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J. Gray
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.07 - Preclinical Rationale for a Phase I/II Study of Pembrolizumab (P) and Vorinostat (V) in Immune Therapy Naïve and Pretreated Stage IV NSCLC (ID 734)
11:20 - 11:25 | Author(s): J. Gray
- Abstract
- Presentation
Background:
The WHO estimated that 1.6 million people died of lung cancer in 2012. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was FDA approved on March 4, 2015 for platinum-refractory, metastatic, squamous-cell NSCLC, based upon a RR to single agent nivolumab of ~15% and improved OS. Combinatorial strategies may enhance these outcomes. Increased tumor expression of T cell chemokines, such as CCL5 and CXCL10, is associated with a better response to immunotherapy. Furthermore, expression of T cell chemokines is strongly and positively associated with increased T cell infiltration and improved patient survival. Therefore, enhancement of expression of T cell chemokines may augment response to PD-1 blockade immunotherapy.
Methods:
FDA-approved oncology agents were utilized from the Approved Oncology Drugs Set (97 agents) from the Developmental Therapeutics program of NCI. LKR cells were plated in 96-well plates, and a viability assay was performed 48 hours after drug administration (Cell Counting Kit-8, Dojindo Laboratories). Mice were bred and housed in the animal facility at Moffitt Cancer Center. Cells were harvested in logarithmic growth phase after being cultured for less than 2 weeks. 1x10[6] LKR or 344SQ cells were injected s.c. and tumors were monitored for growth by measurements 2-3 times per week. Romidepsin was injected i.p. (2mg/kg) on days 14,16, and 18 after tumor inoculation. Anti-PD-1 was injected i.p. (300μg/mouse) on days 15, 17, and 19 after tumor inoculation. Relative tumor size between treatment groups was analyzed using the t test with Welch’s correction.
Results:
Histone deacetylase inhibitors (HDACi), including vorinostat, emerged as the only class of agents in a 97-drug screen capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and CXCL10, in mouse and human lung cancer cell lines and primary tumors. HDACi’s ability to induce T cell chemokine expression was dependent on both JAK-STAT and NF-kB pathways. HDACi (romidepsin) treatment of mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly reduced growth (p<0.0001; final tumor volume). This effect of HDACi was completely T cell dependent. LKR tumor cells had low cell surface expression of PD-L1 but which was substantially increased by IFN-g. PD-1 blockade with mAb reduced tumor growth but rarely induced rejection. However, when PD-1 blockade was combined with HDACi, 9 out of 11 mice demonstrated complete tumor rejection. HDACi anti-tumor response correlated with T cell chemokine induction in tumors and greater presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model (344SQ) that was relatively resistant to anti-PD-1 treatment. PD-1 blockade combined with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice.
Conclusion:
HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors (LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). HDACi induces JAK-STAT and NF-kB dependent chemokine expression and may induce tumor-infiltrating lymphocytes. Thus, a Phase I/randomized Phase II clinical trial of vorinostat, an orally active, small molecule HDACi, plus pembrolizumab, an anti-PD-1 humanized monoclonal IgG4-kappa antibody, is planned in patients with immune therapy naïve and pre-treated metastatic NSCLC.
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MINI 03 - PD1 Axis Inhibition and EGFR (ID 101)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gandhi, Y. Ohe
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F1+F2
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MINI03.08 - Discussant for MINI03.05, MINI03.06, MINI03.07 (ID 3306)
17:25 - 17:35 | Author(s): J. Gray
- Abstract
- Presentation
Abstract not provided
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-006 - Survival Rates after Surgery for Stage-3A (N2) Non-Small Cell Lung Cancer with Induction versus Adjuvant Chemotherapy+/-Radiation Therapy (ID 3151)
09:30 - 09:30 | Author(s): J. Gray
- Abstract
Background:
We compared survival of stage-3A non-small cell lung cancer (NSCLC) patients (pts) after surgery without or with induction versus adjuvant chemotherapy + radiation therapy (chemo+XRT).
Methods:
We retrospectively analyzed pts with clinical stage-3A (cStage3A) NSCLC and who had surgery without or with induction chemo+XRT or who were pathologic stage-3A (pStage3A) and had adjuvant chemo+XRT. Kaplan-Meier survival curves were compared for these 3 groups, with significant differences at p<0.05 by Chi Square test, with Log Rank (Mantel-Cox), Breslow (Generalized Wilcoxon), and Tarone-Ware pairwise comparisons.
