Author of

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  MTE17 - Maintenance Therapy Versus Early Second-Line Therapy in Advanced NSCLC (Ticketed Session) (ID 311)

  • Event: WCLC 2016
  • Type: Meet the Expert Session (Ticketed Session)
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 07:30 - 08:30, Strauss 3

  • 17173

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    MTE17.02 - Maintenance Therapy Versus Early Second-Line Therapy in Advanced NSCLC (ID 6571)

    07:30 - 08:00  |  Author(s): P. Fidias
    • Abstract
    • Presentation
    • Slides

    Abstract:
    Several trials have evaluated the appropriate initial duration of platinum based chemotherapy: 3 versus 6 cycles, 4 versus continuous cycles, or 2 versus 4 cycles after non-progression to the initial 2 treatments. In all situations there was no benefit to longer duration of chemotherapy and both ASCO and NCCN recommend no more than 6 cycles of initial treatment. Continuation of lower intensity therapy (typically with a single agent from the initial doublet) was also tested. Studies of weekly paclitaxel after carboplatin-paclitaxel (Belani et al) or gemcitabine after cisplatin-gemcitabine (Brodowicz et al) showed no OS difference, but a possible benefit in PFS. Studies evaluated the introduction of a non-cross resistant agent (early second line) in patients without progression after initial chemotherapy. Westeel et al. randomized patients after MIC x 3 to either observation versus vinorelbine; Fidias et al. evaluated immediate versus delayed docetaxel after carboplatin-gemcitabine x 4 and JMEN study looked into pemetrexed versus placebo after four cycles of platinum doublet. For the latter two studies, about 50% of patients completed 6 maintenance cycles and 50-60% of patients in the observation arm received second line therapy; this is consistent with rates of second line therapy in multiple studies of NSCLC. Results showed a 2-3 month difference in PFS favoring immediate therapy. In terms of overall survival, there was no difference with vinorelbine, and a 2.6-2.8 month difference with either docetaxel or pemetrexed (significant only with pemetrexed). QoL was not affected by continuous chemotherapy and tumor related symptoms improved with pemetrexed. Erlotinib has been evaluated in 3 randomized trials against placebo (SATURN), observation (IFCT-GFPC 0502) or in combination with bevacizumab against placebo-bevacizumab (ATLAS). In all studies there was a PFS benefit (HR 0.71-0.82), but OS was only significant in the SATURN trial (HR 0.81). PFS benefit was limited to non-squamous histology for pemetrexed, as opposed to the docetaxel and erlotinib trials. Despite the initial negative trials, continuation pemetrexed following platinum-pemetrexed doublet has emerged as a standard option for non-squamous NSCLC. PARAMOUNT randomized between pemetrexed and placebo following four cycles of cisplatin pemetrexed. It showed a PFS benefit (HR 0.64) and also an OS benefit (2.9 month difference, HR 0.78) in favor of continuation maintenance. AVAPERL used a similar design, however with the addition of bevacizumab throughout therapy, i.e. initial cisplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab versus bevacizumab. PFS significantly favored pemetrexed (10.2 versus 6.6 months), and although OS was also superior (19.8 versus 15.9 months) it was not statistically significant. The IFCT-GFPC 0502 trial also evaluated continuation gemcitabine and demonstrated a PFS advantage, but no OS benefit in an underpowered study. Bevacizumab continuation is an accepted approach based on the design of E4599, although its contribution has never been established in a randomized trial. However, a direct comparison between E4599 (carboplatin-paclitaxel-bevacizumab followed by bevacizumab) and carboplatin-pemetrexed-bevacizumab followed by pemetrexed-bevacizumab was undertaken in the POINTBREAK study. It showed no OS differences (numerically favored E4599: 13.4 versus 12.6 months), although in pre-specified analysis of patients going through maintenance (as opposed to ITT) there was a 2-month difference favoring the combination of pemetrexed-bevacizumab. E5508 [ClinicalTrials.gov identifier:NCT01107626] is attempting to answer this question by directly randomizing patients to either bevacizumab, pemetrexed or the combination after carboplatin-paclitaxel-bevacizumab. Subset data from the SATURN trial strongly supports switch maintenance with erlotinib for EGFR mutant patients, who had an impressive three fold higher median PFS (44 vs 14 weeks; HR: 0.10; 95% CI: 0.04–0.25). INFORM included 296 asian patients, who were randomized