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Johan F. Vansteenkiste
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MS 17 - Lessons Learned from Negative Trials (ID 539)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 6
- Moderators:V. Sriuranpong, Johan F. Vansteenkiste
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 303 + 304
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MS 17.01 - PROCLAIM (ID 7721)
15:45 - 17:30 | Presenting Author(s): Anthony Brade
- Abstract
- Presentation
Abstract not provided
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MS 17.02 - MAGRIT (ID 7722)
15:45 - 17:30 | Presenting Author(s): Johan F. Vansteenkiste
- Abstract
- Presentation
Abstract:
Antigen-specific immunotherapy or cancer vaccination has been studied in several large phase III trials in NSCLC in different stages [1]. Agents consisted of two major components: immunogenic tumor-associated antigens, combined with a strong adjuvant to generate the tumor directed attack. Overall, the results of these trials have been disappointing. One of these phase III trials was MAGRIT, the largest therapeutic clinical trial ever performed in NSCLC. The MAGRIT trial (MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy[2]. Other major trials in this setting, such as RADIANT, studying adjuvant erlotinib [3], and ECOG 1505, studying the addition of bevacizumab cisplatin-based adjuvant chemotherapy [4], proved to be negative. As adjuvant cisplatin-based chemotherapy can be hard to tolerate for many patients [5], a less toxic and effective therapy to improve the outcome in this group was of great interest. Melanoma associated antigen (MAGE)-A3 was an interesting target because it is almost exclusively expressed on tumor cells, and not expressed in normal tissue (except in male germline cells, which however do not present the antigen). The MAGE-A3 vaccine was a recombinant protein antigen-based vaccine, containing the recombinant fusion protein (MAGE-A3 and protein D of Haemophilus Influenzae) in combination with an immune response enhancing adjuvant. Clear responses to this compound had been noted in early experience in patients with metastatic melanoma [6]. For NSCLC, the proof of concept study was a double-blind, placebo-controlled, randomized phase II trial [7]. Patients with completely resected MAGE-A3-positive stage IB-II NSCLC were randomly assigned to either MAGE-A3 vaccine (N=122) or placebo (N=60), 5 administrations q3 weeks followed by 8 administrations q3 months. No adjuvant chemotherapy was given, as this therapy was not established in the study interval. Disease-free interval (DFI) was the primary endpoint. After a median post-resection period of 70 months, there was a trend in favor of MAGE-A3, with a Hazard Ratio (HR) for DFI 0.78 (95%CI 0.49-1.24; two-sided P=0.295). No significant toxicity was observed, resulting in very high therapy compliance. Furthermore, a possible gene signature (GS), predictive of clinical activity of the MAGE-A3 vaccine in previous metastatic melanoma experience [6], could be validated in early-stage NSCLC [8]. Actively treated GS-positive NSCLC patients showed a favorable DFI compared with placebo-treated (HR 0.42, 95% CI 0.17-1.03; P=0.06), whereas among GS-negative patients, no such difference was found (HR 1.17, 95% CI 0.59-2.31; P=0.65). This led to the large double-blind, randomized, placebo-controlled phase III trial MAGRIT (ClinicalTrials.gov, number NCT00480025) [9]. MAGE-A3 positive patients with completely resected stage IB, II or IIIA NSCLC, and adjuvant chemotherapy as clinically indicated, were 2:1 randomly assigned to the MAGE-A3 vaccine or placebo. Randomization and treatment allocation was done centrally via internet with stratification for chemotherapy versus no chemotherapy. A minimization algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. Between Oct 18, 2007, and July 17, 2012, a total of 13,849 surgical patients in 443 centers in 34 countries were screened for MAGE-A3 expression, 4210 had MAGE-A3 expression, and 2,272 were treated (active vaccine 1,515; placebo 757). 