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M. Früh
Moderator of
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 8
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.01 - Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients (ID 6149)
11:00 - 11:10 | Author(s): M. Kowanetz, W. Zou, D.S. Shames, C.A. Cummings, N. Rizvi, A. Spira, G.M. Frampton, V. Leveque, S. Flynn, S. Mocci, G. Shankar, R. Funke, M. Ballinger, D. Waterkamp, D.S. Chen, A. Sandler, G. Hampton, L.C. Amler, P.S. Hegde, M.D. Hellmann
- Abstract
- Presentation
Background:
In NSCLC, atezolizumab (anti-PDL1) efficacy correlates with PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC). Here we examined the association between atezolizumab efficacy and TMB assessed by FoundationOne (F1) sequencing panel.
Methods:
Pretreatment tumor specimens from 102 1L and 465 2L+ NSCLC patients enrolled on three Ph 2 atezolizumab monotherapy trials (POPLAR: randomized 2/3L trial comparing atezolizumab vs docetaxel; BIRCH/FIR: single-arm, 1L/2L+ PD-L1‒selected trials) were available for targeted genetic sequencing using the F1 panel of 315 cancer-related genes. TMB was quantified using an updated TMB algorithm and efficacy was assessed in groups defined by the 75th (high) and 50th (median) percentile of each study-specific TMB. Atezolizumab efficacy was examined at Dec 1, 2015 (POPLAR and BIRCH); and Jan 7, 2015 (FIR) data cutoffs.
Results:
Across samples, median TMB was similar in 1L and 2L+ patients (9/MB and 9.9/MB, respectively). In 1L and 2L+ PD-L1–selected patients, atezolizumab benefit was increased in those with ≥ TMB cut-offs (Table). In unselected 2L+ patients from POPLAR, the OS, PFS, and ORR benefits of atezolizumab vs docetaxel were also enhanced in patients with increased TMB. TMB and PD-L1 expression were independently associated with improved atezolizumab efficacy. TMB associations with PD-L1 expression, tumor-infiltrating lymphocyte infiltration and T-effector cell gene expression will be presented.
Conclusion:
For the first time, we demonstrate that TMB assessed with F1 targeted sequencing is associated with improved atezolizumab outcomes in 1L and 2L+ NSCLC. Moreover, this is the first study demonstrating the association of TMB with improved anti-PD-L1/PD-1 efficacy in a randomized trial. Importantly, the association between TMB and atezolizumab efficacy occurred in both unselected and PD-L1-selected patients. Therefore, in addition to PD-L1, TMB may be an independent predictor of improved responsiveness to atezolizumab in advanced NSCLC.Atezolizumab efficacy by TMB subgroups PD-L1‒selected BIRCH+FIR 1L n=102 2L+n=371 Median (≥9/MB) High (≥13.5/MB) Median (≥9.9/MB) High (≥17.1/MB) OS,HR[a] (95% CI) 0.79 (0.39-1.58) 0.45 (0.17-1.16) 0.87 (0.65-1.16) 0.7 (0.49-1.00) PFS,HR[a] (95% CI) 0.58 (0.36-0.94) 0.54 (0.3-0.97) 0.64 (0.5-0.8) 0.5 (0.38-0.67) ORR,above/below cutoff 28%/13% 25%/20% 25%/14% 29%/16% POPLAR 2L+ unselected n=92 Biomarker- evaluable population Median (≥9.9/MB) High (≥15.8/MB) OS,HR[b ] (95% CI) 0.65 (0.38-1.12) 0.48 (0.23-1.04) 0.5 (0.15-1.67) PFS,HR[b] (95% CI) 0.98 (0.63-1.53) 0.49 (0.25-0.93) 0.49 (0.19-1.3) ORR,atezolizumab/docetaxel 13%/15% 20%/4% 20%/8% [a]HR:efficacy-evaluable patients, atezolizumab at/above cutoff vs below.[b]HR:efficacy-evaluable patients, atezolizumab vs docetaxel at/above cutoff.