between gefitinib and placebo. PFS favoured gefitinib maintenance (4.8 vs 2.6 months, HR=0.42; 95% CI: 0.33–0.55; p <0.0001). No overall survival benefit has been found for squamous cell patients. However, a PFS benefit was seen in IFCT-GFPC 0502 for continuation maintenance with gemcitabine and in SATURN for sequential erlotinib. The ABOUND study with carboplatin/ nab-paclitaxel is exploring the nab-paclitaxel maintenance in squamous-cell and results are awaited. The SQUIRE trial evaluated the anti-EGFR monoclonal antibody necitumumab in combination with cisplatin-gemcitabine followed by maintenance necitumumab. It modestly improved overall survival and PFS over chemotherapy alone (median OS 11.5 vs 9.9 months, HR 0.84, p=0.012; PFS HR 0.85, p=0.02). The contribution of bevacizumab maintenance phase was not prospectively been established. However, a retrospective landmark analysis of E4599 evaluated the patients who were alive without progression for at least 3 weeks after completion of 6 cycles of chemotherapy. The PFS favored bevacizumab maintenance (4.4 vs 2.8 months; HR 0.64). OS was also longer (median 12.8 vs 11.4 months). ECOG 5508 is an important ongoing study, as mentioned previously Another ongoing study (MO 22097) is evaluating the role of continuing bevacizumab in combination with a second line chemotherapy, beyond progression to maintenance bevacizumab. In a phase III placebo-controlled study, carboplatin and paclitaxel were given with or without concurrent and maintenance sorafenib, but no improvement in overall survival was shown and the results were detrimental in patients with squamous cell histology. CALGB 30607 of maintenance sunitinib versus placebo met its primary endpoint of improving PFS (4.3 versus 2.8 mos), including squamous histology. There was no effect on OS. EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis. A phase III trial of carboplatin, paclitaxel with or without concomitant and maintenance ipilimumab (an anti-CTLA4 agent) is ongoing, and was initiated taking into account the positive results obtained adding maintenance ipilimumab to the platinum doublet in a previous phase II study. Vaccine therapy has also been studied as maintenance treatment in NSCLC. Belagenpumatucel-L (Lucanix) is an allogeneic cancer vaccine, obtained from TGF-beta2 antisense gene modified whole NSCLC cell lines. There was no difference in overall survival between arms (median survival 20.3 versus 17.8 months with belagenpumatucel-L versus placebo, respectively. Tecemotide (L-BLP-25) is a vaccine against MUC1 antigen. START trial randomized patients with stage III NSCLC who completed chemoradiotherapy between tecemotide injections or placebo. No significant difference in overall survival with the administration of tecemotide after chemoradiotherapy was found - median OS was 25.6 months with tecemotide versus 22,3 months with placebo. References 1. Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vs observation with predefined second-line treatment after cisplatin–gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study. I Borget, M Pérol, D Pérol, A Lavolé, L Greillier, P Dô, V Westeel, J Crequit, H Léna, I Monnet, H Le Caer, P Fournel, L Falchero, M Poudenx, F Vaylet, S Chabaud, A Vergnenegre, G Zalcman, C Chouaïd. BMC Cancer2014,14:953 DOI: 10.1186/1471-2407-14-953) 2. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Tudor Ciuleanu, Thomas Brodowicz, Christoph Zielinski, Joo Hang Kim, Maciej Krzakowski, Eckart Laack, Yi-Long Wu, Isabel Bover, Stephen Begbie, Valentina Tzekova, Branka Cucevic, Jose Rodrigues Pereira, Sung Hyun Yang, Jayaprakash Madhavan, Katherine P Sugarman, Patrick Peterson, William J John, Kurt Krejcy, Chandra P Belani. Lancet Vol 374: 1432, 2009 3. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT):a double-blind, phase 3, randomised controlled trial. Luis Paz-Ares, Filippo de Marinis, Mircea Dediu, Michael Thomas, Jean-Louis Pujol, Paolo Bidoli, Olivier Molinier, Tarini Prasad Sahoo, Eckart Laack, Martin Reck, Jesús Corral, Symantha Melemed, William John, Nadia Chouaki, Annamaria H Zimmermann, Carla Visseren-Grul, Cesare Gridelli. Lancet Vol 13: 247, 2012 4. PointBreak: A Randomized Phase III Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer. Jyoti D. Patel, Mark A. Socinski, Edward B. Garon, Craig H. Reynolds, David R. Spigel, Mark R. Olsen, Robert C. Hermann, Robert M. Jotte, Thaddeus Beck, Donald A. Richards, Susan C. Guba, Jingyi Liu, Bente Frimodt-Moller, William J. John, Coleman K. Obasaju, Eduardo J. Pennella, Philip Bonomi, and Ramaswamy Govindan. JCO 31:4349, 2013
    
    

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