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. At the time of the report, median follow-up was 38.1 months in the MAGE-A3 group and 39.5 months in the placebo group. In the overall population, median disease-free survival (DFS) was 60.5 months (95% CI 57.2–not reached) in the MAGE-A3 vaccine group and 57.9 months (55.7–not reached) in the placebo group (hazard ratio 1.02, 95% CI 0.89–1.18; P=0·74). In the predefined subgroup patients who did not receive chemotherapy, median DFS was 58.0 months (95% CI 56·6–not reached) in the MAGE-A3 group and 56.9 months (44.4–not reached) in the placebo group (hazard ratio 0.97, 95% CI 0.80–1.18; p=0·76). Because of the absence of treatment effect, the predictive gene signature could not be further studied. The frequency of grade 3 or worse adverse events was similar: 246/1515 (16%) in the MAGE-A3 group and 122/757 (16%) in the placebo group. It was concluded that adjuvant treatment with the MAGE-A3 vaccine did not increase DFS compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC, and the further development of the MAGE-A3 vaccine for NSCLC was stopped. REFRERENCES 1. Decoster L, Wauters I, Vansteenkiste J. Vaccination therapy for non-small cell lung cancer: Review of agents in phase III development. Ann Oncol 2012; 23: 1387-1393. 2. The International Adjuvant Lung Cancer Trial Collaborative Group, Arriagada R, Bergman B et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360. 3. Kelly K, Altorki NK, Eberhardt WE et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J Clin Oncol 2015; 33: 4007-4014. 4. Wakelee HA, Dahlberg SE, Keller SM et al. Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. J Thorac Oncol 2015; 10 Suppl 2: 66S. 5. Alam N, Shepherd FA, Winton T et al. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature. Lung Cancer 2005; 47: 385-394. 6. Kruit WH, Suciu S, Dreno B et al. Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: Results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer melanoma group in metastatic melanoma. J Clin Oncol 2013; 31: 2413-2420. 7. Vansteenkiste J, Zielinski M, Linder A et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 8. Ulloa-Montoya F, Louahed J, Dizier B et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 9. Vansteenkiste JF, Cho BC, Vanakesa T et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17: 822-835.
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MS 17.03 - Is There Such a Thing as a ‘Negative’ Trial? (ID 7723)
15:45 - 17:30 | Presenting Author(s): Lucinda Jane Billingham
- Abstract
- Presentation
Abstract:
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MS 17.04 - MET-Lung: A Phase III Trial of Onartuzumab (METMab) Plus Erlotinib vs Erlotinib in Previously Treated Stage IIIB or IV NSCLC (ID 7724)
15:45 - 17:30 | Presenting Author(s): Karen Kelly
- Abstract
- Presentation
Abstract:
A well-known mechanism of resistance to EGFR-TKIs is MET upregulation. MET inhibitors were developed to overcome and prevent this resistance mechanism. Onartuzumab is a monoclonal antibody that binds the extracellular domain of MET. By blocking the interaction with its HGF ligand, activation of the MET signaling pathway does not occur and tumor growth is halted. The clinical evaluation of onartuzumab followed the traditional phase I, II and III registration pathway. In the randomized Phase II trial of erlotinib and placebo versus erlotinib and onartuzumab the trial failed to meet the co-primary endpoint of PFS in the intent to treat population but was positive for the co-primary endpoint of PFS in 66 patients with MET positive tumors defined as IHC > 2+ expression (HR, .53; P .04) (1). Overall survival was also significant (HR, .37; P .002). Objective response rate (ORR) was reported as 8.6% and 3.2% for onartuzumab versus placebo, respectively. Based on these results a randomized placebo controlled phase III trial was launched in patients with MET expressing tumors (2). Surprisingly this trial did not meet its OS primary endpoint and numerically favored the placebo arm. A total of 499 patients were enrolled. The median OS was 6.8 months for onartuzumab versus 9.1 months for placebo (HR, 1.27; 95% CI, 0.98 to 1.65; P = .067). Median progression-free survival was 2.7 months versus 2.6 months (HR, 0.99; 95% CI, 0.81 to 1.20; P = .92) and the ORR was 8.4% compared with 9.6% respectively. When a trial is negative scrutinizing all aspects of the trial and its predecessor trial to determine if there were instructive signals is needed. In this case, reported patient characteristics were similar between the two trials but other patient variables such as the frequency of patients with brain metastases, sites of metastases, and time from previous therapy were not provided. However a large magnitude of difference would be required to significantly alter the results which is unlikely. Adverse events profiles were unrevealing. There were differences related to the MET biomarker that may have influenced the phase III results. In the phase II trial MET IHC expression was retrospectively determined compared to its prospective determination in the phase III trial and its use as a stratification factor. Although the frequency of MET 2+ versus 3+ IHC expression was similar in the two trials, the retrospective nature of the analysis in the