Correspondence

Genentech, Caris, Medscape, Quintiles, Pfizer Research Funding: Glen J. Weiss, Eli Lilly Expert Testimony: None Patents: None Other Remuneration: None REFERENCES 1. 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 31:2895-2902, 2013 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 26:35433551, 2008 3. National Cancer Institute: FDA Approval for Pemetrexed Disodium. Bethesda, MD, National Cancer Institute, 2013. http://www.cancer.gov/cancertopics/druginfo/ fda-pemetrexed-disodium 4. Camidge DR, Kono SA, Lu X, et al: Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Thorac Oncol 6:774-780, 2011 5. Seo JS, Ju YS, Lee WC, et al: The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res 22:2109-2119, 2012

DOI: 10.1200/JCO.2013.53.3893; published online ahead of print at www.jco.org on January 6, 2014

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Reality Check for Pemetrexed and Maintenance Therapy in Advanced Non–Small-Cell Lung Cancer TO THE EDITOR: In the introduction to the Eli Lilly PARAMOUNT study, Paz-Ares et al1 state that the pemetrexed-platinum regimen is efficacious in first-line treatment of advanced non–small-cell lung cancer (NSCLC). There are five randomized trials that have compared pemetrexed-platinum with other platinum doublets for this disease.2-6 They are all negative with respect to demonstration of superior efficacy for the pemetrexed-platinum regimen. The trial by Scagliotti et al2 reports slightly superior survival for nonsquamous histology in a nonstratified subset of patients (stratification was for histologic versus cytologic biopsy, not histologic subtype). This result is hypothesis generating, not practice changing. The trial by Grønberg et al3 of carboplatin-pemetrexed versus carboplatin-gemcitabine showed no difference in survival in the nonsquamous pathology subset. Three prospective trials tested the hypothesis of pemetrexedplatinum superiority for patients with nonsquamous NSCLC by randomly assigning only patients with nonsquamous disease to carboplatin-pemetrexed versus carboplatin-docetaxel,4 cisplatinpemetrexed versus cisplatin– oral vinorelbine,5 and carboplatinpemetrexed-bevacizumab versus carboplatin-paclitaxel-bevacizumab.6 Although not all of these trials are powered to show small differences in survival, examination of the curves consistently shows no trends of efficacy superiority of platinum-pemetrexed when compared with other platinum doublets in populations with NSCLC with exclusively nonsquamous pathology. All prospective trials testing pemetrexed superiority for nonsquamous NSCLC have failed to confirm this hypothesis. The most problematic trial for the advocates of protracted pemetrexed is the outcome of the large PointBreak study that compared carboplatin-pemetrexed-bevacizumab followed by maintenance pemetrexed-bevacizumab versus carboplatin-paclitaxel-bevacizumab followed by maintenance bevacizumab.6 The median survival times in this trial are unremarkable (12-13 months) for these expensive prescriptions, and the survival curves are overlapping. Three conclusions could be drawn from the PointBreak study: first, no advantage was observed for pemetrexed chemotherapy in a patient population selected for nonsquamous histology; second, pemetrexed-carboplatin is specifically not superior to carboplatin-paclitaxel; and third, no benefit was observed for continuation pemetrexed after induction pemetrexed-platinum. That the chemotherapy was given with bevaci482

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zumab is unimportant because the antibody was given in both arms and the impact of bevacizumab on survival outcomes is modest in NSCLC. PointBreak and PARAMOUNT are designed somewhat differently. However, generally speaking, PointBreak6 fails to confirm the principal conclusion of PARAMOUNT1 and is conspicuously not referenced in the final PARAMOUNT article. All of the industry studies (JMEN,7 Sequential Tarceva in Unresectable NSCLC [SATURN],8 and PARAMOUNT1) of maintenance therapy that have influenced practice have fundamental design flaws that systematically result in substandard care in the control arms. JMEN,7 SATURN,8 and PARAMOUNT1 all include four cycles of induction therapy with a platinum doublet. Although four cycles of chemotherapy may be the median number in NSCLC trials of chemotherapy, this should not be the case in a population randomly assigned without progression plus an ECOG performance status of 0 or 1. Although most clinical benefit comes from the first four cycles, it can be argued that responding patients in the control arms of the maintenance studies were shortchanged and could have benefited from two more cycles, according to American Society of Clinical Oncology (ASCO) guidelines.9 More seriously, patients in the control arms received further treatment at investigator discretion. This predictably resulted in a large proportion of control arm patients not receiving evidence-based second-line therapy or any additional systemic treatment at all. Although a sizable fraction of patients beginning chemotherapy for advanced NSCLC fail to receive second-line therapy because of progression or chemotherapy toxicity, this is not true for patients eligible for random assignment. The proportion of patients receiving any additional agent in SATURN8 was 72%, for JMEN7 it was 67%, and for PARAMOUNT,1 only 64%. Contrast this with the ethically designed phase III trial of maintenance therapy by Pe´rol et al,10 in which second-line therapy was predefined and supplied. Under these circumstances, more than 90% of patients in the control group received evidence-based second-line therapy (pemetrexed, erlotinib, or docetaxel). The investigator discretion design feature in the control groups of JMEN, SATURN, and PARAMOUNT resulted in many patients receiving agents that were proven not to help in the second-line setting. The availability/affordability of proper second-line treatment was a factor in these global studies with disparate health care systems. Evidence-based second-line therapy is standard of care for patients with advanced NSCLC,9 and it should not have been a discretionary option for patients volunteering for the PARAMOUNT experiment. Its availability should have been guaranteed. Much of this has been said before.11 The soft target control group design for trials like PARAMOUNT is at variance with ASCO core values.12 It must be recognized that the survival benefit of switch and JOURNAL OF CLINICAL ONCOLOGY

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Correspondence

continuation maintenance treatment has been overestimated by serious study design flaws.

