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D. Rimm
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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:O. Arrieta
- Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1
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MA15.06 - Predictive Value of Measuring Somatic Mutations and Tumor Infiltrating Lymphocytes for PD-1 Axis Therapy in Non-Small Cell Lung Cancer (NSCLC) (ID 6255)
14:20 - 15:50 | Author(s): D. Rimm
- Abstract
Background:
Diverse factors have been associated with clinical benefit to PD-1 axis blockers in NSCLC including PD-L1 protein expression by immunohistochemistry and increased mutation load/predicted class-I neoantigens. However, the association and predictive value of the tumor genomic landscape, composition of the tumor immune microenvironment and T-cell function remain unclear.
Methods:
We performed whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) for T-cells in pre-treatment FFPE samples from 45 NSCLC patients treated with PD-1 axis blockers (alone or in combination) in our institution. Genomic analysis was used to evaluate the mutational load and predicted class-I neoantigens. Multiplexed QIF-based immunoprofiling was used to measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3+ cells) and T-cell activation (Granzyme-B in CD3+ cells). We studied the association between the tumor somatic mutations, predicted neoantigens, T-cell infiltration/function and clinical benefit /survival.
Results:
Increased mutational load was positively associated with predicted class-I neoantigens, variants in DNA-repair genes, smoking and absence of activating mutations in EGFR; but not associated with the level of CD3+ T-cells, T-cell proliferation (Ki-67 in CD3+ cells) and function (Granzyme-B in CD3+ cells). Increased mutations and candidate class-I neoantigens were significantly associated with response to therapy (P=0.02 and 0.03, respectively), but not with overall survival at 3-years (median cut-point, log rank P=0.92 and 0.80, respectively). Higher CD3 positivity was not associated with response to therapy (P=0.17), but was significantly associated with overall survival (median cut-point, log rank P=0.03). Regardless of the mutational load and candidate neoantigen content, elevated CD3 with low Ki-67/Granzyme-B in CD3 predicted longer survival after PD-1 axis blockade than high CD3/high Ki-67/Granzyme-B in CD3, or low T-lymphocyte infiltration.
Conclusion:
Increased somatic mutations are associated with smoking and response to PD-1 agents, but not with tumor T-cell infiltration/activation and overall survival. Regardless of the mutational load, increased T-cell infiltration using QIF is significantly associated with longer survival after PD-1 axis blockade in NSCLC. The subgroup of NSCLC with the highest potential of benefit to immune reinvigoration using PD-1 axis blockade comprise tumors with elevated lymphocyte infiltration but low in situ activation/proliferation.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-017 - The Prognostic Impact of EGFR, KRAS and TP53 Somatic Mutations in Curatively Resected Early-Stage Lung Adenocarcinomas (ID 4527)
14:30 - 15:45 | Author(s): D. Rimm
- Abstract
Background:
As the 5-year survival among individuals undergoing curative-intent resection for early-stage lung cancer approaches 50%, identification of prognostic biomarkers useful for risk stratification is a priority. While somatic mutation profiling drives treatment choice in advanced disease, its usefulness among early-stage patients is not well-established.
Methods:
From May 2011 through December 2014, The Yale Lung Cancer Biorepository enrolled 192 individuals who underwent curative-intent complete resection for Stage IA-IIIA adenocarcinoma. Demographics and lifestyle choices were ascertained by interview using validated questionnaires. Pathologic characterization of index tumors, including CLIA Laboratory-assayed EGFR/KRAS status, was extracted from the medical record. A custom targeted resequencing panel covering all coding exons from 93 lung adenocarcinoma-related genes was designed. Buffy coat-derived germline DNA and tumor DNA, extracted from the FFPE surgical specimen, were sequenced on the Ion Torrent platform with >90% of the assayed amplicons achieving >30x coverage in both tumor and germline from each case. Somatic nonsynonymous tumor variants were identified using the Torrent Variant Caller. Bivariate associations were evaluated by Chi-square or ANOVA. Survival analyses were conducted using Cox modeling.