phase II trial with its inherent imbalance in patient characteristics may have been misleading especially in the context of the small sample size. Had this been a randomized biomarker selected Phase II trial with a larger sample size we might have seen a different outcome. The assay itself was not a factor. Rigorous validation of the MET IHC assay was conducted. The assay was performed at Genentech for the phase II study and these investigators carefully trained the central laboratories personnel performing the assay for the phase III trial. A robust quality check and audit program was followed. A frequently asked question is whether IHC accurately characterize drivers of MET dysregulation that would result in EGFR tyrosine kinase inhibitor (TKI) resistance and onartuzumab responsiveness. In an exploratory biomarker analysis from the Phase II study MET IHC remained the most robust predictor of efficacy for the combination (3). In the phase III trial a detailed EGFR and MET pathway analysis that included MET and EGFR FISH, EGFR amplification and EGFR, KRAS BRAF, PIK3CA mutational analysis failed to find a biological explanation for onartuzumab inactivity (3). An analysis of MET Exon 14 splicing mutations was not conducted because these mutations had not been discovered at the time of study conduct. Although it would be intriguing to know the frequency of these mutations and their association to onartuzumab activity this is unlikely to be performed. The subgroup results supported further investigation of onartuzumab in a MET positive population but the results were modest. The statistically significant 1.4 month improvement in median PFS is not clinically significant and objective response rates were similar between the arms. Driving the phase III design was the impressive 8.8 month improvement in median OS for the combination but without strong efficacy signals in ORR and PFS to account for this survival outcome suggests other factors were at play such as subsequent therapies and warrants caution. The dilemma with encouraging preliminary data is what is the optimal next study design especially in this instance where the findings were modest? Too many times we have seen positive phase II trials lead to negative phase III results. While a phase III trial is the quickest route to a definitive answer it is done at the price of hundreds of patients. This is particularly highlighted by this study where the combination was approaching an inferior overall survival. Alternative design strategies such as a randomized Phase II/III design that can better balance benefit and risk for our patients and still achieve the goal should be considered. Criteria should be established to help investigators select the appropriate design. References 1. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, Krzakowski MJ, Robinet G, Godbert B, Barlesi F, Govindan R, Patel T, Orlov SV, Wertheim MS, Yu W, Zha J, Yauch RL, Patel PH, Phan SC, Peterson AC. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2013, 31:4105-14. 2. Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T. Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. J Clin Oncol. 2017, 35:412-20. 3. Koeppen H, Yu W, Zha J, Pandita A, Penuel E, Rangell L, Raja R, Mohan S, Patel R, Desai R, Fu L, Do A, Parab V, Xia X, Januario T, Louie SG, Filvaroff E, Shames DS, Wistuba I, Lipkind M, Huang J, Lazarov M, Ramakrishnan V, Amler L, Phan SC, Patel P, Peterson A, Yauch RL. Biomarker analyses from a placebo-controlled phase II study evaluating erlotinib±onartuzumab in advanced non-small cell lung cancer: MET expression levels are predictive of patient benefit. Clin Cancer Res. 2014, 20:4488-98.
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MS 17.05 - CheckMate026 (ID 7725)
15:45 - 17:30 | Presenting Author(s): David P Carbone
- Abstract
- Presentation
Abstract not provided
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MS 17.06 - Avoiding Phase II-III Attrition: Enhanced Biomarkers, Better Drugs or Improved Trial Design? (ID 7726)
15:45 - 17:30 | Presenting Author(s): John Crowley
- Abstract
- Presentation
Abstract:
In this talk I will cover reasons why phase III trials are "negative" and what can be done to increase the rate of true positive results. Reasons for failure in phase III include inactive agents, poor statistical design, and inadequate implementation. With targeted agents including immunotherapy, additional issues of statistical design arise, as well as assay reliability. I will review the trials discussed in this section (PROCLAIM, MAGRIT, METLung, CheckMate026) with a view towards assessing the reasons these trials might have been negative, and make some suggestions for future trials.
