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Y.K. Chae
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-004 - Phase I/Ib Study of Nivolumab and Veliparib in Advanced Solid Tumors and Lymphoma with and without Alterations in Selected DNA Repair Genes (ID 8357)
09:30 - 16:00 | Author(s): Y.K. Chae
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been a successful treatment strategy in a minority of patients with many different tumor histologies (non-small cell lung cancer, squamous cell head and neck cancer, melanoma, Hodgkin lymphoma, renal cell carcinoma, urothelial carcinoma). An increase in the proportion of patients that benefit from this emerging mechanism is needed. Veliparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), and it has been shown in preclinical models and in patients with BRCA mutant ovarian cancer to exert anti-tumor effects through lethal exacerbation of DNA repair defects. Extensive genomic sequencing of tumors of varying histologies has revealed that approximately 5% of all tumors harbor defects in DNA repair genes such as BRCA1/2, RAD51, CHEK1, ATM, ATR, CHEK2, FANCD2, FANCA. We propose combining PD-1 inhibition with nivolumab with PARP inhibition with veliparib in patients with DNA repair gene defects in order to maximize the proportion of patients with clinical responses to these novel treatment strategies.
Method:
We are currently enrolling patients on this phase I/Ib clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. The study schema is shown below. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.04-005 - Phase 2 Study of Nivolumab and Metformin in Advanced Non-Small Cell Lung Cancer with and without Prior Treatment with PD-1/PD-L1 Inhibitors (ID 8505)
09:30 - 16:00 | Author(s): Y.K. Chae
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been proven to be a successful treatment strategy in a minority of patients with non-small cell lung cancer. An increase in the proportion of patients that benefit from this emerging mechanism is needed, and many novel combination therapies are being tested. Furthermore, many patients with non-small cell lung cancer are excluded from further clinical trials if they have received prior checkpoint inhibitor therapy, so this trial provides for this additional unmet need. Epidemiologic studies have consistently demonstrated an association between decreased cancer incidence and mortality in patient treated with metformin. Preclinical models have demonstrated that this anti-cancer effect is potentially mediated by inhibition of insulin like growth factor-1 (IGF-1) and mTOR, as well as activation of AMPK and tuberous sclerosis complex (TSC1, TSC2). Also, metformin has recently been found to exert immunomodulatory functions, inhibiting the exhaustion of CD8+ tumor infiltrating lymphocyte (TIL) function, thereby upregulating tumor-specific immune function. It accomplishes this by preventing apoptosis of CD8+ TILs and converting CD8+ TILs from quiescient central memory T cells to effector memory T cells with active anti-tumor effects. In vivo, the addition of metformin to vaccination enhances the generation of effector memory T cells, congruent with the overall hypothesis. We propose a proof-of-concept parallel phase 2 trial using the combination regimen of nivolumab and metformin. We hypothesize that the combination of nivolumab and metformin will be synergistic and can overcome resistance to single agent PD-1/PD-L1 inhibitors.
Method:
We are currently enrolling patients in this phase II clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-037 - Developing a Predictive Clinical Outcome Model for Advanced Non-Small Cell Lung Cancer Patients<br /> Receiving Nivolumab (ID 9453)
09:30 - 16:00 | Author(s): Y.K. Chae
- Abstract
Background:
Despite significant improvement of clinical outcomes of the patients with advanced non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors, our knowledge of optimal predictive and prognostic biomarkers are still evolving.
Method:
We retrospectively evaluated 159 advanced NSCLC patients who received nivolumab after platinum-based chemotherapy. We correlated several variables with progression free survival (PFS) to develop the iSEND model (Sex, ECOG [Performance status], NLR [Neutrophil-to-Lymphocyte Ratio] & DNLR [Delta NLR = NLR after treatment - pretreatment NLR]). We categorized the patients into good, intermediate, and poor iSEND groups and evaluated clinical outcomes of each group. Performance of iSEND model was evaluated at 3, 6, 9, and 12 months by receiver operating characteristic (ROC) curves. We performed bootstrap internal validation to evaluate the predictive performance of the iSEND model by using the split-sample validation technique. We used logistic regression to correlate different iSEND groups and clinical benefit.
Result:
The median follow-up was 11.5 months (95% C.I.: 9.4-13.1). There were 50 deaths and 43 other progressions without death. The 3-, 6-, 9-, and 12-months PFS rates were 78.4%, 63.7%, 55.3%, and 52.2% in the good group, 79.4%, 44.3%, 25.9% and 19.2% in the intermediate group, and 65%, 25.9%, 22.8%, and 17.8% in the poor group, respectively. (Figure 1) Time-dependent area under curves (AUC) of the iSEND model for PFS at 3-, 6-, 9-, and 12-months were 0.718, 0.74, 0.746, and 0.774. The poor iSEND group had significant correlation with progressive disease compared to the good group at 12+/-2 weeks. Figure 1. Kaplan-Meier curves for Progression Free Survival of different iSEND model groups Figure 1
Conclusion:
The iSEND model is an algorithmic model that can categorize clinical outcomes of advanced NSCLC patients receiving nivolumab into good, intermediate, or poor groups and may be useful as a predictive model.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-034 - Acquired Resistance to Osimertinib by CCDC6-RET Fusion in a Patient with EGFR T790M Mutant Metastatic Lung Adenocarcinoma (ID 8597)
09:30 - 16:00 | Author(s): Y.K. Chae
- Abstract
Background:
Resistance to third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is thought to be most commonly mediated by acquisition of a C797S mutation in EGFR. Identification of novel mechanisms of resistance to third generation EGFR TKIs is of critical importance for continued advancement of the field of targeted therapies for patients with EGFR mutant non-small cell lung cancer (NSCLC).
Method:
We report the case of a patient who developed resistance to osimertinib via acquisition of a CCDC6-RET fusion.
Result:
The patient was a 49yo woman with stage IV lung adenocarcinoma who was initially treated with afatinib for EGFR exon 19 deletion disease. She acquired a T790M mutation identified on peripheral blood circulating cell free DNA (cfDNA) assessment at the time of first progression 18 months after diagnosis. She was changed to osimertinib at that time, and nine months into therapy with osimertinib she was noted to have disease progression with acquisition of a CCDC6-RET fusion and no C797S EGFR mutation identified in peripheral blood cfDNA. The CCDC6-RET fusion was not seen on tumor tissue next generation sequencing from the time of initiation of osimertinib, and tumor tissue sequencing was not performed at the of progression on osimertinib.
Conclusion:
The CCDC6-RET fusion protein is known to be pathogenic in lung adenocarcinoma. The identification of this novel mechanism of acquired resistance to a third generation EGFR TKI contributes to the critical landscape of defining all the ways that NSCLC can acquire resistance to the latest targeted therapy agents.
