The maintenance therapy is still under discussion for patients with locally advanced or metastatic nonsquamous non-small-cell lung cancer. PARAMOUNT(1) trial affirms that pemetrexed maintenance conferred superior progression free survival (PFS 2.8 versus 4.4 months, p < 0.001) and increased median overall survival (OS) of 2.9 months (11 versus 13.8 months, p = 0.019; and 14.0 versus 16.9 months from induction, p = 0.019 after excluded the censured) with significant 22% reduction in the risk of death. The induction response rate (RR) assessment did not impact the OS results, but those responders (complete response CR and partial response PR) reached longer median OS (15.5 versus 13.7 months, respectively, p = 0.731). Meanwhile, AVAPERL(2) trial pointed that adding bevacizumab to pemetrexed maintenance was associated with double median PFS time (3.7 versus 7.4 months, p < 0.001) and an expressive 52% reduction in the risk of death over bevacizumab (dose 7.5 mg/kg) alone. Those with CR or PR after induction reached better 8.6 months PFS (p < 0.001) while SD group reached only 6.8 months (p = 0.036). There was just a trend of benefit in OS for the pemetrexed + bevacizumab maintenance arm (p = 0.219). In both trials the induction doublets were cisplatin based.
Recalling, ECOG 4599(3) showed improvement in PFS (4.5 versus 6.2 months, p < 0.001) and OS (10.3 versus 12.3 months, p = 0.003) after induction protocol based on addiction of bevacizumab to carboplatin + paclitaxel followed by bevacizumab maintenance. Otherwise, the AVAil(4) trial confirmed gain in PFS (but less than 1 month, p ≤ 0,03) and did not show OS improvement irrespective of bevacizumab dose (7.5 versus 15 mg/kg) when managed with cisplatin + gemcitabine induction therapy. Furthermore, no pemetrexed alone arm was analyzed and maybe the higher dose bevacizumab might be too excessive and onerous based on this data.
Recently published, PointBreak(5) trial suggests that induction based on carboplatin + pemetrexed + bevacizumab (15 mg/kg) followed by bevacizumab + pemetrexed versus induction based on carboplatin + paclitaxel + bevacizumab followed by bevacizumab alone obtained similar RR (34.1 versus 33%) and no difference in OS was observed (12.6 versus 13.4 months, p = 0.949). PFS improvement was only 0.4 months (5.6 versus 6.0 months, p = 0.012), while the results was insignificant among those non-responders ineligible to receive maintenance therapy (about 2.3 months). However, pemetrexed + bevacizumab maintenance arm reached better survival rates compared than bevacizumab alone (66.5% versus 71.7% at 12 months, and 26.5% versus 34.5% at 24 months, respectively). Furthermore, median OS showed worse for those non-responders to carboplatin + pemetrexed + bevacizumab induction (only 4.7 months).
Based on these data, the statistical significance has possibly been lost because carboplatin did not reaches the results of cisplatin combined with pemetrexed (PARAMOUNT and AVAPERL) while carboplatin could be a good choice to paclitaxel + bevacizumab as noted in ECOG 4599. Confirming previous meta-analyses, EMCTO recently presented new meta-analysis(6) where platinum-based regimens improved OS mainly at first-line and slightly based on cisplatin compared with carboplatin plus new agents (only a trend was seen for carboplatin). The cisplatin response rate is greater (p = 0.001), what may initiate better PFS and also OS when followed by maintenance therapy. Thus, these results highlighted the magnitude of the choice for the best first-line protocol.
Maintenance therapy is an acceptable strategy for “retaining” the induction benefit (CR/PR and SD) with goal in OS and PFS improvement. Thus, we may be losing OS gain while avoiding cisplatin. Maintenance therapy comes after only 4 cycles of platinum based therapy, thereby reducing the risk of adverse events. Besides, cisplatin is cheaper and more accessible than carboplatin as the actual amount used by each cycle (75 mg/m2 versus 300 mg/m2 = AUC6).
- What is currently, according to available evidence, the best first line induction protocol?
- What is currently the best therapy plan regarding induction plus maintenance therapy?
- In the era of targeted therapies and molecular oncology, how to select patients subgroups for particular therapy?
- Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol 2013; 31(23):2895-902.
- Barlesi F, Scherpereel A, Rittmeyer A, et al. (2013) Randomized Phase III Trial of Maintenance Bevacizumab With or Without Pemetrexed After First-Line Induction With Bevacizumab, Cisplatin, and Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: AVAPERL (MO22089). J Clin Oncol 2013; 31(24):3004-11.
- Lopez-Chavez A, Young T, Fages S, et al. Bevacizumab maintenance in patients with advanced non-small-cell lung cancer, clinical patterns, and outcomes in the Eastern Cooperative Oncology Group 4599 Study: results of an exploratory analysis. J Thorac Oncol 2012; 11:1707-12.
- Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009; 27(8):1227-34.
- Patel JD, Socinski MA, Garon EB, et al. 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. J Clin Oncol 2013;31(34):4349-57.
- Berghmans T, Paesmans M, Meert AP, et al. Are first-line platinum-based (PT) regimens improving survival in comparison with non-platinum (NPT) chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC)? A meta-analysis (MA) of randomised trials. Lung Cancer 80(1): S31, I. EMCTO 2013, abstr 670.
The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.