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Matthew A. Gubens
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OA04 - Immuno Combinations and the Role of TMB (ID 126)
- Event: WCLC 2019
- Type: Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Solange Peters, Martin Reck
- Coordinates: 9/08/2019, 15:15 - 16:45, Copenhagen (1980)
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OA04.05 - KEYNOTE-021: TMB and Outcomes for Carboplatin and Pemetrexed With or Without Pembrolizumab for Nonsquamous NSCLC (Now Available) (ID 2630)
15:15 - 16:45 | Author(s): Matthew A. Gubens
- Abstract
- Presentation
Background
KEYNOTE-021 cohort C was the first study to show antitumor activity for pembrolizumab plus platinum-based chemotherapy in previously untreated advanced nonsquamous NSCLC; the combination significantly improved efficacy vs platinum-based chemotherapy alone in cohort G. We explored the relationship between TMB and outcomes in KEYNOTE-021 cohorts C and G.
Method
All patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. Association of TMB (continuous, log10 transformed) with outcomes for pembrolizumab plus chemotherapy and chemotherapy alone were assessed using logistic regression for ORR and Cox proportional hazards models for PFS and OS adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The correlation of TMB (continuous, log10 transformed) with PD-L1 TPS (square root scale) was assessed in the combined population. The clinical utility of TMB for ORR using a prespecified TMB cutpoint of 175 Mut/exome (~13 Mut/Mb by FoundationOne CDx) was assessed for pembrolizumab + chemotherapy.
Result
TMB data were evaluable for 70 patients: 12/24 (50.0%) in cohort C, 32/60 (53.3%) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3%) in the cohort G chemotherapy only arm; median age was 65 years (IQR, 57-70) and 61% were female. Baseline characteristics were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P = 0.180, 0.187 and 0.081, respectively) or chemotherapy alone (one-sided P = 0.861, 0.795 and 0.763, respectively). There was no significant correlation between TMB and TPS (r=0.12, P=0.34). ORR (95% CI) in patients treated with pembrolizumab plus chemotherapy was 60.8% (38.5-80.3) in the 23 patients with TMB <175 and 71.4% (47.8-88.7) in the 21 patients with TMB ≥175.
Conclusion
In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC. TMB was not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups. Sample size is a limitation of this study; exploration in larger datasets is required to understand any differential efficacy of pembrolizumab plus chemotherapy vs chemotherapy alone based on TMB status.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-107 - KEYNOTE-495/KeyImPaCT: Phase 2 Biomarker-Directed Study of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (ID 1355)
09:45 - 18:00 | Author(s): Matthew A. Gubens
- Abstract
Background
Immune checkpoint–based therapy has revolutionized the care of patients with non–small cell lung cancer (NSCLC). Pembrolizumab-based combination therapy aims to improve clinical outcomes over pembrolizumab monotherapy. Identification of biomarkers associated with improved response to different combination therapies may improve overall outcomes and yield a more precise approach to the use of immunotherapies in NSCLC. To test the clinical usefulness of a biomarker-informed, pembrolizumab-based combination therapy, this phase 2 KEYNOTE-495 trial (NCT03516981) will be carried out in patients with treatment-naive, advanced NSCLC.
Method
KEYNOTE-495 is a randomized, multicenter, open-label, phase 2 trial. Tumor tissue from patients with treatment-naive, advanced NSCLC will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on the results of this biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab combined with MK-4280 (anti–LAG-3), lenvatinib, or MK-1308 (anti–CTLA-4). This is a group-sequential, adaptive randomization trial. Patients will be randomly assigned to MK-4280 or lenvatinib first, after which MK-1308 will be introduced; randomization has been modified to accommodate the delayed introduction of MK-1308. Response will be assessed by tumor imaging every 9 weeks for the first year, then every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. After a patient experiences disease progression or starts new anticancer therapy, the patient will be followed up and contacted every 12 weeks until death, withdrawal of consent, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment or before initiation of a new anticancer treatment, whichever occurs first. Treatment arms may be terminated during the interim analysis because of safety, prespecified futility criteria, or both. The primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 14 countries and will continue until ~288 patients are randomly assigned across the biomarker-defined groups to determine the optimal treatment for each subgroup.
Result
Section not applicable
Conclusion
Section not applicable
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-09 - Drop the Scalpel: Long-Term Survival in Mesothelioma Without Extrapleural Pneumonectomy or Pleurectomy Decortication (ID 2610)
10:15 - 18:15 | Author(s): Matthew A. Gubens
- Abstract
Background
Survival times following multimodality treatment with extrapleural pneumonectomy (EPP) and pleurectomy decortication (P/D) for malignant pleural mesothelioma (MPM) are poor with a need to identify factors that predict long-term survival.
Method
A retrospective single-institution review was performed on all patients who underwent EEP or P/D for histologically confirmed MPM between 1996 and 2015. Patients who underwent a diagnostic biopsy or limited tumor excision were included for survival comparison in a non-operative group (NO). Clinical characteristics, perioperative outcomes, stage, nodal disease, R1 versus R2 resection, treatment modalities, and survival data were collected. The top decile of patients with longest overall survival were studied in subgroup analysis as “long-term survivors.”
Result
A total of 206 patients with MPM underwent any type of operations with a median survival time of 13 months (range, 0-134 months) and a 3-year and 5-year survival rates of 15.9% and 8.1% respectively among all patients. Median survival times following EPP (n=28), P/D (n=102) and NO (n=76) were 14 months, 13 months, and 11 months respectively. Better survival was observed in patients with epithelial histology (16 months, n=146) than biphasic histology (7 months, n=28) or sarcomatoid histology (5 months, n=27) (logrank p<.001). Patients with epithelial histology had the greatest median survival times, EPP (29 months, n=23), P/D (16 months, n=77) and NO (16 months, n=46). Three-year and 5-year overall survival rates among patients with epithelial histology were 34.7%, 14.9% after EPP, 16.7, 10.4% after PD and 25.9%, 8.1% after NO, with the patients in the NO group presenting with the most advanced disease. The top decile of long-term survivors all had epitheliod histology and were treated with a variety of chemotherapy regimens leading to a median survival of 64 months with a mean of 71 months. Patients with disease too advanced for surgical resection in the NO group were equally likely to become long-term survivors (9.2%, median survival 57 months) compared with patients who underwent major surgical resection like EPP or P/D (10.0%, median survival 72 months).
Conclusion
In this non-randomized retrospective review, patients with MPM too advanced for EPP or PD, who instead underwent palliative limited operations as part of a multimodality treatment regimen had long-term survival rates of approximately 10% that were equivalent to rates of long-term survival following major resections like EPP or P/D. Long-term survival is mesothelioma is therefore more likely determined by outside factors such as disease biology and pace of tumor growth than it is major surgical resection.