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Author of
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.03 - 3-Year Survival and Duration of Response in Randomized Phase II Study of Atezolizumab vs Docetaxel in 2L/3L NSCLC (POPLAR) (ID 8703)
11:00 - 12:30 | Author(s): Johan F. Vansteenkiste
- Abstract
- Presentation
Background:
Atezolizumab (anti–PD-L1) has demonstrated OS benefit over docetaxel in a randomized Phase II study, POPLAR, in patients with advanced NSCLC. This benefit has been confirmed in the randomized Phase III study OAK (Rittmeyer, 2017). The 3-year survival analysis of the POPLAR study presented here describes the longest survival follow-up reported to date of an all-comer randomized PD-L1/PD-1 immunotherapy trial in 2L+ NSCLC.
Method:
Patients were randomized 1:1 to receive atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. Tumors were prospectively evaluated for tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression using the VENTANA SP142 IHC assay. Landmark OS was estimated using the Kaplan-Meier method. Data cutoff, April 7, 2017; minimum follow-up, 3 years.
Result:
The 2-year and 3-year survival with atezolizumab vs docetaxel were 32.2% vs 16.6% and 18.7% vs 10.0%, respectively. The long-term OS benefit of atezolizumab vs docetaxel was observed across histology and PD-L1 expression subgroups (Table). While the TC3 or IC3 subgroup derived the greatest OS benefit, the TC0 and IC0 subgroup also had improved long-term OS with atezolizumab vs docetaxel. The ITT ORR was 15% in both atezolizumab and docetaxel arms, but the median duration of response was 3 times longer with atezolizumab (22.3 months [95% CI: 11.6, 31.1] vs 7.2 months [95% CI: 5.8, 12.2] with docetaxel). Seven of the 11 docetaxel-arm 3-year survivors received subsequent non-protocol therapy with anti–PD-L1/PD-1 agents. Atezolizumab had a favorable safety profile compared with docetaxel that was consistent with previous reports.
Conclusion:
Atezolizumab demonstrates superior 2-year and 3-year OS benefit compared with docetaxel, and this benefit is observed across histology and PD-L1 expression subgroups (including TC0 and IC0). Atezolizumab is well tolerated, and responses are highly durable. These results are consistent with long-term OS results from OAK, presented separately.Table. Landmark OS in the ITT, PD-L1 expression, and histology subgroups in POPLAR Population (n, atezolizumab vs docetaxel) 2-year OS rate, % 3-year OS rate, % Atezolizumab Docetaxel P value[a] Atezolizumab Docetaxel P value[a] ITT (144 vs 143) 32.2% 16.6% 0.0027 18.7% 10.0% 0.0419 PD-L1 Expression Subgroups TC3 or IC3 (24 vs 23) 41.7% 19.9% 0.1003 37.5% 14.9% 0.0724 TC2/3 or IC2/3 (50 vs 55) 36.1% 13.8% 0.0082 21.2% 9.9% 0.1166 TC1/2/3 or IC1/2/3 (93 vs 102) 36.0% 19.8% 0.0124 18.0% 11.0% 0.1759 TC0 and IC0 (51 vs 41) 25.0% 6.8% 0.0202 20.5% 6.8% 0.0693 Histology Subgroups Non-squamous (95 vs 95) 32.2% 21.1% 0.0960 23.3% 12.4% 0.0585 Squamous (49 vs 48) 32.7% 7.8% 0.0020 9.4% 5.2% 0.4603 [a ]For descriptive purpose only. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC2/3 or IC2/3 = PD-L1 ≥ 5% TC or IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT01903993.