Nevin Murray University of British Columbia and British Columbia Cancer Agency, Vancouver, British Columbia, Canada

AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. 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 31:2895-2902, 2013 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 26:35433551, 2008 3. Grønberg BH, Bremnes RM, Fløtten O, et al: Phase III study by the Norwegian lung cancer study group: Pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non–smallcell lung cancer. J Clin Oncol 27:3217-3224, 2009 4. Rodrigues-Pereira J, Kim JH, Magallanes M, et al: A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol 6:1907-1914, 2011 5. Bennouna J, Zatloukal P, Krzakowski MJ, et al: Prospective randomized phase II trial of oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P in first-line

metastatic or locally advanced non-small cell lung cancer (M or LA NSCLC) patients (pts) with nonsquamous (non SCC) histologic type: NAVoTRIAL01—Preliminary results. J Clin Oncol 30:498s, 2012 (suppl; abstr 7575) 6. Garon EB, Patel JD, Myrand S, et al: Translational research (TR) results from PointBreak: A randomized, open-label, phase III study of pemetrexed (Pem)⫹carboplatin (Cb)⫹bevacizumab (Bev) followed by maintenance Pem⫹Bev (Pem Arm) versus paclitaxel (Pac)⫹Cb⫹Bev followed by maintenance Bev (Pac Arm) in patients (pts) with stage IIIB or IV nonsquamous non-small cell lung cancer (ns-NSCLC). J Clin Oncol 30:507s, 2013 (suppl; abstr 8086) 7. Ciuleanu T, Brodowicz T, Zielinski C, et al: 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. Lancet 374:1432-1440, 2009 8. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521-529, 2010 9. Azzoli CG, Baker S Jr, Temin S, et al: American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol 27:6251-6266, 2009 10. Pe´rol M, Chouaid C, Pe´rol D, et al: Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol 30:3516-3524, 2012 11. Edelman MJ, Le Chevalier T, Soria JC: Maintenance therapy and advanced non-small-cell lung cancer: A skeptic’s view. J Thorac Oncol 7:1331-1336, 2012 12. Pentz RD, Joffe S, Emanuel EJ, et al: ASCO core values. J Clin Oncol 24:5780-5782, 2006

DOI: 10.1200/JCO.2013.53.3448; published online ahead of print at www.jco.org on January 6, 2014

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Reply to S. Barni et al, K.R. Dearing et al, and N. Murray The PARAMOUNT trial1 was designed as the next step in an orderly progression of studies to ascertain pemetrexed efficacy for treatment of advanced non–small-cell lung cancer (NSCLC). Two major issues regarding the PARAMOUNT study design have been raised. First is the use of four cycles rather than six cycles during the induction phase. Some postulate that four cycles is suboptimal and leads to an overestimation of trial results.2 The choice of four cycles minimizes platinum toxicity, is endorsed by current treatment guidelines,3-5 and is backed by a number of studies,6-8 including the JMDB trial, wherein more than 90% of patients with a tumor response achieved that response within the first four cycles.9 The second issue questions the nonmandated second-line treatment.2 PARAMOUNT employed a customary study design, following accepted standard-of-care practices, discontinuing patients at the point of progression so that physicians might determine best treatment options unfettered by additional study restrictions. Although some might suggest that lack of a predefined second-line treatment overestimates results, the authors reject this hypothesis because both arms had equal access to second-line treatment. If anything, discretionary use of second-line postdiscontinuation therapy skewed results slightly in favor of placebo, given that more placebo-arm patients received additional therapy after discontinuing the trial (placebo, 72%; pemetrexed, 64%).1 Furthermore, the majority of these patients received approved second-line therapy, with percentages comparable with other maintenance trials and with those observed in clinical practice. Some have noted that a low percentage of patients received pemetrexed after study discontinuation; this is not surwww.jco.org

prising, given that all patients received first-line pemetrexed. Additionally, rechallenge chemotherapy is not an evidenced-based approach, nor is it aligned with usual clinical practice or recommended by professional guidelines.10 A predefined second-line could be considered more relevant for a switch maintenance trial, in which there is a higher risk of cross over and associated difficulty in interpreting the results. A number of large phase III trials and associated analyses have established the differential efficacy of pemetrexed in nonsquamous histology for first-line treatment,11,12 second-line treatment,12 switch maintenance,12-14 and now continuation maintenance in advanced NSCLC,1 notwithstanding claims to the contrary. Because these trials each enrolled many hundreds of patients, prespecified subgroup analysis allowed clear delineation of pemetrexed preferential efficacy for tumors with nonsquamous histology. In contrast, some of the trials Murray2 cited to question pemetrexed efficacy seem insufficiently powered.15,16 Another trial cited used a substantially different population (including patients with Eastern Cooperative Oncology Group performance status of 2 or squamous tumors) and a nonstandard pemetrexed dosing schema with elderly patients.17 Additionally, some cited studies used carboplatin-pemetrexed rather than cisplatin-pemetrexed.15,17,18 The PointBreak trial18 was also cited2 as failing to confirm pemetrexed-cisplatin first-line superiority and the PARAMOUNT pemetrexed maintenance results. PointBreak comparator arms consisted of pemetrexed-carboplatin-bevacizumab versus paclitaxelcarboplatin-bevacizumab for induction, followed by pemetrexedbevacizumab or bevacizumab alone (respectively) as maintenance therapy. The addition of bevacizumab makes it difficult to compare this trial with trials using first-line pemetrexed-platinum followed by maintenance, given that bevacizumab could have antagonistic or © 2014 by American Society of Clinical Oncology

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Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer.

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