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M. Cobo
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ORAL 18 - Non PD1 Immunotherapy and Angiogenesis (ID 114)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:C. Butts, K. Reckamp
- Coordinates: 9/08/2015, 10:45 - 12:15, Four Seasons Ballroom F1+F2
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ORAL18.01 - TG4010 Immunotherapy plus Chemotherapy as First Line Treatment of Advanced NSCLC: Phase 2b Results (ID 669)
10:45 - 12:15 | Author(s): M. Cobo
- Abstract
- Presentation
Background:
TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2. Previous Phase 2 trials have demonstrated the efficacy and safety of TG4010 in combination with chemotherapy. In addition, Triple Positive Activated Lymphocytes (TrPAL; CD16+, CD56+, CD69+) was identified as a potential biomarker predictive of efficacy
Methods:
TIME is a double blind, placebo-controlled phase 2b/3 study. The Phase 2b part compared first line chemotherapy combined with TG4010 or placebo and further assessed the predictive value of baseline level of TrPAL. Eligibility criteria included stage IV NSCLC not previously treated, MUC1+ tumor by immunohistochemistry, PS ≤1. TG4010 10[8] pfu or placebo was given SC weekly for 6 weeks (w), then every 3w up to progression in immediate combination with chemotherapy. Patients were randomized using TrPAL cut-off value (normal vs high) that was previously pre-determined in healthy subjects. Primary efficacy endpoint was progression-free survival (PFS) using a Bayesian design to confirm that, with a 95% probability, the true hazard ratio (HR) is <1 in patients with normal TrPAL level. Secondary objectives were response rate (ORR), duration of response, survival, safety and subgroup analyses according to histology and level of TrPAL.
Results:
222 patients (pts) were randomized 1:1. In pts with normal TrPAL the study met the primary endpoint with a Bayesian probability of 98.4% that the PFS HR is <1 in favor of TG4010. In the whole study population, ORR was 39.6% vs 28.8% and duration of response was 30.1w versus 18.7w in the TG4010 and placebo arms respectively. Survival data will be presented at the time of the meeting. Preplanned subgroup analyses showed that PFS was significantly improved in the TG4010 arm in pts with low TrPAL (n=152; HR=0.66 [CI95% 0.46-0.95] p= 0.013) while it was not the case in pts with high TrPAL (n=70; HR=0.97 [CI 95% 0.55-1.73] p=0.463). In addition, PFS was also significantly improved in pts with non-squamous tumors (n=196; HR=0.69 [CI95% 0.51-0.94] p=0.009) as well as in pts with non-squamous tumors and low TrPAL (n=131; HR=0.61 [CI95% 0.42-0.89] p=0.005). In this last group, PFS at 9 months was 37% with TG4010 versus 18% with placebo. Frequency and severity of adverse events were similar in both treatment arms except injection site reactions which were more frequent in the TG4010 arm but all of mild or moderate intensity. Exploratory analysis of the impact of PDL1 expression in the tumor of patients treated with TG4010 in TIME study supports the activity of TG4010 whether the tumor is positive or negative for PDL1 expression.
Conclusion:
These results provide additional data supporting the efficacy of TG4010, particularly in patients with non-squamous tumors and/or a low level of TrPAL at baseline. The Phase 3 part of the TIME study is planned to continue in patients with non-squamous tumors with OS as primary endpoint.
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.01 - Tumor Genomic Analysis from LUX-Lung 8: A Phase III Trial of Afatinib versus Erlotinib in Squamous Cell Carcinoma of the Lung (ID 1401)
16:45 - 18:15 | Author(s): M. Cobo
- Abstract
- Presentation
Background:
Overexpression of EGFR and other ErbB receptors, and/or dysregulation of their downstream pathways are implicated in the pathogenesis of squamous cell carcinoma (SCC) of the lung, generating interest in exploring EGFR/ErbB-targeted agents in this setting. Recent analyses from the global LUX-Lung 8 trial (n=795) in patients with SCC of the lung demonstrated that second-line afatinib (an irreversible ErbB family blocker) conferred overall survival (OS; median 7.9 vs 6.8 months; HR [95% CI] 0.81 [0.69‒0.95]; p=0.008) and progression-free survival (PFS; median 2.6 vs 1.9 months; HR [95% CI] 0.81 [0.69‒0.96]; p=0.010) benefit over erlotinib (a reversible EGFR inhibitor). To assess biomarkers for efficacy for these agents in SCC we conducted an exploratory analysis using archival tumor tissue collected at time of study entry.
Methods:
Among all randomized patients, samples were retrospectively enriched for those from patients with PFS >2 months and appropriate controls (PFS ≤2 months; Figure 1) and were selected for analysis using the Foundation Medicine (FM) FoundationOne™ next-generation sequencing (NGS) platform (n=433); 300 cancer-related genes were analyzed for copy number alterations (CNAs), rearrangements and single nucleotide variants (SVs). Preliminary results from the 238 samples analyzable so far (~30% of the randomized patients), focusing on genomic alterations of EGFR and their potential association to survival endpoints PFS and OS, are presented.
Results:
Fourteen EGFR SVs (5.8%) were detected of which 10 were novel with unknown clinical significance (Figure 1). Figure 1 Four had been previously reported; 2 (E114K [afatinib arm], Q1021* [erlotinib arm]) occurred in the non-kinase domains and 2 (L861Q [afatinib arm], L858R [erlotinib arm]) in the kinase domain. The frequency of EGFR CNAs (n=15 [6.3%]; afatinib: 9; erlotinib: 6) was also low. At the time of these ongoing analyses, these low frequencies of EGFR mutations/amplifications were deemed not to be associated with the observed improvements in PFS and OS. Genomic alterations aggregated across two key gene groups (ErbB and FGF families) and their association with survival outcomes will be presented.
Conclusion:
The frequency of EGFR genomic aberrations in the samples tested was low. Based on this analysis of a subgroup of patients, PFS and OS improvements conferred by afatinib in LUX-Lung 8 were not driven by the presence of activating EGFR mutations or amplifications and may be related to afatinib’s ability to inactivate multiple aberrant signaling cascades associated with, and downstream of, ErbB receptors.
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