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MS 17 - Lessons Learned from Negative Trials (ID 539)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:V. Sriuranpong, Johan F. Vansteenkiste
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 303 + 304
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MS 17.02 - MAGRIT (ID 7722)
15:45 - 17:30 | Presenting Author(s): Johan F. Vansteenkiste
- Abstract
- Presentation
Abstract:
Antigen-specific immunotherapy or cancer vaccination has been studied in several large phase III trials in NSCLC in different stages [1]. Agents consisted of two major components: immunogenic tumor-associated antigens, combined with a strong adjuvant to generate the tumor directed attack. Overall, the results of these trials have been disappointing. One of these phase III trials was MAGRIT, the largest therapeutic clinical trial ever performed in NSCLC. The MAGRIT trial (MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy[2]. Other major trials in this setting, such as RADIANT, studying adjuvant erlotinib [3], and ECOG 1505, studying the addition of bevacizumab cisplatin-based adjuvant chemotherapy [4], proved to be negative. As adjuvant cisplatin-based chemotherapy can be hard to tolerate for many patients [5], a less toxic and effective therapy to improve the outcome in this group was of great interest. Melanoma associated antigen (MAGE)-A3 was an interesting target because it is almost exclusively expressed on tumor cells, and not expressed in normal tissue (except in male germline cells, which however do not present the antigen). The MAGE-A3 vaccine was a recombinant protein antigen-based vaccine, containing the recombinant fusion protein (MAGE-A3 and protein D of Haemophilus Influenzae) in combination with an immune response enhancing adjuvant. Clear responses to this compound had been noted in early experience in patients with metastatic melanoma [6]. For NSCLC, the proof of concept study was a double-blind, placebo-controlled, randomized phase II trial [7]. Patients with completely resected MAGE-A3-positive stage IB-II NSCLC were randomly assigned to either MAGE-A3 vaccine (N=122) or placebo (N=60), 5 administrations q3 weeks followed by 8 administrations q3 months. No adjuvant chemotherapy was given, as this therapy was not established in the study interval. Disease-free interval (DFI) was the primary endpoint. After a median post-resection period of 70 months, there was a trend in favor of MAGE-A3, with a Hazard Ratio (HR) for DFI 0.78 (95%CI 0.49-1.24; two-sided P=0.295). No significant toxicity was observed, resulting in very high therapy compliance. Furthermore, a possible gene signature (GS), predictive of clinical activity of the MAGE-A3 vaccine in previous metastatic melanoma experience [6], could be validated in early-stage NSCLC [8]. Actively treated GS-positive NSCLC patients showed a favorable DFI compared with placebo-treated (HR 0.42, 95% CI 0.17-1.03; P=0.06), whereas among GS-negative patients, no such difference was found (HR 1.17, 95% CI 0.59-2.31; P=0.65). This led to the large double-blind, randomized, placebo-controlled phase III trial MAGRIT (ClinicalTrials.gov, number NCT00480025) [9]. MAGE-A3 positive patients with completely resected stage IB, II or IIIA NSCLC, and adjuvant chemotherapy as clinically indicated, were 2:1 randomly assigned to the MAGE-A3 vaccine or placebo. Randomization and treatment allocation was done centrally via internet with stratification for chemotherapy versus no chemotherapy. A minimization algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. Between Oct 18, 2007, and July 17, 2012, a total of 13,849 surgical patients in 443 centers in 34 countries were screened for MAGE-A3 expression, 4210 had MAGE-A3 expression, and 2,272 were treated (active vaccine 1,515; placebo 757). 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. At the time of the report, median follow-up was 38.1 months in the MAGE-A3 group and 39.5 months in the placebo group. In the overall population, median disease-free survival (DFS) was 60.5 months (95% CI 57.2–not reached) in the MAGE-A3 vaccine group and 57.9 months (55.7–not reached) in the placebo group (hazard ratio 1.02, 95% CI 0.89–1.18; P=0·74). In the predefined subgroup patients who did not receive chemotherapy, median DFS was 58.0 months (95% CI 56·6–not reached) in the MAGE-A3 group and 56.9 months (44.4–not reached) in the placebo group (hazard ratio 0.97, 95% CI 0.80–1.18; p=0·76). Because of the absence of treatment effect, the predictive gene signature could not be further studied. The frequency of grade 3 or worse adverse events was similar: 246/1515 (16%) in the MAGE-A3 group and 122/757 (16%) in the placebo group. It was concluded that adjuvant treatment with the MAGE-A3 vaccine did not increase DFS compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC, and the further development of the MAGE-A3 vaccine for NSCLC was stopped. REFRERENCES 1. Decoster L, Wauters I, Vansteenkiste J. Vaccination therapy for non-small cell lung cancer: Review of agents in phase III development. Ann Oncol 2012; 23: 1387-1393. 2. The International Adjuvant Lung Cancer Trial Collaborative Group, Arriagada R, Bergman B et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360. 3. Kelly K, Altorki NK, Eberhardt WE et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non-small cell lung cancer (RADIANT): A randomized, double-blind, phase III trial. J Clin Oncol 2015; 33: 4007-4014. 4. Wakelee HA, Dahlberg SE, Keller SM et al. Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. J Thorac Oncol 2015; 10 Suppl 2: 66S. 5. Alam N, Shepherd FA, Winton T et al. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature. Lung Cancer 2005; 47: 385-394. 6. Kruit WH, Suciu S, Dreno B et al. Selection of immunostimulant AS15 for active immunization with MAGE-A3 protein: Results of a randomized phase II study of the European Organisation for Research and Treatment of Cancer melanoma group in metastatic melanoma. J Clin Oncol 2013; 31: 2413-2420. 7. Vansteenkiste J, Zielinski M, Linder A et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 8. Ulloa-Montoya F, Louahed J, Dizier B et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 9. Vansteenkiste JF, Cho BC, Vanakesa T et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; 17: 822-835.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.02 - Osimertinib vs SoC EGFR-TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA): Plasma ctDNA Analysis (ID 8978)
15:45 - 17:30 | Author(s): Johan F. Vansteenkiste
- Abstract
- Presentation
Background:
FLAURA (NCT02296125) is a Phase III, double-blind, randomized study assessing efficacy and safety of osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment for patients with EGFRm advanced NSCLC. Concordance between tissue and plasma testing for EGFRm (Ex19del/L858R), and progression-free survival (PFS) by baseline plasma EGFRm status were evaluated.
