Purpose
Platinum-based chemotherapy is the standard treatment for advanced urothelial carcinoma (aUC). Switch maintenance therapy after first-line (1L) treatment may delay disease progression. This study evaluated pemetrexed as switch maintenance therapy versus observation in aUC patients without disease progression after initial chemotherapy.
Materials and Methods
Eligible aUC patients who did not progress after 4–6 cycles of cisplatin or carboplatin-based chemotherapy were randomized 1:1 to receive maintenance pemetrexed (500 mg/m2 IV every 3 weeks, up to 16 cycles) or observation. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and safety.
Results
The trial was closed early due to slow accrual after avelumab approval. From October 2016 to December 2022, 97 patients were randomized to pemetrexed (n=49) or observation (n=48). The median age was 69 years (range: 43–90) and 66 (range33–82), respectively, with 63% and 73% of patients being male, respectively. The median PFS was 6.0 months (95% CI, 3.4–8.5) with pemetrexed versus 2.3 months (1.8–2.7) with observation (p=0.044, HR 0.64; 95% CI, 0.41–0.99). The median OS was 18.1 months (95% CI, 6.9–29.4) for pemetrexed and 17.9 months (16.1–19.7) for observation (p=0.913, HR 1.03; 95% CI, 0.61–1.73). Common adverse events in the pemetrexed group included anemia (30%), fatigue (18%), and neutropenia (12%), primarily grade 1 or 2.
Conclusion
The PREMIER trial showed that switch maintenance pemetrexed significantly prolonged PFS in aUC patients post-1L platinum-based chemotherapy, with a favorable safety profile. Further studies on combination maintenance therapies are warranted.
Purpose
Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression.
Materials and Methods
In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate.
Results
Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2.
Conclusion
Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.
Citations
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Bioengineered miR-7-5p modulates non–small cell lung cancer cell metabolism to improve therapy Gavin M. Traber, Mei-Juan Tu, Su Guan, Neelu Batra, Ai-Ming Yu Molecular Pharmacology.2025; 107(1): 100006. CrossRef
Kwai Han Yoo, Su Jin Lee, Jinhyun Cho, Ki Hyeong Lee, Keon Uk Park, Ki Hwan Kim, Eun Kyung Cho, Yoon Hee Choi, Hye Ryun Kim, Hoon-Gu Kim, Heui June Ahn, Ha Yeon Lee, Hwan Jung Yun, Jin-Hyoung Kang, Jaeheon Jeong, Moon Young Choi, Sin-Ho Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
Cancer Res Treat. 2019;51(2):718-726. Published online September 3, 2018
Purpose
The optimal cytotoxic regimens have not been established for patients with non-small cell lung cancer (NSCLC) who develop disease progression on first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).
Materials and Methods
We conducted a multi-center randomized phase II trial to compare the clinical outcomes between pemetrexed plus cisplatin combination therapy followed by maintenance pemetrexed (PC) and pemetrexed monotherapy (P) after failure of first-line EGFR-TKI. The primary objective was progression-free survival (PFS), and secondary objectives included overall response rate (ORR), overall survival (OS), health-related quality of life (HRQOL), and safety and toxicity profiles.
Results
A total of 96 patientswere randomized, and 91 patientswere treated at 14 centers in Korea. The ORR was 34.8% (16/46) for the PC arm and 17.8% (8/45) for the P arm (p=0.066). With 23.4 months of follow-up, the median PFS was 5.4 months in the PC arm and 6.4 months in the P arm (p=0.114). The median OS was 17.9 months and 15.7 months in PC and P arms, respectively (p=0.787). Adverse events ≥ grade 3 were reported in 12 patients (26.1%) in the PC arm and nine patients (20.0%) in the P arm (p=0.491). The overall time trends of HRQOL were not significantly different between the two arms.
Conclusion
The outcomes of pemetrexed therapy in NSCLC patients with disease progression after firstline EGFR-TKI might not be improved by adding cisplatin.
