Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-Line Platinum-Based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05)

Inkeun Park; Shinkyo Yoon; Ilhwan Kim; Kwonoh Park; Suee Lee; Bhumsuk Keam; Joo-Hwan Park; Jin Young Kim; Yoon Ji Choi; Byeong Seok Sohn; Jae Lyun Lee

doi:10.4143/crt.2024.1003

Articles

Page Path: HOME > Cancer Res Treat > Volume 57(4); 2025 > Article

Original Article Genitourinary cancer Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-Line Platinum-Based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05): Inkeun Park¹, Shinkyo Yoon¹, Ilhwan Kim², Kwonoh Park^3,4, Suee Lee⁵, Bhumsuk Keam⁶, Joo-Hwan Park⁷, Jin Young Kim⁸, Yoon Ji Choi⁹, Byeong Seok Sohn¹⁰, Jae Lyun Lee¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2025;57(4):1167-1177.
DOI: https://doi.org/10.4143/crt.2024.1003
Published online: December 27, 2024

¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Division of Oncology, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea

³Division of Hematology-Oncology, Department of Internal Medicine, Hanyang University Seoul Hospital, Hanyang University College of Medicine, Seoul, Korea

⁴Division of Medical Oncology and Hematology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea

⁵Division of Hematology-Oncology, Department of Internal Medicine, Dong-A University Hospital, Busan, Korea

⁶Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

⁷Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea

⁸Division of Hematology-Oncology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea

⁹Division of Hematology-Oncology, Department of Medicine, Korea University Anam Hospital, Seoul, Korea

¹⁰Department of Internal Medicine, Inje University Sanggye Paik Hospital, Seoul, Korea

Correspondence: Jae Lyun Lee, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
Tel: 82-2-3010-5977 E-mail: jaelyun@amc.seoul.kr

^*The preliminary results were presented during a poster session at Genitourinary Cancers Symposium 2024, January 25-27, 2024, San Francisco, CA, USA.

• Received: October 16, 2024 • Accepted: December 26, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2,593 Views
126 Download

prev next

Full Article

Download PDF

Abstract

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 intravenously 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 to 90) and 66 (range, 33 to 82), respectively, with 63% and 73% of patients being male, respectively. The median PFS was 6.0 months (95% confidence interval [CI], 3.4 to 8.5) with pemetrexed versus 2.3 months (95% CI, 1.8 to 2.7) with observation (p=0.044; hazard ratio [HR], 0.64; 95% CI, 0.41 to 0.99). The median OS was 18.1 months (95% CI, 6.9 to 29.4) for pemetrexed and 17.9 months (95% CI, 16.1 to 19.7) for observation (p=0.913; HR, 1.03; 95% CI, 0.61 to 1.73). Common adverse events in the pemetrexed group included anemia (30.6%), fatigue (18.4%), and neutropenia (12.2%), 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.
Key words: Urothelial carcinoma, Platinum, Pemetrexed, Maintenance

Introduction

Since the introduction of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), which demonstrated superior therapeutic efficacy compared to cisplatin monotherapy [1], platinum-based combination chemotherapy has long been the standard first-line treatment for advanced urothelial carcinoma (aUC). Although MVAC and gemcitabine plus cisplatin (GP) are commonly used standard treatments [2], the optimal number of cycles for these regimens has not been established. These treatments are associated with hematologic and nonhematologic toxicities, often leading to dose delays and dose reductions. Furthermore, some adverse events of cisplatin are cumulative and long-lasting [3]. Patients with urothelial cancer are often elderly and susceptible to complications such as infections (especially urosepsis) and nephrotoxicity. Therefore, if disease progression does not occur after 4-6 cycles of first-line chemotherapy, clinicians typically cease treatment and monitor patients until the initiation of second-line therapy becomes necessary due to disease progression.

At the time this study was designed, no standard salvage treatment had demonstrated a statistically significant survival benefit. The relative rarity of metastatic urothelial cancer and the fragility of the patient population have hindered the conduct of large-scale phase III clinical trials for salvage chemotherapy, resulting in a limited number of agents being evaluated in prospective clinical trials. For second-line treatment, taxanes and vinflunine were recommended by clinical guidelines [4]. However, in real-world practice, patients with urothelial cancer often experience rapid clinical deterioration after or during first-line treatment, which often prevents them from receiving second-line therapy [5].

