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M.M. Awad
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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:O. Arrieta
- Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1
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MA15.02 - Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade (ID 5780)
14:26 - 14:32 | Author(s): M.M. Awad
- Abstract
Background:
Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.
Methods:
Tumor nonsynonymous mutation data derived from clinical targeted next generation sequencing (309 genes) of lung carcinomas from 94 patients treated with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progression-free survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if ≥1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and non-regulatory and regulatory T cell populations, which were manually quantified per mm[2].
Results:
The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p = 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with ≤9 (p = 0.015). Increasing smoking history correlated with higher mutation load (p = 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p = 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p = 0.47) or PFS (p = 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p = 0.0002), and non-regulatory and regulatory T cells (p = 0.0038 and 0.01 respectively).
Conclusion:
The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.03 - Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers (ID 4325)
14:26 - 14:32 | Author(s): M.M. Awad
- Abstract
- Presentation
Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.
Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).
Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.
Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-008 - Phase 1/2 Study of Mocetinostat and Durvalumab (MEDI4736) in Patients with Advanced Solid Tumors and Non Small Cell Lung Cancer (NSCLC) (ID 5521)
14:30 - 14:30 | Author(s): M.M. Awad
- Abstract
Background:
Immune checkpoint inhibitors produce durable clinical responses in a subset of patients, however strategies are needed to improve clinical efficacy of these agents and overcome innate or acquired resistance to therapy. Growing evidence suggests that tumors evade immune detection through modulation of intrinsic immunogenicity and inhibition of both innate and adaptive anti-tumor immune responses. Mocetinostat, a class I histone deacetylase inhibitor, has multiple potential immunomodulatory features including: 1) induction of tumor associated antigens and major histocompatibility complex Class I and Class II expression on tumor cells, 2) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells, 3) enhanced function of T effector cells, and 4) decreased function of immunosuppressive cell subsets including regulatory T cells and myeloid derived suppressor cells. Given these pleiotropic immune activating effects, combination therapy of mocetinostat and PD-L1 blocking mAb, durvalumab, is a rational approach to restoring or enhancing the clinical activity of immune checkpoint blockade in patients with NSCLC.
Methods:
This open-label Phase 1/2 study is evaluating the tolerability and clinical activity of mocetinostat in combination with durvalumab. Secondary objectives include pharmacokinetics, incidence of anti-drug antibodies, and changes in tumor PD-L1 expression. Exploratory objectives evaluate changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations and cytokines. Phase 1 explores increasing doses of mocetinostat administered orally (50, 70, 90 mg three times weekly [TIW]) in combination with durvalumab in patients with advanced solid tumors. The regimen begins with a 7-Day Lead-in Period of mocetinostat single agent TIW followed by the combination regimen with durvalumab (1500 mg intravenously every 28 days). Phase 2 evaluates the clinical activity of mocetinostat and durvalumab, as assessed by Objective Response Rate (ORR) by RECIST 1.1., in patients with NSCLC who have previously received at least one platinum containing doublet chemotherapy regimen for advanced disease. Four population cohorts are included: 1) immunotherapy naïve, no/low PD-L1 expression, 2) immunotherapy naïve, high PD-L1 expression, 3) prior clinical benefit with PD-L1 or PD-1 inhibitor treatment followed by progression, 4) prior treatment with PD-L1 or PD-1 inhibitor with progression within 16 weeks of initiation of treatment. Tumor PD-L1 expression will be determined by the SP263 assay. The sample sizes for the populations are based on two-stage Simon Optimal Designs. Status: Enrollment into the study opened in June 2016. Clinical Trial Information: NCT02805660
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-006 - Immune Recognition of ALK Fusion Proteins in Patients with ALK-Rearranged Non-Small Cell Lung Cancer (ID 6091)
14:30 - 14:30 | Author(s): M.M. Awad
- Abstract
Background:
Although several tyrosine kinase inhibitors have potent antitumor activity against ALK-rearranged non-small cell lung cancers (NSCLC), resistance to these small molecules emerges through a number of mechanisms. Preclinical evidence suggests that ALK-positive NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. Immunologic responses against the ALK protein have been reported in ALK-positive anaplastic large cell lymphoma, and we sought to determine whether ALK could be recognized by the immune systems of patients with ALK-positive NSCLC.
Methods:
Serum was collected from 32 ALK-positive and 29 ALK-negative NSCLC patients over the course of routine clinical care who had consented to an institutional review board approved translational research protocol. We developed a novel enzyme-linked immunosorbent assay (ELISA) to detect autoantibodies against the ALK cytoplasmic domain in patients with ALK-rearranged NSCLC, and the specificity of these autoantibodies was validated using Western blot analysis. Short peptides spanning the length of the ALK cytoplasmic domain were synthesized to more narrowly define the precise immunogenic peptide sequences.
Results:
Among 32 ALK-positive NSCLC patients, very high ALK autoantibody titers were detected in the serum of 3 patients (9%), and ALK autoantibodies were not detected in any of the 29 patients with ALK-negative NSCLC. These autoantibodies specifically recognized only the ALK cytoplasmic domain and not the ALK extracellular domain. Epitope mapping demonstrated that the autoantibodies from each of the 3 patients with high autoantibody titers recognized distinct ALK peptide sequnces within the ALK cytoplasmic domain.
Conclusion:
ALK is capable of being recognized by the immune systems in some patients with ALK-positive NSCLC. Further investigation is needed to determine whether the presence of anti-ALK antibodies impacts prognosis in NSCLC. The naturally immunogenic properties of ALK in NSCLC may be able to be exploited using therapeutic ALK vaccines in patients.