Citations
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The Survival and Financial Benefit of Investigator-Initiated Trials Conducted by Korean Cancer Study Group Bum Jun Kim, Chi Hoon Maeng, Bhumsuk Keam, Young-Hyuck Im, Jungsil Ro, Kyung Hae Jung, Seock-Ah Im, Tae Won Kim, Jae Lyun Lee, Dae Seog Heo, Sang-We Kim, Keunchil Park, Myung-Ju Ahn, Byoung Chul Cho, Hoon-Kyo Kim, Yoon-Koo Kang, Jae Yong Cho, Hwan Jung Yu Cancer Research and Treatment.2025; 57(1): 39. CrossRef
Osimertinib with Chemotherapy in
EGFR
-Mutated NSCLC
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Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors Balazs Halmos, Pragya Rai, Jae Min, Xiaohan Hu, Diana Chirovsky, Mark Shamoun, Bin Zhao Frontiers in Oncology.2024;[Epub] CrossRef
Clinical efficacy and safety of pemetrexed with or without either Bevacizumab or Pembrolizumab in patients with metastatic nonsquamous non–small cell carcinoma Wang Chun Kwok, Tan Fong Cheong, Ka Yan Chiang, James Chung Man Ho, David Chi Leung Lam, Mary Sau Man Ip, Terence Chi Chun Tam Asia-Pacific Journal of Clinical Oncology.2023; 19(1): 87. CrossRef
Factors associated with outcomes of second-line treatment for EGFR-mutant non-small-cell lung cancer patients after progression on first- or second-generation EGFR-tyrosine kinase inhibitor treatment Cheng-Yu Chang, Chung-Yu Chen, Shih-Chieh Chang, Ching-Yi Chen, Yi-Chun Lai, Chun-Fu Chang, Yu-Feng Wei Frontiers in Oncology.2023;[Epub] CrossRef
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Risk factors of nephrotoxicity of maintenance pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung Wang Chun Kwok, Ka Yan Chiang, James Chung Man Ho, David Chi Leung Lam, Mary Sau Man Ip, Terence Chi Chun Tam Lung Cancer.2021; 162: 169. CrossRef
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Real world experience on maintenance chemotherapy with gemcitabine in second line setting for advanced non-small cell lung carcinoma Wang Chun Kwok, David Chi Leung Lam, Ka Yan Chiang, James Chung Man Ho, Mary Sau Man Ip, Terence Chi Chun Tam Journal of Chemotherapy.2020; 32(8): 429. CrossRef
Makoto Nishio, Dong-Wan Kim, Yi-Long Wu, Kazuhiko Nakagawa, Benjamin J. Solomon, Alice T. Shaw, Satoshi Hashigaki, Emiko Ohki, Tiziana Usari, Jolanda Paolini, Anna Polli, Keith D. Wilner, Tony Mok
Cancer Res Treat. 2018;50(3):691-700. Published online July 6, 2017
Purpose
Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials.
Materials and Methods
This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and “as-treated” populations for efficacy and safety endpoints, respectively.
Results
In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity.
Conclusion
These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.
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Cancer Res Treat. 2016;48(1):80-87. Published online March 2, 2015
Purpose This study aimed to evaluate the efficacy and safety of pemetrexed versus gefitinib in patients with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. Materials and Methods Patients with advanced (stage IIIB or IV) or recurrent NSCLC were randomly assigned to receive either 500 mg/m² of pemetrexed intravenously every 3 weeks or gefitinib 250 mg/day orally. The primary end point was progression-free survival (PFS) at 6 months.
Results A total of 95 patients were enrolled (47 for pemetrexed and 48 for gefitinib). Most patients were male (72%) and current/ex-smokers (69%), and 80% had non-squamous cell carcinoma. The epidermal growth factor receptor (EGFR) mutation status was determined in 38 patients (40%); one patient per each arm was positive for EGFRmutation. The 6-month PFS rates were 22% and 15% for pemetrexed and gefitinib, respectively (p=0.35). Both arms showed an identical median PFS of 2.0 months and a median overall survival (OS) of 8.5 months. In EGFR wild-type patients, higher response rate (RR) and longer PFS as well as OS were achieved via pemetrexed compared with gefitinib, although there were no significant differences (RR: 39% vs. 9%, p=0.07; median PFS: 6.6 months vs. 3.1 months, p=0.45; median OS: 29.6 months vs. 12.9 months, p=0.62). Toxicities were mild in both treatment arms. Frequently reported toxicities were anemia and fatigue for pemetrexed, and skin rash and anorexia for gefitinib. Conclusion Both pemetrexed and gefitinib had similar efficacy with good tolerability as second-line treatment in unselected patients with advanced NSCLC. However, pemetrexed is considered more effective than gefitinib for EGFR wild-type patients.
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A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer Himani Aggarwal, Kerigo Ndirangu, Katherine B Winfree, Catherine Elizabeth Muehlenbein, Emily Zhu, Vanita Tongbram, Howard Thom Journal of Comparative Effectiveness Research.2023;[Epub] CrossRef
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Efficacy and Safety of Pemetrexed and Gefitinib in the Treatment of Non-Small-Cell Lung Cancer: A Meta-Analysis Zhihao Zhang, Xiyong Wang, Huaiqing Xiao, Dongqiang Wu, Dongliang Zhang, Qun Yu, Linna Yuan, Tao Huang Computational and Mathematical Methods in Medicine.2021; 2021: 1. CrossRef
A meta-analysis of the safety and effectiveness of pemetrexed compared with gefitinib for pre-treated advanced or metastatic NSCLC Xiaoxin Lu, Shengshu Li, Weizong Chen, Dongyang Zheng, Yuzhu Li, Fang Li Medicine.2020; 99(29): e21170. CrossRef
Pemetrexed versus Gefitinib as Second-line Treatment for Advanced Non-small Cell Lung Cancer: A Meta-analysis Based on Randomized Controlled Trials Huiyu Wang, Zunjing Zhang, Feng Liu, Miaoying Zhou, Handi Lv Pteridines.2019; 30(1): 171. CrossRef
Gefitinib for advanced non-small cell lung cancer Esther HA Sim, Ian A Yang, Richard Wood-Baker, Rayleen V Bowman, Kwun M Fong Cochrane Database of Systematic Reviews.2018;[Epub] CrossRef
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Purpose Platinum-based doublet chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC); however, the role of a platinum-based doublet as second-line therapy after failure of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for NSCLC patients has not yet been elucidated. The purpose of this study was to compare the clinical efficacy of pemetrexed versus a platinum-based doublet as second-line therapy after failure of EGFR TKI used as first-line therapy for NSCLC patients with EGFR mutations. Materials and Methods We designed a multicenter retrospective cohort study of 314 NSCLC patients with EGFR mutations who received an EGFR TKI as first-line palliative chemotherapy. Our analysis included 83 patients who failed EGFR TKI therapy and received second-line cytotoxic chemotherapy.