Given the potential for rapid deterioration during treatment breaks, maintenance therapy using a relatively effective and well-tolerated salvage regimen for patients without disease progression after standard first-line treatment is an attractive approach. In non-small cell lung cancer, several clinical trials have demonstrated maintenance therapy after first-line platinum-based chemotherapy can lead to improved progression-free survival (PFS) and overall survival (OS) [6,7].

Although taxanes and vinflunine have been most frequently recommended in the salvage setting for aUC, their efficacy as single agents has been modest [8-11]. Additionally, both taxanes and vinflunine are associated with cumulative neurotoxicity, limited their suitability for maintenance therapy. Pemetrexed, however, has shown moderate efficacy with a tolerable toxicity profile and cumulative toxicity when tested in urothelial cancer [12,13]. Pemetrexed has also demonstrated promising activity as a first-line chemotherapy agent combination with cisplatin for aUC [14]. Given its efficacy and safety profile in urothelial carcinoma, pemetrexed appears to be a promising candidate for maintenance therapy. Based on this background, we designed this trial to evaluate the role of pemetrexed as maintenance therapy in patients with aUC who have completed first-line platinum-based chemotherapy without disease progression.

Materials and Methods

1. Study design

PREMIER was a multicenter, open-label, prospective, randomized phase III trial designed to evaluate the efficacy of pemetrexed as switch maintenance therapy compared with surveillance in patients with unresectable locally advanced, recurrent, or metastatic urothelial cancer who had not experienced disease progression after 4 to 6 cycles of first-line chemotherapy. The primary endpoint of the trial was PFS as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 criteria, while secondary endpoints included response rate, safety and tolerability of maintenance pemetrexed, and OS of each group.

2. Patients

Eligible patients were those aged 20 years or older with histologically or cytologically confirmed urothelial carcinoma (UC) of bladder, ureter, renal pelvis, or urethra. They had to have locally advanced, recurrent, or metastatic disease considered unsuitable for curative-intent local treatment. Patients were required to have completed 4-6 cycles of cisplatin-based or carboplatin-based first-line chemotherapy (GP, gemcitabine plus carboplatin [GC], classical MVAC) or dose-dense MVAC with no evidence of disease progression on a computed tomography (CT) scan performed within 3 weeks following the last chemotherapy cycle. Additional inclusion criteria were measurable disease per RECIST v1.1 (when first-line chemotherapy was administered), an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, and adequate bone marrow (absolute neutrophil count ≥ 1,500/mm³, hemoglobin ≥ 9 g/dL, and platelet ≥ 100,000/mm³), hepatic (bilirubin < 1.5 mg/dL, transaminases < 1.5×upper limit of normal, alkaline phosphatase < 2.5×upper limit of normal) and renal function (serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 45 mL/min).

Patients were excluded if they had received prior systemic chemotherapy for palliative purposes before or after first-line cisplatin-based or carboplatin-based chemotherapy. However, prior intravesical chemotherapy or immunotherapy was permitted. For patients with recurrent disease who had received prior adjuvant or neoadjuvant chemotherapy, the last administration had to be at least 6 months before the start of first-line chemotherapy. Other exclusion criteria included disease progression during or after first-line platinum-based chemotherapy, prior exposure to pemetrexed as systemic anticancer therapy, known central nervous system metastasis, a diagnosis of any serous secondary malignancy within the past 2 years (except for adequately treated basal cell or squamous cell carcinoma of the skin), early gastric carcinoma, early-stage thyroid carcinoma, insignificant prostate carcinoma, or in situ carcinoma of the cervix uteri), serious hypersensitivity reaction to pemetrexed its excipients (mannitol, hydrochloric acid, or sodium hydroxide), other serious medical or psychiatric conditions, and being pregnant or breastfeeding.

