The results of this trial, A Randomized, Open-label, Phase 3, Superiority Study Of Pemetrexed (Pem)+Carboplatin (Cb)+Bevacizumab (B) Followed By Maintenance Pem+B Versus Paclitaxel (Pac)+Cb+B Followed By Maintenance B In Patients (pts) With Stage IIIB Or IV Non-squamous Non-small Cell Lung Cancer (NS-NSCLC), also referred to as the POINTBREAK trial, were presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology this past September.
While the trial did not fully accomplish its main objective—aiming to identify whether a pemetrexed-based first-line and maintenance chemotherapy regimen is superior to an established standard first-line and maintenance therapy regimen—key clinical insights were still brought to the forefront. Dr. Mark Socinski of UPMC Cancer Pavilion, Pittsburgh, PA, tells us more in a Q&A session with ChemotherapyAdvisor.com.
Can you give us some background on the POINTBREAK trial and what led to its initiation (i.e., previous studies that brought up more questions that needed to be answered)?
Dr. Socinski: The initial trial evaluating bevacizumab in combination with chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) was done with carboplatin/paclitaxel (ECOG 4599).1 Emerging evidence with pemetrexed clearly identified this agent as the preferred agent in non-squamous NSCLC, at least compared to gemcitabine in the Scagliotti trial.2 Drs. Patel and Hensing lead a phase II trial exploring the activity of the triplet regimen carboplatin/pemetrexed with bevacizumab and in the trial used both pemetrexed and bevacizumab as continuation maintenance after four cycles.3 The clinical outcomes were promising and given these data, a direct comparison of this novel triplet to the ECOG 4599 regimen of carboplatin/paclitaxel with bevacizumab was launched.4
What is the significance or importance of maintenance therapy of NSCLC?
Dr. Socinski: The importance of maintenance therapy is that this therapeutic strategy has been proven to improve progression-free survival (PFS) and overall survival (OS) compared to placebo in randomized trials. This has been shown with both switch (pemetrexed and erlotinib) as well as continuation (pemetrexed) maintenance approaches. One of the dangers of not using maintenance therapy and administering second-line therapy upon progression of disease is the fact that approximately 30% to 50% of patients never receive subsequent therapy likely due to disease-related complications precluding further therapy. Practicing maintenance therapy or administering “early second-line therapy” ensures that more patients are exposed to a greater number of active agents, thereby improving outcomes in advanced NSCLC.
Although the results of the POINTBREAK trial were ultimately negative (no difference in survival between the two arms), what were some of the important lessons learned that can be applied to treating NSCLC?
Dr. Socinski: POINTBREAK showed equivalent OS as well as response rates when comparing carboplatin/paclitaxel and carboplatin/pemetrexed given with bevacizumab. There was a statistically significant benefit in PFS on the pemetrexed arm, which may be related to the maintenance strategy that differed between the arms and compared bevacizumab alone to bevacizumab with pemetrexed.
This trial supports the use of either regimen allowing more flexibility for physicians when choosing the best regimen for an individual patient, which often involves patterns of toxicities. Toxicities also differed, but both regimens appeared to be similarly tolerated. For instance, alopecia was significantly less common on the pemetrexed arm of POINTBREAK, so if an individual patient had concerns about alopecia, the pemetrexed regimen used in the POINTBREAK trial would be a reasonable choice and one that would not compromise OS in a bevacizumab-eligible population.
Are there other trials that have been reported on recently or that are currently underway that might be of interest to clinical practitioners?
Dr. Socinski: The PARAMOUNT5 and AVAPERL trials have explored issues regarding maintenance therapy and contribute to our knowledge in this setting. Both trials looked at the role of continuation pemetrexed maintenance therapy, with the AVAPERL trial involving and evaluating a bevacizumab-eligible population. Both trials showed a significant benefit in PFS. The PARAMOUNT trial did improve OS; however, the OS data from AVAPERL remains too premature to be informative at this point.
Other results that are of interest are from clinical trials evaluating targeted therapies in molecularly defined populations. Two examples are available to date and involve patients with EGFR mutations6,7 and ALK translocations.8 In these molecularly-defined subsets of patients, targeted agents (erlotinib, gefitinib, and afatinib in the EGFR mutant population and crizotinib in the ALK-translocated population) have been shown to improve response rates and PFS with more favorable toxicity profiles compared with standard cytotoxic approaches in either the first- or second-line setting. These trials underscore the importance of testing patients for these actionable genotypes to be sure patients receive the best therapy for their advanced NSCLC.
1) 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;7(11):1707-1712. doi: 10.1097/JTO.0b013e318265b500.
2) Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551. doi: 10.1200/JCO.2007.15.0375. Epub 2008 May 27.
3) Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol. 2009;27(20):3284-3289. doi: 10.1200/JCO.2008.20.8181. Epub 2009 May 11.
4) Patel JD, Bonomi P, Socinski MA, et al. Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2009 Jul;10(4):252-6. doi: 10.3816/CLC.2009.n.035.
5) L. G. Paz-Ares, F. De Marinis, M. Dediu, et al. PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pem plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol 29: 2011 (suppl; abstr CRA7510).
6) Schuler MH, Planchard D, Yang JC-H, et al. Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy. J Clin Oncol 30, 2012 (suppl; abstr 7557).
7) Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi: 10.1016/S1470-2045(11)70393-X. Epub 2012 Jan 26.
8) Shaw AT, Camidge DR, Felip E, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Abstract presented at the 37th ESMO Conference, Vienna, Austria. Ann Oncol. 2012;23(Supplement 9):ix153. Abstract 4400.