Results:
181/192 (94.3%) participants underwent EGFR/KRAS somatic mutation profiling with 43 EGFR mutations and 71 KRAS mutations detected. EGFR mutations were more common among well- and moderately-differentiated lesions (p=0.06) and among never or former light smokers (p=0.0007). Seventy-two percent of EGFR and 81.7% of KRAS mutations were found among female patients (p=0.0008). The joint distribution between smoking and gender favored EGFR mutations among female never/former smokers, KRAS mutations among female ever-smokers and EGFR/KRAS wild-type status among male ever-smokers (p=0.0002). After adjustment for AJCC 7[th] edition Tstage, Nstage and presence of lymphovascular invasion, KRAS mutations (HR=2.14; 95% CI:1.04-4.43; p=0.04) but not EGFR mutations (p=0.63) were prognostic for poorer disease-free survival. Targeted resequencing data is available on 148 cases. The nonsynonymous mutation burden ranged from 0-7 with 84% of cases having ≤3. In addition to KRAS and EGFR, frequent mutations were noted in p53 (n=40; 27.0%), STK11 (n=10; 6.8%) and PIK3CA (n=7; 4.7%) with 4 genes mutated in 6 cases. TP53 mutations were associated with high nonsynonymous mutation burden (p<0.0001) and the joint distribution with EGFR/KRAS status revealed the highest burden among KRAS[mut]/TP53[mut] (3.94±1.57) followed by EGFR[mut]/TP53[mut] (3.07±1.61) and EGFR_KRAS[wt]/TP53[mut] (2.20±1.40; p<0.0001).
Conclusion:
KRAS[mut], like EGFR[mut], is associated with female gender but only KRAS[mut] is prognostic following curative-intent resection. Elevated mutation burden observed among KRAS[mut]/TP53[mut] may offer novel therapeutic options following recurrence.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-088 - Acquired Resistance to Programmed Death-1 Axis Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ID 5625)
14:30 - 15:45 | Author(s): D. Rimm
- Abstract
Background:
Programmed death-1 (PD-1) axis inhibitors are increasingly being used to treat patients with advanced NSCLC. Despite durable responses relative to chemotherapy, resistance to such therapy develops in the majority of responders, with median duration of response from 12-17 months. Mechanisms of acquired resistance (AR) to PD-1 axis inhibitors are poorly understood.
Methods:
Patients with advanced NSCLC and acquired resistance (AR) to PD-1 axis inhibitor therapy were enrolled to an IRB approved repeat biopsy protocol allowing collection of clinical data, archived and fresh tumor tissue, and blood for analysis. Molecular analyses including whole exome sequencing of pre- and post-treatment tumor specimens were performed.
Results:
Twelve cases were available for analysis (table 1). Eight and two patients developed resistance limited to lymph nodes (LNs) and adrenal gland respectively. The two remaining patients experienced tumor progression in LNs with other sites of tumor growth (one in liver, one in lung). Nine patients had sufficient archived pre- PD-1 axis inhibitor tumor tissue for analysis/ comparison, leaving three unpaired cases. Genomic analysis of tumor specimens identified two patients with acquired tumor beta-2-microglobulin (B2M) defects at resistance. A patient derived xenograft generated from one of the resistance samples (patient #6) lacked production of B2M protein and did not express surface MHC-1. Additional analyses including immunophenotyping with multiplexed quantitative immunofluorescence on these and other patient samples are ongoing. Figure 1
Conclusion:
Lymph nodes may be a particularly susceptible area to AR to PD-1 axis inhibitors. Defects in B2M leading to loss of tumor MHC-1 presentation may represent a unique mechanism of AR to immune checkpoint inhibitors. Further studies to determine the frequency of defects in antigen presentation machinery in tumors with resistance to PD1 axis inhibitors are warranted.