3. Treatment plan

Patients were enrolled and treated by the investigators at participating study center on an outpatient basis. After completing 4-6 cycles of first-line chemotherapy, patients who did not exhibit disease progression on CT scans conducted within 3 weeks of the last chemotherapy administration were randomized within 6 weeks to the maintenance pemetrexed group or the observation group. Treatment commenced within 2 weeks after randomization. Patients were randomly allocated in a 1:1 ratio to either the pemetrexed group or the observation group, and randomization was stratified based on total score (0-60 point vs. 61-120 point vs. 121 or more) derived from the post-treatment prognostic nomogram for patients with metastatic UC completing first-line cisplatin-based chemotherapy, as suggested by Galsky et al. [15], comprising baseline PS, baseline number of visceral metastatic sites, baseline white blood cell counts, and response to treatment. Randomization was performed centrally through an interactive web-based randomization system managed by the data center, and random table was generated by an independent statistical group. Group allocations were disclosed to the data center staff member only after all the participant details had been entered into the system and then the patient randomization number and assignment to treatment groups were provided by this system. Patients, investigators, and their teams, and those analyzing data were not masked to study treatment.

Patients in the pemetrexed maintenance group received pemetrexed 500 mg/m² mixed in 100 mL normal saline as a 10-minute intravenous infusion on day 1 of each 21-day cycle, along with vitamin supplementation (folic acid 1,000 μg daily orally beginning 7 days before treatment initiation and vitamin B12 1,000 μg administered intramuscularly 7 days before treatment initiation, then every 3 cycles). Subsequently, vitamin B12 could be administered on the same day of pemetrexed infusion. Dexamethasone 4 mg was given orally twice daily for 3 days starting the day before treatment to minimize cutaneous reactions. Treatment continued until disease progression or intolerable toxicity, up to maximum of 16 cycles.

In the pemetrexed group, subsequent cycles were not initiated unless treatment-emergent toxicity had recovered to grade 1 or less (except anemia and alopecia). Dose adjustments or delays were permitted according to the protocol guidelines. Depending on the severity and recurrence of toxicity, the pemetrexed dose could be reduced from 500 to 400 mg/m² or from 400 to 300 mg/m². Patients requiring a third dose reduction or a treatment delay of more than 3 weeks were withdrawn from the study.

Patients allocated to the surveillance group received best supportive care according to institutional practice guidelines and underwent regular clinic visits with CT assessments as per the assessment protocol.

4. Assessment of response and toxicity

Baseline evaluations included a complete medical history, physical examination, ECOG PS assessment, laboratory measurements including a complete blood count (CBC), serum chemistry and electrolytes, chest X-ray, and electrocardiography. For women of childbearing potential, a urine beta human chorionic gonadotropin test was required. Tumor assessments using chest and abdominopelvic CT were performed during screening and subsequently every 9 weeks by the investigator according to RECIST ver. 1.1. If patients did not experience disease progression after the third disease evaluation, subsequent tumor assessments were performed every 12 weeks. Safety assessments included regular monitoring of vital signs, physical examinations, ECOG PS, CBC, serum chemistry and electrolytes, adverse events, and documentation of all concomitant medications and therapies, performed on D1 of each cycle. Toxicity was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03.

5. Statistical analysis

This study was designed to demonstrate the superiority of pemetrexed maintenance therapy over observation in terms of PFS. The sample size was determined to detect an improvement in PFS from 1.5 months with observation [8] to 2.6 months with pemetrexed [13], with a two-sided α=0.05, β=0.2 (power=80%), and assumption of 10% loss to follow-up, requiring a total of 156 patients (78 per group).

All randomized patients were included in the efficacy and safety analyses (intention-to-treat analysis). Baseline characteristics and safety profiles were summarized descriptively. Kaplan-Meier estimates and the log-rank test were utilized for analyzing the time-to-event endpoints, while hazard ratios (HRs) were estimated using the Cox proportional hazards model. PFS was defined as the time from randomization to the first occurrence of either disease progression or death from any cause. OS was defined as the time from randomization to death from any cause. The duration of follow-up was assessed using the reverse Kaplan-Meier method. All analyses were conducted with SPSS Statistics for Windows ver. 20.0 (IBM Corp.) and Kaplan-Meier plots were made by using GraphPad Prism 10. The R package Publish (R Foundation for Statistical Computing) was used to run the post-hoc PFS and OS subgroup analysis.

Results

1. Patient characteristics

This trial was terminated early due to poor patient accrual after the approval of avelumab as maintenance therapy. From October 2016 to December 2022, a total of 97 patients were randomized to either pemetrexed maintenance group (n=49) or the observation group (n=48) (Fig. 1).

