|LETTERS TO THE EDITOR
|Year : 2019 | Volume
| Issue : 3 | Page : 276-278
Tolerance and efficacy of branded generic pemetrexed maintenance in Indian patients of metastatic non-squamous non-small-cell lung cancer
Amit Sehrawat1, KM Parthasarathy1, Deni Gupta1, Arun Gera2
1 Department of Medical Oncology, Dharamshila Narayana Suparspeciality Hospital, New Delhi, India
2 Department of Nuclear Medicine, Dharamshila Narayana Suparspeciality Hospital, New Delhi, India
|Date of Web Publication||19-Jul-2019|
Department of Medical Oncology, Dharamshila Narayana Suparspeciality Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sehrawat A, Parthasarathy K M, Gupta D, Gera A. Tolerance and efficacy of branded generic pemetrexed maintenance in Indian patients of metastatic non-squamous non-small-cell lung cancer. Indian J Cancer 2019;56:276-8
|How to cite this URL:|
Sehrawat A, Parthasarathy K M, Gupta D, Gera A. Tolerance and efficacy of branded generic pemetrexed maintenance in Indian patients of metastatic non-squamous non-small-cell lung cancer. Indian J Cancer [serial online] 2019 [cited 2019 Oct 14];56:276-8. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/276/263027
Lung cancer is one of the most common cancers in the world including India. Patients of metastatic non-squamous non-small cell lung cancer (NS-NSCLC) post 1st line systemic therapy, achieving complete response (CR)/partial response (PR)/stable disease (SD), can be offered observation or maintenance therapy with respective pros and cons. Maintenance chemotherapy trials such as PARAMOUNT, SATURN, and AVAPERL  have shown benefit with different agents. Maintenance can be either continuation maintenance or switch maintenance. The concept of maintenance holds good to a greater extent in the setting of advanced NSCLC as a majority of the patients' progress following first-line therapy. Recurrence can be with devastating consequences resulting in loss of “window of opportunity” for second-line therapy.
Platinum-based first-line chemotherapy has improved OS in patient with advanced NSCLC, but no additional benefit is realized after 4–6 cycles, and toxicities prevent more cycles. As of now, there are no biomarkers to predict outcome after first-line therapy. The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines suggest options of continuation maintenance pemetrexed, bevacizumab, or pemetrexed with bevacizumab in non-squamous NSCLC after first-line therapy response. Pemetrexed switch maintenance is also one option. Previous studies have shown a survival benefit with pemetrexed maintenance (PM).
Maintenance options are scarce for metastatic solid cancers, and rarer are the studies using branded generics for maintenance. There is a paucity of such data exclusively from India. This study was according to the hypothesis that the same would hold true for the Indian population, and our study was aimed to highlight the special issues with Indian population including adverse effects (AEs) profile.
This study investigated the role of PM in advanced NS-NSCLC in terms of PFS, OS, and AEs. It was a hospital-based, single center, single arm prospective, observational study conducted from May 2015 to June 2017 on Indian patients. Biopsy proven NSCLC, age >18 and <75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, adequate bone marrow reserves (absolute neutrophil counts >1500 cell/mm 3), acceptable renal (serum creatinine <2.0 mg/dl), and liver functions (SGOT/SGPT <2 times upper normal limit), showing response post six cycles of pemetrexed + platinum (cisplatin or carboplatin) and having at least one measurable lesion as per PERCIST criteria were included. Squamous cell Histology, positive targetable mutations EGFR, and EML4-ALK rearrangement (if done) were excluded.
A baseline routine hematology, biochemistry, histopathology ± immunohistochemistry to diagnose NS-NSCLC, and mutation testing were done whenever feasible. PET/CT ± MRI brain were done for staging workup.
Patients received three weekly, 6 cycles of pemetrexed (500 mg/m 2) + cisplatin (75 mg/m 2) or carboplatin 5-6 AUC. The response was assessed using PERCIST criteria. Patients with CR, PR, or SD were offered 3 weekly maintenance pemetrexed (500 mg/m 2) a 10 min infusion. Evaluation with PET-CT every four cycles of maintenance or at clinical suspicion of the disease progression was done. AEs were monitored and documented using Common Terminology Criteria for Adverse Events Version 4.0.
Study endpoints were disease progression, death, or completion of the study tenure. Progression free survival was defined as an interval between first induction chemotherapy to the date of disease progression (documented by PET-CT). One-year OS was also calculated for all eligible patients.
Data analysis was done using descriptive statistics, and correlation of qualitative variables was done using Chi-square test/Fisher's exact test. Survivals were analyzed using Kaplan-Meier survival analysis curve.
Lung cancer, especially in developing countries like India, is diagnosed at an advanced stage and remains incurable. The goal of treatment is to prolong life with tolerable toxicity profile. One such option in this situation is the cytotoxic therapy in the form of maintenance therapy. Branded generic remain mainstay of therapy option in Indian subcontinent considering the economic constraints of majority of the population.
