Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer

Lingzhi Hong; Muhammad Aminu; Shenduo Li; Xuetao Lu; Milena Petranovic; Maliazurina B Saad; Pingjun Chen; Kang Qin; Susan Varghese; Waree Rinsurongkawong; Vadeerat Rinsurongkawong; Amy Spelman; Yasir Y Elamin; Marcelo V Negrao; Ferdinandos Skoulidis; Carl M Gay; Tina Cascone; Saumil J Gandhi; Steven H Lin; Percy P Lee; Brett W Carter; Carol C Wu; Mara B Antonoff; Boris Sepesi; Jeff Lewis; Don L Gibbons; Ara A Vaporciyan; Xiuning Le; J Jack Lee; Sinchita Roy-Chowdhuri; Mark J Routbort; Justin F Gainor; John V Heymach; Yanyan Lou; Jia Wu; Jianjun Zhang; Natalie I Vokes

doi:10.1038/s41467-023-36328-z

Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer

Nat Commun. 2023 Feb 8;14(1):695. doi: 10.1038/s41467-023-36328-z.

Authors

Lingzhi Hong^#^{1

2}, Muhammad Aminu^#², Shenduo Li^#³, Xuetao Lu⁴, Milena Petranovic⁵, Maliazurina B Saad², Pingjun Chen², Kang Qin¹, Susan Varghese¹, Waree Rinsurongkawong⁴, Vadeerat Rinsurongkawong⁴, Amy Spelman¹, Yasir Y Elamin¹, Marcelo V Negrao¹, Ferdinandos Skoulidis¹, Carl M Gay¹, Tina Cascone¹, Saumil J Gandhi⁶, Steven H Lin⁶, Percy P Lee⁶, Brett W Carter⁷, Carol C Wu⁷, Mara B Antonoff⁸, Boris Sepesi⁸, Jeff Lewis⁴, Don L Gibbons¹, Ara A Vaporciyan⁸, Xiuning Le¹, J Jack Lee⁴, Sinchita Roy-Chowdhuri⁹, Mark J Routbort⁹, Justin F Gainor¹⁰, John V Heymach¹, Yanyan Lou³, Jia Wu^{1

2}, Jianjun Zhang^{11

12}, Natalie I Vokes^{13

14}

Affiliations

¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
⁴ Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷ Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jzhang20@mdanderson.org.
¹² Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jzhang20@mdanderson.org.
¹³ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. nvokes@mdanderson.org.
¹⁴ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. nvokes@mdanderson.org.

^# Contributed equally.

Abstract

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Drug Therapy, Combination
Humans
Immune Checkpoint Inhibitors / pharmacology
Immune Checkpoint Inhibitors / therapeutic use
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Retrospective Studies

Substances

Immune Checkpoint Inhibitors

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States