Table 1 demonstrates baseline characteristics. The median age was 69 years (range, 43 to 90 years) in the pemetrexed group and 66 years (range, 33 to 82 years) in the observation group, with a predominance of males (63.3% and 72.9%, respectively). The first-line treatment regimen included GP in 83.7% and 83.3% of patients, GC in 12.2% and 6.2% of patients, and MVAC in 4.1% and 10.4% of patients in the pemetrexed and observation groups, respectively. Most patients received 6 cycles of first-line treatment. The response rates to first-line therapy were complete response (CR) in 8.2% of patients in the pemetrexed group and 18.8% in the observation group, partial response (PR) in 69.4% and 66.7%, and stable disease (SD) in 22.4% and 14.6%, respectively. The most common sites of metastasis were abdominopelvic lymph nodes (61.2% in the pemetrexed group and 64.6% in the observation group) and the lung (36.7% and 29.2%, respectively). The Galsky score, which was used as a stratification factor, was well balanced between the two arms. In the overall study population, 31 patients (63.3%) in pemetrexed group and by 29 patients (60.4%) in the observation group received subsequent anticancer therapy, including immunotherapy, platinum-based chemotherapy, and taxane (Table 2).

2. Efficacy

In the pemetrexed group, the median number of administered cycles was 6 (range, 1 to 16). The most common reason for discontinuation was disease progression (53.1%), followed by completion of the planned cycles (22.4%). After a median follow-up of 36.4 months, the median PFS was 6.0 months (95% confidence interval [CI], 3.4 to 8.5) in the pemetrexed group compared with 2.3 months (95% CI, 1.8 to 2.7) in the observation group (log-rank p=0.044), with a HR of 0.64 (95% CI, 0.41 to 0.99) (Fig. 2A). The median OS was 18.1 months (95% CI, 6.8 to 29.4) in the pemetrexed group versus 17.9 months (95% CI, 16.1 to 19.7) in the observation group (p=0.913; HR, 1.03; 95% CI, 0.61 to 1.73) (Fig. 2B). In the post-hoc exploratory subgroup analysis, there was a tendency toward better PFS with pemetrexed across all subgroups, while no difference in OS was observed in any subgroup (Fig. 3). The best response to maintenance pemetrexed included CR in five patients (10.2%), PR in six (12.2%), SD in 23 (46.9%), progressive disease in 14 patients (28.6%), and data not available for one patient (2.0%).

3. Safety

Adverse events in patients allocated to the pemetrexed group are presented in Table 3. The most frequent adverse events were anemia (30.6%), fatigue (18.4%), and neutropenia (12.2%). Notably, there were no reported cases of febrile neutropenia. With prophylactic dexamethasone use, skin rash occurred infrequently (4 patients, 8.2%). Overall, the adverse events were primarily grade 1 or 2 and were manageable with routine supportive care. One patient experienced grade 4 acute kidney injury, which was caused by urinary tract obstruction due to disease progression and resolved after a percutaneous nephrostomy.

Discussion

This phase III trial aimed to investigate the efficacy of maintenance pemetrexed in patients with aUC whose disease had not progressed after first-line platinum-based chemotherapy. The trial was prematurely terminated due to slow patient accrual after the approval of avelumab as a maintenance therapy. In this study, patients in the maintenance pemetrexed group achieved a median PFS of 6.0 months (95% CI, 3.4 to 8.5) and a median OS of 18.1 months (95% CI, 6.8 to 29.4). These results compare favorably with the observation group, which showed a median PFS of 2.3 months (95% CI, 1.8 to 2.7 months) and a median OS of 17.9 months (95% CI, 16.1 to 19.7) (PFS: p=0.044; HR, 0.64; OS: p=0.913; HR, 1.03). This study met its primary endpoint, demonstrating that maintenance pemetrexed significantly delayed disease progression. Additionally, pemetrexed maintenance was associated with a favorable toxicity profile, with manageable adverse events.