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OA20.02 - Neoantigen Targeting in NSCLC Patients with Complete Response to Anti-PD-1 Immunotherapy (ID 4352)
11:10 - 11:20 | Author(s): K.N. Smith, V. Anagnostou, P. Forde, J. Brahmer, V. Velculescu, D. Pardoll
- Abstract
- Presentation
Background:
Anti-PD-1 immunotherapy has resulted in durable clinical responses in heavily pretreated patients with non-small cell lung cancer (NSCLC). While NSCLC is typically seen as non-immunogenic, there is a 15-20% objective response rate and a median duration of response of 17 months in patients treated with the PD-1 inhibitor, nivolumab. This duration of response has not been reported with other systemic therapies in advanced NSCLC. While tumor PD-L1 expression may be a biomarker of sensitivity to anti-PD-1 therapy, and the number of somatic mutations may play a role in PD-1 upregulation on T cells, the mechanisms underlying response vs. progressive disease have yet to be fully elucidated.
Methods:
Whole exome sequencing and mutation-associated neoantigen (MANA) prediction was performed on tumor sections from two advanced NSCLC patients with complete response to nivolumab. Peptides representing MANAs were synthesized and tested against PBMC in a 10-day cultured IFNg ELISpot assay. Reactive MANAs were assessed in binding and stability assays. TCR sequencing was performed on reactive cell cultures and on DNA obtained from tumor resections to match MANA-reactive TCR clones with clones that were infiltrating the tumor.
Results:
The mean mutational burden in NSCLC as reported previously is 360 sequence alterations. In our study, patient 1 had 30 sequence alterations and patient 2 had 314. Despite the difference in mutational load, MANA reactivity was detected in peripheral blood of both patients >1 year after being declared cancer-free. TCR clones of MANA-reactive peripheral T cells were detected in tumor resections and were expanded in MANA-stimulated T cell cultures. Binding and stability assays confirmed that these MANAs bind to their cognate HLA with high affinity and stability.
Conclusion:
These findings show that NSCLC tumors with differential mutational burden can show regression following checkpoint blockade and suggest that the quality of mutations may be more influential in immunogenicity than the overall quantity of mutations. Our data also show that MANA reactivity may be the underlying mechanism by which T cells eliminate tumor following anti-PD-1 immunotherapy. Additional studies should evaluate mechanisms of enhancing MANA reactivity in patients who do not respond to checkpoint blockade and should further validate the link between MANA reactivity and clinical response to anti-PD-1.
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- Abstract
- Presentation
Background:
IL-7/IL-7 receptor (IL-7R) interactions have been shown to prevent apoptosis in lung cancer cells and promote stromal pro-tumor immune cell homing and differentiation. The aim of this study is to investigate the correlation between tumoral IL-7R expression and stromal pro-tumor immune cells (FoxP3+ Tregs and CD163+ M2 macrophages) and to determine prognostic impact of the combination of these markers in lung adenocarcinomas.
Methods:
In resected stage I lung adenocarcinoma (n=913; 1995-2009), antigen expression of IL-7R, FoxP3 and CD163 was evaluated by immunohistochemistry (IHC) using tissue microarrays and mRNA expression was quantified by RT-PCR. Prognosis was analyzed by both recurrence free probability (RFP) and lung cancer-specific survival (LCSS).
Results:
In IHC analysis, high tumoral IL-7R, stromal FoxP3, and stromal CD163 expression were individually associated with lymphatic/vascular invasion, and increasing percentage of solid histological patten. A correlation was seen between IL-7R, FoxP3 and CD163 expression by mRNA and IHC analyses (Figure1). The co-existence of high expression of these 3 markers was found in 16% of patients and was associated with worse outcomes (Figure2). In multivariable analysis, triple marker co-existence was an independent risk factor for RFP (p=0.004) and LCSS (p=0.008).
Conclusion:
Tumoral IL-7 receptor is a potential target for lung adenocarcinoma immunotherapy. Figure 1 Figure 2
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OA20.04 - Discussant for OA20.01, OA20.02, OA20.03 (ID 7098)
11:20 - 11:35 | Author(s): W. Hilbe
- Abstract
- Presentation
Abstract not provided
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OA20.05 - The Influence of Neoadjuvant Chemotherapy, on Immune Response Profile in Non-Small Cell Lung Carcinomas (ID 5738)
11:35 - 11:45 | Author(s): E.R. Parra, J. Rodriguez-Canales, C. Behrens, M. Jiang, A. Pataer, A.M. Correa, S. Swisher, B. Sepesi, A. Weissferdt, N. Kalhor, W.N. William Jr, J.J. Lee, J. Heymach, C. Moran, J. Zhang, D.L. Gibbons, I. Wistuba
- Abstract
- Presentation
Background:
The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).