Results Forty-six patients were treated using a platinum-based doublet and 37 patients were treated using singlet pemetrexed. The overall response rates of patients receiving a platinum-based doublet and patients receiving pemetrexed were17.4% and 32.4%, respectively (p=0.111). The median progression-free survival (PFS) of patients receiving pemetrexed was significantly longer than that of patients receiving a platinum-based doublet (4.2 months vs. 2.7 months, respectively; p=0.008). The hazard ratio was 0.54 (95% confidence interval, 0.34 to 0.86; p=0.009). Conclusion Our retrospective analysis found that second-line pemetrexed singlet therapy provided significantly prolonged PFS compared to second-line platinum-based doublet chemotherapy for NSCLC patients with EGFRmutations who failed first-line EGFR TKI. Conduct of prospective studies for confirmation of our results is warranted.
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Purpose
This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC).
Materials and Methods
Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model.
Results
Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months).
Conclusion
The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients.
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Pemetrexed versus Gefitinib as Second-line Treatment for Advanced Non-small Cell Lung Cancer: A Meta-analysis Based on Randomized Controlled Trials Huiyu Wang, Zunjing Zhang, Feng Liu, Miaoying Zhou, Handi Lv Pteridines.2019; 30(1): 171. CrossRef
A Review of Regimens Combining Pemetrexed With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in the Treatment of Advanced Nonsquamous Non–Small-Cell Lung Cancer James Chih-Hsin Yang, Tony Mok, Baohui Han, Mauro Orlando, Tarun Puri, Keunchil Park Clinical Lung Cancer.2018; 19(1): 27. CrossRef
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Purpose A recent phase III study (PARAMOUNT) demonstrated that pemetrexed continuation maintenance therapy is a new treatment paradigm for advanced nonsquamous non-small cell lung cancer (NSCLC). The majority of patients enrolled in PARAMOUNT were Caucasian (94%). We reviewed efficacy and safety data from two clinical trials, which enrolled East Asian (EA) patients, to supplement data from PARAMOUNT on pemetrexed continuation maintenance therapy in patients with nonsquamous NSCLC. Materials and Methods Study S110 was a phase II, multicenter, randomized, controlled, open-label trial in never-smoker, chemonaïve, EA patients (n=31) with locally advanced or metastatic nonsquamous NSCLC (n=27). Study JMII was a multicenter, open-label, single-arm, postmarketing, clinical trial in Japanese patients (n=109) with advanced nonsquamous NSCLC. PARAMOUNT was a multicenter, randomized, double-blind, placebo-controlled trial in patients with advanced nonsquamous NSCLC. Results In EA patients with nonsquamous NSCLC, the median progression-free survival (PFS) for pemetrexed continuation maintenance therapy was 4.04 months (95% confidence interval [CI], 3.22 to 5.29 months) in study S110 and 3.9 months (95% CI, 3.2 to 5.2 months) in study JMII. The median PFS for pemetrexed continuation maintenance therapy in PARAMOUNT was 4.1 months (95% CI, 3.2 to 4.6 months). Pemetrexed continuation maintenance therapy in EA patients in studies S110 and JMII did not lead to any unexpected safety events, and was consistent with PARAMOUNT’s safety profile. Conclusion The efficacy and safety data in the EA trials were similar to those in PARAMOUNT despite differences in patient populations and study designs. These data represent consistent evidence for pemetrexed continuation maintenance therapy in EA patients with advanced nonsquamous NSCLC.
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Effect of pemetrexed on brain metastases from nonsmall cell lung cancer with wild-type and unknown EGFR status Xiaoqing Yu, Yun Fan Medicine.2019; 98(3): e14110. CrossRef
Best Practices in Treatment Selection for Patients with Advanced NSCLC Mark A. Socinski, Nathan A. Pennell Cancer Control.2016; 23(4_suppl): 2. CrossRef
Pemetrexed is approved as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) with cisplatin and as a single agent for second-line treatment or for patients who show no disease progression after four cycles of platinum-based doublet induction chemotherapy as maintenance therapy. Pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis. Here, we report on a rare case of pemetrexed-induced pneumonitis in a patient with NSCLC.
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