The trial was designed in 2015, with patient enrollment beginning in September 2016. At that time, there was no universally accepted second-line treatment option for aUC, and immunotherapy was just beginning to emerge as a potential treatment modality. Therefore, this study focused on evaluating cytotoxic chemotherapy as a maintenance therapy. The ideal agent for maintenance therapy should possess palliative efficacy and a manageable safety profile without cumulative toxicity. Although gemcitabine is widely used as a first-line chemotherapy agent for UC, gemcitabine monotherapy as a second-line treatment has demonstrated only modest activity and a substantial incidence of grade 3 or higher toxicity, particularly hematologic toxicity [16,17]. A retrospective study on gemcitabine maintenance therapy in UC reported considerable grade 3 or higher toxicity (17% grade 3 neutropenia and 3% grade 3 febrile neutropenia) [18]. Given these safety concerns and the weekly administration schedule of gemcitabine, we opted to design a switch maintenance strategy rather than using gemcitabine.

Prior to this study, no phase III clinical trial has demonstrated a survival advantage for any salvage chemotherapy regimen compared to another or to best supportive care as second-line treatment following first-line platinum-based chemotherapy. Various drugs have been tested in phase II trials, but their efficacy was generally modest, with an overall response rate (ORR) ranging from 5% to 28% [9-13,19,20]. Vinflunine was the only agent tested in a randomized phase III trial [8], but failed to demonstrate a statistically significant benefit in an intention-to-treat analysis. Pemetrexed showed an ORR of 28% in one trial [13], along with a favorable toxicity profile without cumulative neurotoxicity, making it a suitable candidate for maintenance therapy.

The treatment landscape of aUC has evolved rapidly. Avelumab became the standard maintenance therapy after the JAVELIN Bladder 100 trial, which demonstrated significant PFS and OS benefits with avelumab maintenance plus best supportive care compared with best supportive care alone (PFS, 5.5 months vs. 2.1 months; HR, 0.54 [95% CI, 0.46 to 0.64]; p < 0.001; median OS, 23.8 months vs. 15.0 months; HR, 0.76 [95% CI, 0.63 to 0.91]; p=0.0036) [21,22]. In our trial, pemetrexed showed a promising effect in delaying disease progression (median PFS, 6.0 months in the pemetrexed group vs. 2.3 months in the observation group) comparable to avelumab (median PFS, 5.5 months in the avelumab group vs. 2.1 months in the best supportive care group). However, there was no significant difference in OS. The discrepancy between PFS and OS might be attributable to subsequent treatments after progression and baseline patient characteristics. The pemetrexed group had somewhat unfavorable baseline characteristics, including a higher median age (69 vs. 66 years), fewer patients with locally advanced cancer (2% vs. 12.5%), and fewer patients achieving CR after first-line treatment (8% vs. 19%).

Other trials have also explored switch maintenance therapy in aUC. The SOGUS 2011/02 MAJA trial investigated maintenance vinflunine compared with best supportive care. Vinflunine maintenance resulted in better PFS (median PFS, 6.5 months vs. 4.2 months; p=0.031), but there was no significant difference in OS (median OS, 16.7 months vs. 13.2 months; p=0.182) [23,24]. The most common grade 3 or 4 adverse events in the vinflunine group were neutropenia (18%), fatigue (16%), and constipation (14%). The adverse event profile was better than second-line vinflunine, likely due to the inclusion of patients with ECOG PS 0-1 and a starting dose adjusted based on depending on patients characteristics. Although both the MAJA trial and our study are underpowered, the results suggest that maintenance therapy may have a role in delaying progression. Considering the adverse events, pemetrexed appears to be a more favorable choice for maintenance therapy.

This study has several limitations. First, the premature termination of the trial resulted in a smaller sample size than initially planned, rendering the study statistically underpowered. Second, we did not collect quality-of-life data, which would have provided additional insights into the patient experience during treatment. Third, the standard treatment paradigm for aUC changed during the enrollment period, limiting the applicability of our findings to current clinical practice. Although the PFS benefit of pemetrexed maintenance is noteworthy, these results may not be directly translatable to the real-world setting given the shift in first-line treatment strategies.

