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V. Sriuranpong
Moderator of
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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 - 15:55 | Presenting Author(s): Anthony Brade
- Abstract
- Presentation
Abstract not provided
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MS 17.02 - MAGRIT (ID 7722)
15:55 - 16:05 | 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)
16:05 - 16:30 | 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)
16:30 - 16:40 | 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)
16:40 - 16:50 | 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)
16:50 - 17:15 | 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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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)
15:55 - 16:05 | Author(s): V. Sriuranpong
- 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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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-042 - Efficacy & Tolerability of Afatinib in NSCLC Patients Prior Exposure to 1st Generation EGFR TKI: Thailand Multicenter Study (ID 9455)
09:30 - 09:30 | Author(s): V. Sriuranpong
- Abstract
Background:
The Compassionate-Use-Program (CUP) was available in Thailand for requesting afatinib during 2012-2014 for patients whom had failed at least one-line of platinum-based-chemotherapy and progressed following at least 6 months on 1[st]-generation EGFR-TKIs. This is a multicenter-retrospective-study in Thailand aimed to explore the efficacy and tolerability of afatinib in this group of patients.
Method:
Full medical-records of 79 patients from 7 institutions were reviewed. Clinical and tumor characteristics were analyzed using descriptive statistics. The efficacy in brain metastases was explored. Survival curves were constructed using the Kaplan-Meier method. All analysis was done in Stata version14.
Result:
Sixty-eight percent of patients were younger than 65 years old, 60% were female, and 67% received more than 2 of prior-regimen. EGFR-mutation was tested in 75% of patients; comprise of 86% common-mutations, 14% uncommon-mutations. Eleven patients had T790M acquired-resistance in combination with sensitive-mutation before receiving afatinib. One patient had De-novo-T790M. The mOS, mPFS, and mTTF were 11.5, 3.9, and 5.1 months, respectively. Eighteen patients had brain-metastases at enrollment and 6 patients had new brain-metastases during afatinib treatment. The mOS, mPFS, and mTTF were not statistically different among new brain-metastases or pre-existing brain-metastases. There was no dose-reduction in 38%, 1 dose-reduction 44%, 2 dose-reductions 12%, and 3 dose-reductions 6% of patients. The mean dose for every patient was 35 mg. Time-to-first-dose-reduction significantly affected the mPFS and mTTF as shown in Table. Furthermore, number of prior-treatment more than 2 was the significant factor causing first-dose-reduction within 1 month and age younger than 65 years-old was the significant factor causing first-dose-reduction within 2 and 3 months in multivariate and univariate model, respectively.Time to 1[st] dose reduction OS PFS TTF Hazard ratio (95%CI) P-value Hazard ratio (95%CI) P-value Hazard ratio (95%CI) P-value > 1 month <= 1 month 1 1.59 (0.74-3.41) 0.23 1 1.52 (0.82-2.82) 0.19 1 1.45 (0.77-2.74) 0.25 >2 month <= 2 months 1 1.54 (0.72-3.3) 0.27 1 2.11 (1.14-3.92) 0.02 1 1.63 (0.88-3.04) 0.12 >3 months <= 3 months 1 2.31 (0.98-5.45) 0.06 1 2.67 (1.38-5.20) 0.004 1 2.12 (1.09-4.12) 0.03
Conclusion:
The mOS, mPFS, and mTTF of our study were comparable with LUX-Lung1 study. Number of prior-treatment and age were the significant factors causing dose-reduction. Taken together with time-to-first-dose-reduction also affected the survival of patients.
