MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or 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

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy

J Thorac Oncol. 2023 Jul;18(7):907-921. doi: 10.1016/j.jtho.2023.02.016. Epub 2023 Feb 24.

Authors

Kai He¹, David Berz², Shirish M Gadgeel³, Wade T Iams⁴, Debora S Bruno⁵, Collin M Blakely⁶, Alexander I Spira⁷, Manish R Patel⁸, David M Waterhouse⁹, Donald A Richards¹⁰, Anthony Pham¹¹, Robert Jotte¹², David S Hong¹³, Edward B Garon¹⁴, Anne Traynor¹⁵, Peter Olson¹⁶, Lisa Latven¹⁶, Xiaohong Yan¹⁶, Ronald Shazer¹⁶, Ticiana A Leal¹⁷

Affiliations

¹ Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, Ohio. Electronic address: kai.he@osumc.edu.
² Department of Cellular Therapeutics, Beverly Hills Cancer Center, Beverly Hills, California; Current Affiliation: Valkyrie Clinical Trials, Los Angeles, California.
³ Henry Ford Cancer Institute, Henry Ford Health System, Detroit, Michigan.
⁴ Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
⁵ University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
⁶ Department of Medicine, University of California San Francisco, San Francisco, California; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
⁷ Virginia Cancer Specialists, Fairfax, Virginia; US Oncology Network, The Woodlands, Texas.
⁸ Division Of Hematology, Oncology and Transplantation, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
⁹ US Oncology Network, The Woodlands, Texas; Department of Clinical Research, Oncology Hematology Care, Cincinnati, Ohio; Current affiliation: Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center, Milford, Massachusetts.
¹⁰ US Oncology Network, The Woodlands, Texas; Texas Oncology, Tyler, Texas.
¹¹ Northwest Cancer Specialists, Tigard, Oregon.
¹² US Oncology Network, The Woodlands, Texas; Rocky Mountain Cancer Centers, Denver, Colorado.
¹³ MD Anderson Cancer Center, The University of Texas, Houston, Texas.
¹⁴ Department Of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California; Winship Cancer Institute, Emory University, Atlanta, Georgia.
¹⁵ University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
¹⁶ Mirati Therapeutics, Inc., San Diego, California.
¹⁷ University of Wisconsin Carbone Cancer Center, Madison, Wisconsin; Current Affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.

PMID: 36842467
PMCID: PMC10330304 (available on 2024-07-01)
DOI: 10.1016/j.jtho.2023.02.016

Abstract

Introduction: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity.

Methods: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points.

Results: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). 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-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or 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 exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.

Keywords: Antitumor activity; NSCLC; Nivolumab; Sitravatinib; Tyrosine kinase inhibitor.

Publication types

Clinical Trial, Phase II

MeSH terms

Anilides / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / pathology
Humans
Lung Neoplasms* / drug therapy
Nivolumab / pharmacology
Nivolumab / therapeutic use
Tumor Microenvironment

Substances

Nivolumab
sitravatinib
Anilides

Abstract

Publication types

MeSH terms

Substances

Grants and funding