Looking forward, the role of maintenance therapy in aUC may be redefined within novel treatment frameworks. In 2023, the standard first-line therapy for aUC changed for the first time in 30 years. The EV302 trial demonstrated that pembrolizumab combined with enfortumab vedotin (EV) achieved impressive response rates, PFS, and OS (68%, 12.5 months, and 31.5 months, respectively) [25]. Consequently, previous strategies, such as platinum induction followed by avelumab maintenance, are no longer standard. Future research should focus on optimizing first-line treatment regimens to enhance efficacy and reduce toxicity. Given the PFS benefit observed with pemetrexed, combining maintenance pemetrexed with pembrolizumab could be explored after induction therapy with EV and pembrolizumab. This approach may mitigate some of the cumulative toxicities associated with EV, such as skin toxicity, neuropathy, and fatigue [26], which led to treatment discontinuation in 22% of patients in the EV302 trial (any grade: 97%; grade ≥ 3: 56%) [25]. There are also intriguing preclinical data suggesting that pemetrexed may enhance the efficacy of immunotherapy [27,28]. On the other hand, pemetrexed maintenance can also be considered in a later line. Although there is a lack of consensus on the subsequent treatment after EV plus pembrolizumab, European Society of Medical Oncology guidelines recommend platinum-based chemotherapy as a second-line therapy [29]. If platinum-based chemotherapy is used, pemetrexed maintenance can be followed in patients without disease progression. Currently, we do not know which patients may benefit from pemetrexed maintenance, so its use should be approached with caution and validation in this setting is needed.

The PREMIER trial demonstrated that switch maintenance therapy with pemetrexed significantly prolonged PFS in patients with aUC who had not progressed after first-line platinum-based chemotherapy, with a favorable safety profile. Further investigation into combination maintenance therapies involving pemetrexed is warranted.

NOTES

Ethical Statement

This study was reviewed and approved by the Institutional Review Board and Ethics Committee of Asan Medical Center (approval number 2016-0401) and the local committees of all other participating centers and was registered on ClinicalTrials.gov (NCT03193788). It was carried out in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines. Obtaining written informed consent was a mandatory requirement.

Author Contributions

Conceived and designed the analysis: Park I, Lee JL.

Collected the data: Park I, Yoon S, Kim I, Park K, Lee S, Keam B, Park JH, Kim JY, Choi YJ, Sohn BS, Lee JL.

Contributed data or analysis tools: Park I, Yoon S, Lee JL.

Performed the analysis: Park I, Lee JL.

Wrote the paper: Park I, Lee JL.

Critically reviewing or revising the manuscript for important intellectual content: Park I, Yoon S, Kim I, Park K, Lee S, Keam B, Park JH, Kim JY, Choi YJ, Sohn BS, Lee JL.

Conflicts of Interest

Inkeun Park: Consulting or advisory role: Chong Kun Dang Pharmaceutical Co., Boryung Pharmaceuticals Co., Janssen Korea, and Astellas Pharma Korea

Research funding: Chong Kun Dang Pharmaceutical Co. and Boryung Pharmaceuticals Co.,

Jae Lyun Lee: Stock and other ownership interests: Johnson & Johnson/Janssen, Amgen, Merck, Innovent Biologics, Black Diamond Therapeutics, Karyopharm Therapeutics, and Zymeworks

Honoraria: Bristol-Myers Squibb, AstraZeneca, MSD Korea

Consulting or advisory role: Merck, AstraZeneca, Astellas Korea, Novartis, Amgen, Daiichi Sankyo/AstraZeneca

Research funding; Pfizer, Janssen, Novartis, Bristol-Myers Squibb, Roche/Genentech, AstraZeneca/MedImmune, MSD, Bayer Schering Pharma, Seagen, GI Innovation, Amgen, Oscotec, Arcus Biosciences, Eutilex, LG Chem, Merk KGaA, Loxo/Lilly.

The authors thank Samyang Biopharmaceuticals Corporation for the generous donation of pemetrexed.

Funding

This research was supported by the Korean Cancer Study Group (KCSG).

Fig. 1.

Patient flowchart.

Fig. 2.

Kaplan-Meier curves for progression-free survival (PFS) (A) and overall survival (OS) (B).

Fig. 3.

Forest plot of progression-free survival (A) and overall survival (B) subgroup analysis. CI, confidence interval; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LLB, liver, lung, and bone; LTUC, lower tract urothelial carcinoma; OBS, observation; PEM, pemetrexed maintenance; PR, partial response; SD, stable disease; UTUC, upper tract urothelial carcinoma.

Table 1.

