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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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. Zelterman
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.
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.
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.
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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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
P3.02c-048 - A Phase I/II Trial Evaluating the Combination of Stereotactic Body Radiotherapy and Pembrolizumab in Metastatic NSCLC (ID 5249)
14:30 - 15:45 | Author(s): D. Zelterman
Immune checkpoint inhibitors are taking on a growing role in the treatment of patients with metastatic NSCLC. Pre-clinical evidence suggests that radiotherapy may increase the frequency, or enhance the strength of the host anti-cancer immune response. We report the preliminary results of an ongoing phase I/II trial combining stereotactic body radiotherapy (SBRT) and the anti-PD-1 antibody pembrolizumab in patients with metastatic NSCLC.
Eligible patients are those with metastatic NSCLC who have received no prior immune-directed therapy, and have at least 2 sites of measurable disease as per RECIST 1.1. PD-L1 expression is not required for study entry. All patients are treated with pembrolizumab at 200 mg every 3 weeks until development of progressive disease by immune-related RECIST criteria (irPD). After irPD, patients receive SBRT to a single site of disease and continue pembrolizumab. The primary endpoint is safety and tolerability. Secondary endpoints include the pre- and post-SBRT overall response rate.
27 patients with advanced NSCLC have enrolled and started trial therapy. The overall response rate (irPR and irCR) to the initial course of pembrolizumab is 35%. To date, 13 patients have had irPD: 5 were not eligible for SBRT and stopped study treatment (2 developed new brain metastases, 3 had decline in PS), and 8 patients received SBRT to a single site of disease (6 thoracic, 1 adrenal, 1 vertebral) and continued pembrolizumab. 5 of these patients are evaluable for post-SBRT response: 1 patient had confirmed irPD, 4 have irSD and continue pembrolizumab post-SBRT at a median duration of 3 months (range 1 to 5 months). 2 of the 4 patients with irSD have had > 20% decrease in the sum of diameters of their unirradiated targets, since SBRT. Regarding adverse events, in the pre-SBRT phase 6 of 27 patients (22%) developed grade 3 treatment-related toxicity (2 colitis, hepatitis, pneumonitis, hypothyroidism, conjunctivitis). In the SBRT and post-SBRT phases, there have been no grade 2 or greater treatment-related events.
The addition of SBRT to pembrolizumab has not resulted in an increase in treatment-related toxicity. Several patients who had serially confirmed irPD to pembrolizumab monotherapy underwent SBRT and now have irSD, with some evidence of tumor regression. Updated results will be presented.