Methods:
We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.
Results:
Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).
Conclusion:
We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).
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OA20.06 - Prospective ImmunogenomiC PrOfiling of Non-Small Cell Lung Cancer - The ICON Project (ID 5560)
11:45 - 11:55 | Author(s): B. Sepesi, I. Team, J. Heymach, P. Sharma, J. Allison, B. Fang, J. Zhang, H. Wagner, E. Bogatenkova, I. Wistuba, S. Swisher, C. Bernatchez, D.L. Gibbons
- Abstract
- Presentation
Background:
Previous attempts to define tumor and stromal immunologic environment in non-small cell lung cancer (NSCLC) utilized archival tissue. We established prospective comprehensive immonogenomic profiling protocol in NSCLC (ICON Project). The goal is to integrate immunomic, genomic, transcriptomic, proteomic, demographic, clinical, pathologic, and outcome data from 100 surgically resected early stage NSCLC.
Methods:
Tumor and normal lung tissue are collected at the time of surgery, blood samples before and after surgery. Tumor samples are processed for tumor infiltrating lymphocyte (TILs) isolation and expansion; development of patient derived xenografts (PDX), immunohistochemical immune markers, and immunopeptidome profiling. Blood samples are analyzed with flow cytometry.
Results:
57 patients with median age of 65 years (27 males) have been enrolled within 5 months, of which 33 (66%) contributed samples to the study. Four were never smokers, with others being former or current smokers. Majority (N=27) had adenocarcinoma, 4 squamous cell carcinoma, and 2 pleomorphic carcinoma. 15 patients had stage I, 11 stage II, and 7 stage III disease; 5 patients received induction chemotherapy. Median tumor size was 3.5 cm and 29 underwent R0 and 4 R1 resection. Pre-REP TIL expansion was successful in the majority of samples (68.2%, n=22). Twelve PDX models with a take rate of 40% have been generated. Interim analysis of tumor samples by IHC demonstrated higher median distribution of all cell types: CD3+ T cells, cytotoxic T cells CD8+, PD1+ cells, tumor associated macrophages (TAM) CD68+, TAM CD68+PD-L1+, CD20+B cells, memory T cells CD45R0, natural killer cells CD57+, regulatory FOXP3+ T cells, and cytotoxic granzyme B cells (cells/mm[2]) in the stroma as compared to the tumor compartment. Intra-tumoral regulatory FOXP3+T cells were more abundant in squamous cell carcinomas compared to adenocarcinomas (median 312 vs 51 cells/mm[2], p = 0.05). Higher concentration of intra-tumoral CD68+PD-L1+ expressing cells was observed following neoadjuvant chemotherapy (median 97 vs 60 cells/mm[2] no chemo; p= 0.077), as was the concentration of memory T cells CD45R0 (median 129 vs 30 cells/mm[2], no chemo; p = 0.077). Mass spectrometry-based immunopeptidome analysis identified several thousand peptides, of which 4 promising antigens have been chosen for further development as immunotherapeutic T-cell targets.
Conclusion:
The ICON is an ongoing, ambitious prospective project that aims to define the baseline immunologic characteristics of surgically resectable NSCLC. The rapid enrollment illustrates the enthusiasm for tumor immunoprofiling amongst patients and physicians alike. Data from this patient cohort will serve as a baseline comparison for upcoming neoadjuvant immunotherapy trials.
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OA20.07 - HHLA2, a New Immune Checkpoint Member of the B7 Family, is Widely Expressed in Human Lung Cancer and Associated with Mutational Status (ID 5184)
11:55 - 12:05 | Author(s): H. Cheng, M. Janakiram, A.C. Borczuk, J. Lin, W. Qiu, H. Liu, J. Chinai, B. Halmos, R. Perez-Soler, X. Zang
- Abstract
- Presentation
Background:
Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.
Methods:
We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients.
Results:
Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
Conclusion:
HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.
