Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non鈥揝mall-Cell Lung Cancer

鈥� An ASCO Reading Room selection

May 24, 2024

Biagio Ricciuti, MD, PhD, Giuseppe Lamberti, MD, PhD, Sreekar R. Puchala, PhD, Navin R. Mahadevan, MD, PhD, Jia-Ren Lin, PhD, Joao V. Alessi, MD, Alexander Chowdhury, PhD, Yvonne Y. Li, PhD, Xinan Wang, PhD, Liam Spurr, MD, Federica Pecci, MD, Alessandro Di Federico, MD, Deepti Venkatraman, BS, Adriana P. Barrichello, MD, Malini Gandhi, BS, Victor R. Vaz, MD, Andy J. Pangilinan, BS, Danielle Haradon, BS, Elinton Lee, BS, Hersh Gupta, PhD, Kathleen L. Pfaff, BS, Emma L. Welsh, BS, Mizuki Nishino, MD, Andrew D. Cherniack, PhD, Bruce E. Johnson, MD, Jason L Weirather, PhD, Ian D Dryg, PhD, Scott J. Rodig, MD, Lynette M. Sholl, MD, Peter Sorger, PhD, Sandro Santagata, MD, Renato Umeton, PhD, and Mark M. Awad, MD, PhD

Journal of Clinical Oncology

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Below is the abstract of the article.

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Purpose

Although immune checkpoint inhibitors (ICIs) have extended survival in patients with non–small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown.

Methods

Comprehensive tumor genomic profiling, machine learning–based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls.

Results

We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1–PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P=0.005) and the targeted therapy (P=0.01) cohorts.

Conclusion

These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.

Read an interview about the study here and expert commentary about it here.

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Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non鈥揝mall-Cell Lung Cancer

Primary Source

Journal of Clinical Oncology

Source Reference:

番茄社区