Method:
Eligible patients: ≥18 years (Japan ≥20 years); Ex19del/L858R mutation-positive lung adenocarcinoma; no prior systemic anti-cancer/EGFR-TKI therapy for advanced NSCLC. Randomization: 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC (gefitinib 250 mg or erlotinib 150 mg, qd po). At baseline, patients provided tumor tissue samples for central analysis of EGFRm status (cobas EGFR Mutation Test) and blood samples for retrospective analysis of EGFRm status by plasma ctDNA (cobas EGFR Mutation Test v2). PFS by baseline plasma EGFRm status was assessed. Comparison of EGFRm status between baseline tumor tissue and evaluable ctDNA samples was an exploratory endpoint.
Result:
Globally, 556 patients were randomized: osimertinib, n=279; SoC, n=277. Good concordance was observed between central laboratory tissue and plasma testing for EGFRm in the screened population (see table). In plasma EGFRm-positive patients (n=359), osimertinib (n=183) reduced the risk of progression or death by 56% vs SoC (n=176), hazard ratio (HR) 0.44 (95% CI 0.34, 0.57). This was consistent with the overall PFS result observed with osimertinib vs SoC in the full analysis set (FAS; tumor tissue EGFRm-positive by local/central testing), HR 0.46 (95% CI 0.37, 0.57); p<0.0001 and in plasma EGFRm-negative patients (n=124: osimertinib, n=60; SoC, n=64), HR 0.48 (95% CI 0.28, 0.80).Figure 1
Conclusion:
In the subgroup of plasma EGFRm-positive patients, clinical benefit of osimertinib was superior to SoC, consistent with the overall FLAURA FAS. These results, and good concordance between tissue and plasma testing for EGFRm, support the utility of plasma EGFRm testing for selecting patients eligible for first-line osimertinib treatment.
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P1.13 - Radiology/Staging/Screening (ID 699)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.13-007 - Is Central Lung Tumor Location Really Predictive for Occult Mediastinal Nodal Disease in (Suspected) NSCLC Staged cN0 on PET-CT? (ID 8779)
09:30 - 16:00 | Author(s): Johan F. Vansteenkiste
- Abstract
Background:
Based on a 20-30% prevalence of occult mediastinal disease, current guidelines recommend preoperative invasive mediastinal staging in patients with central tumour location and negative mediastinum on PET-CT. A uniform definition of central tumour location is lacking. Our objective was to determine the best definition in predicting occult mediastinal disease.
Method:
A single institution prospective database was queried for patients with (suspected) NSCLC staged cN0 after PET-CT and referred to invasive staging and/or primary surgery. We evaluated 5 definitions of central tumour location (table 1).
Result:
Between 2005 and 2015, 822 patients were eligible. Radio-occult lesions were excluded from analysis (n=9). Preoperative histology was NSCLC in 49% and unknown in 51%. The lesion was subsolid in 7%. Tumour stage was cT1, cT2, cT3 and cT4 in 43%, 28% 17% and 11%, respectively. Invasive mediastinal staging (EBUS and/or mediastinoscopy) was performed in 31%. Surgical resection was performed in 97%, a median of 5 (IQR 3-6) nodal stations were examined. The final pathology was squamous NSCLC, non-squamous NSCLC, or other in 38%, 54% and 7%, respectively. Any nodal upstaging was found in 21% (13% pN1 and 8% pN2-3). Central tumour location demonstrated, compared to peripheral location, a 4 times higher risk for any nodal upstaging but not for N2-3 upstaging (table 1).