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OA20.08 - Discussant for OA20.05, OA20.06, OA20.07 (ID 7099)
12:05 - 12:20 | Author(s): H. Popper
- Abstract
- Presentation
Abstract not provided
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Author of
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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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MA15.12 - Discussant for MA15.09, MA15.10, MA15.11 (ID 7097)
15:38 - 15:50 | Author(s): M. Früh
- Abstract
Abstract not provided
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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. Früh
- 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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P1.08 - Poster Session with Presenters Present (ID 460)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.08-065 - Resection of Isolated Brain Metastasis Improves Outcome of Non Small-Cell Lung Cancer (NSCLC) Patients: A Retrospective Multicenter Study (ID 6132)
14:30 - 14:30 | Author(s): M. Früh
- Abstract
Background:
Metastatic non-small cell lung cancer (NSCLC) is an incurable disease. Selected patients with solitary brain metastasis from NSCLC can achieve long-term survival following metastasectomy. We analyzed the outcome of all consecutive and unselected patients undergoing resection of brain metastases in two cancer centers in Switzerland to assess safety and efficacy of brain metastasis resection in NSCLC.
Methods:
119 consecutive NSCLC patients undergoing surgical resection of brain metastases from two centers in Switzerland (University Hospital Basel, Cantonal Hospital St. Gallen) between 2000 and 2014 were analyzed. Measured outcomes were extent of resection, resection status, postoperative complications and overall survival (OS). We used the log-rank test to compare unadjusted survival probabilities and multivariable Cox regression to investigate potential prognostic factors with respect to OS.
Results:
Median age was 60.5 years, 56% were male, 74% were smokers, 55% had adenocarcinoma. Median OS of the whole cohort was 18.0 months. 1-year survival rate was 63%, 12% of patients were alive after 5 years. In total, 146 brain metastases were resected; the maximum number of resected metastases was 4 (median: 1). Median diameter of resected metastases was 25 millimeters (range, 6-70 mm). About half of metastases were localized in the frontal cortex or the cerebellum. 86% of patients received postoperative radiotherapy. 63% of patients were treated with whole brain radiation, 12.6% received stereotactic radiotherapy. Median dose of postoperative radiotherapy was 30 Gy. Patients not receiving adjuvant radiotherapy (n=11) had a significantly worse outcome (median OS 9.0 vs. 20.2 months, p=0.002). Patients with more than one brain metastasis (n=21) had a significantly worse outcome compared to those with a solitary metastasis (median OS 13.5 vs. 19.5 months, p=0.006). Also patients with extracerebral metastases (n=33) had a significantly poorer outcome (median OS 14.0 vs. 23.1 months, p=0.005). Patients with non-squamous histology (n=98) had a better outcome than patients with squamous cell carcinoma (median OS 22.6 vs. 12.0 months, p=0.019). 21% of patients experienced postoperative complications, including need for surgical reintervention (5.8%), neurological deficits (4.2%), infection (4.2%), stroke (3.4%) and others (11.8%). The occurrence of postoperative complications was not associated with outcome. In the multivariate analysis existence of extracerebral metastases and resection of more than one brain metastasis were independent negative prognostic factors.
Conclusion:
Patients with isolated brain metastasis from NSCLC in the absence of extracranial metastasis should be evaluated for metastasectomy. Prospective trials are needed to characterize the patient population experiencing the greatest benefit from a surgical procedure.
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P3.02c - Poster Session with Presenters Present (ID 472)
- 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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P3.02c-091 - Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC (ID 4735)
14:30 - 14:30 | Author(s): M. Früh
- Abstract
Background:
Preclinical studies demonstrated that local radiotherapy (RT) acts synergistically with RNActive[® ]vaccines to increase tumor-infiltrating immune cells and enhance anti-tumor effects. BI 1361849 (CV9202) is an immunotherapeutic cancer vaccine comprising optimized mRNA constituents (RNActive[®]) encoding six NSCLC-associated antigens. Here we report clinical outcomes and immune response data of a phase Ib study, employing local RT and BI 1361849 in advanced NSCLC.
Methods:
Patients (Pts) with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) were enrolled in three cohorts based on histological and molecular NSCLC subtypes (non-squamous vs. squamous vs. EGFR-mutated NSCLC). Pts received two initial vaccinations with BI 1361849 prior to local RT to the primary tumor or a metastatic lesion (four consecutive daily fractions of 5 Gy), followed by further vaccinations until start of another treatment. Maintenance Pemetrexed (mP) and EGFR-TKIs were continued according to the label. Primary endpoint was safety; secondary endpoints included objective response, PFS and OS. Cellular and humoral immune responses were measured ex vivo by multifunctional intracellular cytokine staining, IFN-γ ELISpot, and ELISA in pre- and post-treatment blood samples.
