speaker, or Advisory role: Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, AUM Biosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COG, COR2ed, Cowen, EcoR1, Erasca, F. Hoffmann-La Roche, Genentech, Gennao Bio, Gilead, GLG, Group H, Guidepoint, HCW Precision Oncology, Immunogenesis, Janssen, Liberium, MedaCorp, Medscape, Numba, Oncologia Brasil, ORI Capital, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, RAIN, SeaGen, STCube, Takeda, Tavistock, Trieza Therapeutics, Turning Point Therapeutics, WebMD, YingLing Pharma, Ziopharm; Financial Interests, Institutional, Research Grant: AbbVie, Adaptimmune, Adlai Nortye, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Deciphera, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Immunogenesis, Infinity, Merck, Mirati Therapeutics, Inc., Navier, NCT-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Revolution Medicine, SeaGen, STCube, Takeda, TCR2, Turning Point Therapeutics, VM Oncology; Financial Interests, Personal, Travel, Accommodations, Expenses: AACR, ASCO, Bayer, Genmab, SITC, Telperian.

E.B. Garon: Consultant and/or Advisor: Abbvie, ABL-Bio, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio; Grant/Research Support: ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Inc., Neon, Novartis.

A. Traynor: Dr Traynor reports no disclosures

P. Olson: Royalties or licenses: UCSF; Consulting fees: Boxer Capital; Stock or stock options: Pfizer, Tango Therapeutics; Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.

L. Latven: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics, Inc.

X. Yan: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.; Stock or stock options: Mirati Therapeutics, Inc.

R. Shazer: Financial Interests, Personal, Full-time Employment: Mirati Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics, Inc.

T.A. Leal: Financial Interests, Personal, Advisory Board: Invision First Lung, Beyond Spring Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Merck, Takeda, Genentech, Novocure, Jazz Pharmaceuticals, EMD Serono, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo; Financial Interests, Personal, Consulting Fees: AstraZeneca, Genentech, Invision First Lung, Merck, Jazz Pharmaceuticals, EMD Serono, Boehringer-Ingelheim, Blueprint Medicines, Bayer, Eli Lilly, Janssen, Daiichi Sankyo, Takeda, Eisai, Novocure, Amgen, Roche, Regeneron; Financial Interests, Institutional, Research grant or contract: Pfizer, Advaxis, Bayer.

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DOI: https://doi.org/10.1016/j.jtho.2023.02.016

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MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Non-Squamous Non-Small Cell Lung Cancer Progressing On/After Checkpoint Inhibitor Therapy or Chemotherapy

ABSTRACT

Introduction

Methods

Results

Conclusions

Keywords

Article info

Publication history

Publication stage

Footnotes

Identification

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