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Biagio Ricciuti
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.26 - Diminished Efficacy of PD-(L)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma is Impacted by KRAS Mutation Status (ID 2343)
00:00 - 00:00 | Presenting Author(s): Biagio Ricciuti
- Abstract
Introduction
STK11 and KEAP1 mutations (STK11m and KEAP1m) are commonly mutated in lung adenocarcinoma (LUAD). STK11m have been associated with resistance to immune checkpoint inhibition (ICI) in KRAS-mutant (KRASm) LUAD. However, whether STK11m status also impacts clinical outcomes to ICI in KRAS wild-type (wt) LUAD is unknown. Whether KEAP1m impact outcomes to ICI in KRASm and KRASwt LUAD is also unknown.
Methods
We analyzed clinical outcomes of patients (pts) with LUAD treated with ICI according to KRAS and STK11 and KEAP1 mutation status in two independent cohorts (Cohort 1 [DFCI/MGH] and Cohort 2 [MSKCC/MDACC]). TCGA and xCell data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 co-mutation status.
Results
Of 1261 pts with advanced LUAD treated with ICI, 42.5% had a KRASm, 20.6% and 19.2% had pathogenic STK11 and KEAP1 mutations, respectively. Co-occurring mutations in KRAS/STK11, KRAS/KEAP1, and STK11/KEAP1 were found in 10.9%, 8.4%, and 9.4% of cases, respectively. In both Cohort 1 and Cohort 2, STK11 and KEAP1 mutations were associated with significantly worse clinical outcomes to ICI among KRASm cases, but not among KRASwt cases (Table 1). The presence of an STK11 and KEAP1 mutation in KRASm NSCLCs was confirmed to be independent predictors of shorter PFS (STK11: HR 1.51, P=0.006; KEAP1: HR 2.01, P<0.01) and shorter OS (STK11: HR 1.81, P <0.001; KEAP1: HR 2.41, P<0.0001) in multivariable analysis in the combined cohort (Cohort 1 + Cohort 2). Gene ontology analysis from TCGA revealed that among KRASm but not KRASwt LUAD, STK11m was associated with the downregulation of MHC class II-related genes, including CD74 (P<0.01), HLA-DOA (P<0.01), HLA-DRB5 (P=0.03), HLA-DRB1 (P=0.03), and HLA-DMB (P<0.01). KEAP1m was associated with a significant downregulation of positive regulators of type I interferon and inflammatory cytokine production, such as STING (P<0.001), DDX58 (P<0.01), TLR4 (P<0.01), and TLR7 (P<0.01) among KRASm but not KRASwt LUAD. Cell subset transcriptome analysis showed that STK11m was associated with a significantly lower proportions of M1 macrophages among KRASm but not KRASwt LUAD (P<0.01). KEAP1m was associated with a significantly lower proportions of CD8+ T cells (P<0.001) and B cells (P<0.01) among KRASm but not KRASwt LUADs.
Conclusion
The deleterious impact of STK11 and/or KEAP1 mutations on ICI efficacy in patients with advanced LUAD differs according to KRAS mutation status. KRAS/STK11 and KRAS/KEAP1 co-mutations identify subsets of lung cancers with distinct therapeutic outcomes and immune profiles.
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P33 - Pathology - Immunotherapy Biomarker (ID 101)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P33.04 - Programmed Death-Ligand 1 (PD-L1) Changes in Non-Small-Cell Lung Cancer (NSCLC): Clinical, Pathologic, and Genomic Correlates (ID 3320)
00:00 - 00:00 | Author(s): Biagio Ricciuti
- Abstract
Introduction
PD-L1 tumor proportion score (TPS) is imperfect in predicting response to immune checkpoint inhibitors (ICIs) in NSCLC, as PD-L1 expression can be heterogenous and dynamic. Because characteristics associated with changes in PD-L1 expression (ΔPD-L1) are poorly understood, we sought to analyze factors associated with ΔPD-L1, including mutations and copy number (CN) changes in CD274 (which encodes PD-L1). We also evaluated STK11 and KEAP1, where alterations have been associated with lower PD-L1 TPS.
Methods
We retrospectively collected clinical, pathologic, and genomic data from patients with NSCLC and at least two quantitative PD-L1 assessments. We evaluated ΔPD-L1 (second PD-L1 – first PD-L1) within each patient. When evaluating ΔPD-L1 categorically, we divided our cohort into three groups: patients with a major decrease, defined as a change from ≥50% to <50% or ≥1% to <1%; patients with a major increase, defined as a change from <1% to ≥1% or <50% to ≥50%; and patients without a major ΔPD-L1. Next generation sequencing (NGS, OncoPanel) was used to identify mutations and CN alterations. Multiple comparisons corrections used the Benjamini-Hochberg procedure, with q < 0.25 considered significant.
Results
Among 238 patients identified, 46 (19.3%) had a major decrease, 61 (25.6%) had a major increase, and 131 (55.0%) had no major ΔPD-L1 (Fig. 1A); ΔPD-L1 ranged from -90% to 95%, with a median of 0%. There was no significant difference in ΔPD-L1 as a continuous or categorical variable based on smoking status, histology, sex, genomic driver, or intervening therapy. Tissue NGS was available on both biopsies in 44 (18.5%) patients. Five cases (45.5%) with a major decrease showed acquired CN loss at CD274, whereas only two patients (8.3%) with no change and one patient (11.1%) with a major increase demonstrated acquired CD274 CN loss (Fig. 1B). Acquired CN loss in STK11 or KEAP1 was more frequent in patients with a major decrease in PD-L1, seen in approximately 30% of patients in this group, as compared to approximately 10% of patients with no change or a major increase in PD-L1 TPS. There were no acquired loss of function mutations seen in CD274, STK11, or KEAP1.
Conclusion
PD-L1 expression is dynamic, with few clinicopathologic correlates of ΔPD-L1. A major decrease in PD-L1 occurred in cases with acquired CD274, STK11 and KEAP1 CN loss.