Results:
26 pts were enrolled. 15 pts received mP, two received EGFR TKIs. Most frequent AEs were mild to moderate injection-site reactions and flu-like symptoms. Two pts experienced BI 1361849-related grade 3 AEs (fatigue, pyrexia). No BI 1361849-related SAE or grade 4 AE was reported. Interim results indicate one confirmed PR in a patient receiving mP and SD in 13/25 evaluable pts (52%, 8 pts on mP, 3 pts without maintenance therapy, 2 pts on EGFR-TKI), with two pts showing remarkably long-lasting disease stabilization of up to 72 and 54 weeks, respectively. Shrinkage of lesions outside the irradiated field of ≥15% occurred in 7 pts, all but one receiving mP. Longitudinal assessment of tumor response allows for further insight into patterns of progression. BI 1361849 was capable of eliciting antigen-specific immune responses in the majority of the patients including both cellular and humoral immune responses.
Conclusion:
BI 1361849 elicits antigen-specific immune responses and can be safely combined with local RT and mP treatment. Shrinkage of non-irradiated lesions and prolonged disease stabilization was observed in a subset of pts, mainly in combination with mP. Final clinical outcomes and analyses of cellular and humoral immune responses will be presented.
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P3.06 - Poster Session with Presenters Present (ID 492)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Trial Design/Statistics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.06-010 - Clinical Outcomes of Non-Small Cell Lung Cancer (NSCLC) Patients with ALK Co-Mutations (EGFR or KRAS) Receiving Tyrosine Kinase Inhibitors (TKI) (ID 4729)
14:30 - 14:30 | Author(s): M. Früh
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) rearrangements with concurrent epidermal growth factor (EGFR) or Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur very rarely. Outcomes with TKI in these patients (pts) are poorly understood.
Methods:
Outcomes of pts with metastatic NSCLC and double mutations of ALK/EGFR or ALK/KRAS detected by FISH (ALK) and PCR or NGS (EGFR/KRAS) from six oncology centres in Switzerland were retrospectively analysed.
Results:
A total of 15 pts with adenocarcinoma were identified, 53% were females and tumor stages were IIIB (6%), IVA (27%) and IVB (67%). Six pts had a co-mutation of ALK/EGFR and nine ALK/KRAS. ALK/EGFR pts were younger (54 vs. 64 years) and less likely to be (ex-) smokers (34% vs. 77%). In total, 12 pts received an ALK-TKI (11x crizotinib, 1x alectinib, 2x ceritinib, 1x lorlatinib). EGFR-TKIs were given to five EGFR/ALK pts (4x afatinib, 2x osimertinib, 3x erlotinib). 33% received > 1 ALK-or EGFR-TKI. TKI were given as first-line (1L) in 40% (4x ALK/KRAS, 2x ALK/EGFR). Pts with ALK/KRAS co-mutation: Seven of eight pts (88%) were primary refractory to ALK-TKI treatment (all crizotinib). One patient has ongoing disease stabilization since 26 months. Three of six pts responded to 1L platinum-based chemotherapy with a median progression free survival (PFS) of 4.25 months (range: 1 month - NR). Pts with ALK/EGFR co-mutation: Two of four pts responded to ALK-TKI: one PR to crizotinib+erlotinib combination, one PR to alectinib and lorlatinib. Median PFS on first ALK-TKI was 3.75 months (range: 1-7months). Three of five pts (60%) achieved one or more responses to EGFR-TKI in different lines of therapy (4x PR: 3x afatinib, 1x osimertinib, CR: 1x osimertinib). Median PFS on first EGFR-TKI was 4.5 months (range: 3-7 months). Two of five pts responded to platinum-based chemotherapy (median PFS: 5.5 months (range: 0.25-10 months)).
Conclusion:
De novo concurrent ALK/KRAS alterations are associated with resistance to ALK-TKI treatment in seven out of eight pts, although one patient achieved ongoing disease stabilization for 26 months. Thus, platinum-based chemotherapy should be 1L treatment for these patients. In ALK/EGFR pts outcomes with ALK and EGFR-TKI seem inferior to what would be expected in pts with either alteration. EGFR-TKIs may potentially be more active compared to ALK-TKIs in ALK/EGFR pts. Worse outcomes to ALK-TKI may partly be related to false-positive ALK test results. Further studies are needed to clarify which patients may still benefit from the respective TKI.