Conclusion:
When modern PET-CT fusion imaging points at clinical N0 NSCLC, the prevalence of occult mediastinal nodal disease was only 8% in our patient cohort. None of the five definitions of centrality we studied was predictive for occult pN2-N3. Overall nodal upstaging was 21%, however, and all definitions of centrality then had discriminatory value. These data question whether the indication of preoperative invasive mediastinal staging should be based on centrality alone. Table 1 Figure 1
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P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.04-005 - GEOMETRY Mono-1: Phase II, Multicenter Study of MET Inhibitor Capmatinib (INC280) in EGFR Wt, MET-Dysregulated Advanced NSCLC (ID 8961)
09:30 - 16:00 | Author(s): Johan F. Vansteenkiste
- Abstract
Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].
Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.
Result:
Section not applicable
Conclusion:
Section not applicable
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P2.04-013 - ElevatION:NSCLC-101 – A Phase 1b Study of PDR001 Combined with Chemotherapy in PD-L1 Unselected, Metastatic NSCLC Patients (ID 8936)
09:30 - 16:00 | Author(s): Johan F. Vansteenkiste
- Abstract
Background:
PDR001 is a high-affinity, humanized antiprogramed cell death-1 (PD-1) antibody that blocks interaction with programmed cell death ligands, PD-L1 and PD-L2. Results from phase 1/2 study have shown that PDR001 has a manageable safety profile and preliminary antitumor activity in advanced solid tumors. ElevatION:NSCLC-101 is the first study to evaluate the safety and preliminary efficacy of PDR001 plus platinum-doublet chemotherapy in patients with PD-L1 unselected, advanced NSCLC.
Method:
ElevatION:NSCLC-101 is an open-label, multicenter, phase 1b study (NCT03064854) of PDR001 plus platinum-doublet chemotherapy in patients (≥18 years) with squamous or nonsquamous, stage IIIB (not a candidate for definitive multimodality therapy) or stage IV or relapsed locally advanced or metastatic NSCLC, lacking EGFR-sensitizing mutation and/or ALK- or ROS1-rearrangements. Other inclusion criteria: ECOG PS 0-1, ≥1 measurable lesion (per RECIST v1.1), relapse for >12 months from the end of neoadjuvant or adjuvant systemic therapy. PD-L1 expression will be assessed but will not be used to determine eligibility. This study comprises 2 parts (dose-confirmation and dose-expansion) and 4 treatment groups (A, B, C, and D). Groups A, B, and C (dose-confirmation and dose-expansion parts) will include treatment-naïve patients. Group D (dose-expansion part) will include second line patients – those who have received only 1 prior systemic therapy consisting of a PD-1 and/or PD-L1 inhibitor ± CTLA-4 inhibitor (last dose of prior immunotherapy, ≥6 weeks prior to start of study treatment). The treatment-naïve patients will receive gemcitabine/cisplatin (group A) or pemetrexed/cisplatin (group B) or paclitaxel/carboplatin (group C) plus PDR001 (initially 300 mg q3w; if intolerable, a provisional dose level (−1) of 300 mg q6w will be explored) for up to 4 cycles followed by maintenance with PDR001 ± pemetrexed (group B). The second-line patients (group D) will be randomized (1:1) to either platinum-doublet chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) alone/combined with PDR001. Primary endpoints: dose-confirmation part – MTD and/or recommended dose for expansion (DLTs during first 6 weeks of therapy; for groups A, B, and C); dose-expansion part – investigator-assessed ORR per RECIST v1.1 (for groups A, B, and C). Secondary endpoints: ORR (for group D); PFS, DCR, DOR, TTR (for groups A, B, C, and D); OS, PK, and safety. The study enrollment is still ongoing. Approximately 6 to 20 treatment-naïve patients will be assigned to each group (A, B, C) and once MTD/RDE is established, ~20 additional patients will be enrolled in each treatment group; ~60 pretreated patients will be enrolled in group D.
Result:
Not-applicable.
Conclusion:
Not-applicable.