This study tested the concept of continuation branded generic PM in Indian population for efficacy and AEs. A majority of the patients had ECOG PS1, 71.43% (n = 20). This study also included poorer ECOG-PS 2, which was not the case in previous landmark studies.
All patients in the study were of non-squamous NSCLC histology, i.e. adenocarcinoma with its various degree of differentiation. PARAMOUNT and AVAPERL trials included varied histologies. During induction, 64.29% (n = 18) cisplatin + pemetrexed doublet six cycles and remaining 35.71% (n = 10) patients received carboplatin. POINTBREAK  trial included only carboplatin-based regimens, and only four cycles of cisplatin + pemetrexed were used in both PARAMOUNT  and AVAPERL. After induction, three patients (10.71%) had SD vs. 25 PRs (89.29%), which was significantly higher in comparison to PARAMOUNT trial i.e. 53% SD and 44% PR/CR. Two extra cycles of induction doublet and usage of PRECIST criteria instead of RECIST for assessment would have shown higher response received but at the cost of increased toxicity.
Patients received 8.25 ± 9.07 mean number of PM cycles, with a median of four cycles (2-34). The mean number of maintenance cycles was 7.9 (1-44) in PARAMOUNT trial.
PFS in this study was longer as compared to any previously published trial. When calculated from the date of 1st induction chemotherapy mean PFS was 10.30 months, median PFS was 7.27 months with 95% CI, and standard error 1.19. This was remarkably higher than in PARAMOUNT trial viz. 6.9 months. This was also significantly better than any of the previous studies with continuation maintenance pemetrexed. 3.91 months in PRONOUNCE trial, 4.4 months in study by Karayama et al., 4.3 months in study by Ciuleanu et al., (switch maintenance).
The median PFS was 8.64 months in females vs. 6.9 months in males. One-year OS was 64.28% (n = 18). Correlation between number of PM cycles received and chances of achieving 1-year OS was statistically significant with a P value of 0.007.
Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis, and the 5-year survival is less than 18%. The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%). Previous studies like PARAMOUNT trial have reported 1-year OS to be 58%.
In the present study, most of the patients tolerated treatment well with manageable grade1 or grade 2 toxicities. Four patients had grade 4 toxicities, but next due cycle was given within 21 days of the due date in all patients. Most common symptoms because of possible drug-related AEs reported by the patients were fatigue and dyspnea. These were mostly well manageable of grade 1 or 2. In total, 17.86% patients had grade 3/4 AEs including sepsis, hyponatremia, neutropenia, deep venous thrombosis (DVT), and thrombocytopenia. Incidence was significantly higher than reported in PARAMOUNT study. This can be because of more prolonged exposure to induction chemotherapy, overall poor PS, and more metastatic disease burden in our study population. There was no grade 5 toxicity.
We understand the sample size is a major drawback of our study, but the studied sample size was only feasible considering single-center study, and eligible patients were only those who had response to the induction chemotherapy. In addition, this study tries to highlight the experience with branded generics and Indian patient specific adverse effects. Although 28 patients is a small sample size to power major landmark results, these numbers will definitely guide us for further large scale analysis in the future.
Present study further consolidates the evidence that benefit of continuation branded generic PM is as good as the original molecule reports.
During induction chemotherapy, six cycles of branded generic PM plus cisplatin/carboplatin-based chemotherapy is recommended over four cycles. This is usually well tolerated and significantly improves tumor response rates. Since there are many effective second line treatment options including immunotherapeutic agents are available, it is very crucial to promptly detect and document progression on first line therapy so that appropriate option can be offered to the patient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol J-L, Bidoli P, 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;31:2895-902.
Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, et al
. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521-9.
Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, FerrerTur N, Kim J-H, et al
. 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;31:3004-11.
Socinski MA, Schell MJ, Peterman A, Bakri K, Yates S, Gitten R, et al
. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002;20:1335-43.
Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S, Brahmer JR, et al
. Systemic therapy for stage IV non–small-cell lung cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2015;33:3488-515.
Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, 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;31:4349-57.
Paz-Ares L, Marinis F
de, Dediu M, Thomas M, Pujol J-L, Bidoli P, et al.
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. Lancet Oncol 2012;13:247-55.
Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, et al
. PRONOUNCE: Randomized, open-label, phase III study of first-line pemetrexed+carboplatin followed by maintenance pemetrexed versus paclitaxel+carboplatin+bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol 2015;10:134-42.
Karayama M, Inui N, Fujisawa T, Enomoto N, Nakamura Y, Kuroishi S, et al
. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexedmonotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Eur J Cancer 2016;58:30-7.
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, 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 2009;374:1432-40.