Results:
From 1/1986 to 12/2010, there were 300 NSCLC pts who were cStage3A at surgery. Another 52 pts were not cStage3A at surgery, but were then pStage3A. Of these 352 pts, 192 had curative resection, with 56 pts having surgery alone (SURG), 43 pts having surgery after induction therapy (NEOADJ), and 93 pts having surgery then adjuvant therapy (ADJ). Kaplan-Meier survival for SURG was worse than that for either NEOADJ (p=0.03) or ADJ (p=0.005), while NEOADJ and ADJ had similar survival (p=0.90). Median survival was 18+3 mon (95%CI: 12-24 mon) for SURG, 37+6 mon (95%CI: 25-50 mon) for NEOADJ, and 41+5 mon (95%CI: 31- 51 mon) for ADJ. Survival for NEOADJ chemo-alone pts was better than for SURG pts (p=0.031), while that of NEOADJ chemo+XRT pts was similar to SURG survival (p=0.488). Survival for ADJ chemo-alone pts was better than for SURG pts (p=0.007), while that of ADJ chemo+XRT pts was similar to SURG survival (p=0.163).
Conclusion:
Stage-3A NSCLC pts have improved survival with either induction or adjuvant therapy compared to surgery alone. Patients with induction or adjuvant chemo alone, but not those with induction or adjuvant chemo+XRT, have improved survival compared to surgery alone.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-086 - A Phase I Dose-Escalation Study of Pirfenidone Combined with Standard First-Line Chemotherapy in Advanced-Stage Lung NSCLC (ID 712)
09:30 - 09:30 | Author(s): J. Gray
- Abstract
Background:
Approximately 1.6 million people are diagnosed with lung cancer annually, of which 85% of cases are NSCLC. Due to limited efficacy of current conventional chemotherapy, the majority of patients face poor prognosis; thus, combining chemotherapy with agents targeting the tumor microenvironment may be a novel approach to improving survival outcomes. Pirfenidone (5-methyl-1-phenyl-1H-pyridine-one), an agent demonstrating activity against fibroblasts and growth-promoting cytokines (TGF-β1, fibroblast growth factor [FGF], epidermal growth factor [EGF], and platelet-derived growth factor [PDGF]), has demonstrated clinical efficacy in IPF but has not yet been studied in lung cancer. We propose a proof-of-concept trial testing a novel combination of pirfenidone plus standard first-line chemotherapy in the treatment of advanced-stage NSCLC. Pirfenidone Pirfenidone has demonstrated activity against growth-promoting cytokines such as TGF-β1, FGF, EGF, and PDGF. A recent Phase III clinical trial of pirfenidone compared to placebo in patients with IPF demonstrated improved lung function, exercise tolerance, and progression-free survival (PFS) with an acceptable side-effect profile. To date, pirfenidone has not been studied in cancer, but its anti-fibroblast properties may play an important role in the tumor microenvironment. Our hypothesis is that pirfenidone (by targeting CAFs) in combination with standard chemotherapy will act synergistically and proffer a more potent strategy for NSCLC treatment. Data Generated in Dr Antonia’s Lab at Moffitt Cancer Center Using low doses of pirfenidone (0.5 mg/ml), we observed a small decrease in cell proliferation (20%), also noted with low doses of cisplatin (10%). When both drugs were used, we observed a synergistic decline in proliferation (60%). An in vivo model was performed to verify this data: nude mice were inoculated with a combination of A549 cells and CAF cells at a 1:1 ratio. Treatment with pirfenidone and cisplatin began as soon as tumors were palpable. Cisplatin- or pirfenidone-treated mice had a larger tumor size than mice treated with the combination, and on the final day (43 days after start of treatment), the combination showed statistically significant improvement compared to controls. This led to our hypothesis that similar tumor regression may occur in NSCLC patients.Figure 1
Methods:
Phase I, single-center, dose-escalation study. Phase I trial, followed by an expansion of 20 pts with non-squamous and 10 pts with squamous cell lung cancer. Primary Objectives: Determine safety, tolerability, and MTD of pirfenidone plus chemotherapy in pts with advanced NSCLC, and obtain the preliminary ORR. Secondary Objectives: Determine OS and PFS of pts treated with pirfenidone plus standard first-line chemotherapy.
Results:
Not applicable
Conclusion:
Not applicable