Baseline characteristics of patients (n=97)

	Pemetrexed (n=49)	Observation (n=48)
Age (yr)	69 (43-90)	66 (33-82)
Male sex	31 (63.3)	35 (72.9)
ECOG PS
0	6 (12.2)	7 (14.6)
1	42 (85.7)	39 (81.2)
2	1 (2.0)	2 (4.2)
Disease status
Recurrent	19 (38.8)	18 (37.5)
Locally advanced	1 (2.0)	6 (12.5)
Initially metastatic	29 (59.2)	24 (50.0)
First-line regimen
GP	41 (83.7)	40 (83.3)
Classic MVAC	2 (4.1)	1 (2.1)
Dose-dense MVAC	0	4 (8.3)
GC	6 (12.2)	3 (6.2)
No. of first-line treatments	6 (4-7)	6 (3-6)
Response to first-line therapy
CR	4 (8.2)	9 (18.8)
PR	34 (69.4)	32 (66.7)
SD	11 (22.4)	7 (14.6)
Location of disease
Bladder	20 (40.8)	25 (52.1)
Ureter	13 (26.5)	12 (25.0)
Renal pelvis	12 (24.5)	8 (16.7)
Urethra	1 (2.0)	2 (4.2)
Multifocal	3 (6.1)	0
Metastatic site
Abdomen–pelvis LN	30 (61.2)	31 (64.6)
Lung	18 (36.7)	14 (29.2)
Thoracic LN	10 (20.4)	10 (20.8)
Bone	6 (12.2)	11 (22.9)
Liver	5 (10.2)	5 (10.4)
Galsky score	52 (4-142.5)	48 (0-110)
0-60	30 (61.2)	32 (66.7)
61-120	18 (36.7)	16 (33.3)
121 or higher	1 (2.0)	0

Values are presented as median (range) or number (%). CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; GC, gemcitabine and carboplatin; GP, gemcitabine and cisplatin; LN, lymph node; MVAC, methotrexate, vinblastine, adriamycin, and cisplatin; PR, partial response; SD, stable disease.

Table 2.

Subsequent anticancer treatment in study population (n=97)

	Pemetrexed (n=49)	Observation (n=48)
Any subsequent treatment^a)	31 (63.3)	29 (60.4)
Subsequent treatment unknown^b)	5 (10.2)	5 (10.4)
Immunotherapy	25 (51.0)	25 (52.1)
Platinum-based chemotherapy	17 (34.7)	14 (29.2)
Taxane	10 (20.4)	9 (18.8)
Pemetrexed	1 (2.0)	6 (12.5)
Enfortumab vedotin	2 (4.1)	1 (2.1)
Sacituzumab govitecan	2 (4.1)	1 (2.1)

Values are presented as number (%).

^a) Some patients received > 1 category of subsequent therapy,

^b) Subsequent treatment data could not be collected in patients who were lost to follow-up or withdrawn from the study.

Table 3.

Adverse event in patients who were allocated into pemetrexed group (n=49)

	All grades	Grade 3	Grade 4
Hematological adverse events
Anemia	15 (30.6)	3 (6.1)	0
Neutropenia	6 (12.2)	2 (4.1)	0
Thrombocytopenia	1 (2.0)	0	0
Febrile neutropenia	0
Non-hematological adverse events
Fatigue	9 (18.4)	1 (2.0)	0
Anorexia	5 (10.2)	0	0
Neuropathy	6 (12.2)	0	0
Creatinine increased	5 (10.2)	0	1 (2.0)
Nausea	4 (8.2)	1 (2.0)	0
Edema	4 (8.2)	0	0
Rash	4 (8.2)	0	0
Vomiting	2 (4.1)	1 (2.0)	0
Constipation	2 (4.1)	0	0
ALT increased	2 (4.1)	0	0
AST increased	1 (2.0)	0	0
Alopecia	1 (2.0)	0	0
Bleeding	3 (6.1)	1 (2.0)	0
Mucositis, oral	1 (2.0)	0	0
Infection	2 (4.1)	1 (2.0)	0

Values are presented as number (%). ALT, alanine aminotransferase; AST, aspartate aminotransferase.

REFERENCES

1. Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992;10:1066–73. Article PubMed
2. von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18:3068–77. Article PubMed
3. Chovanec M, Abu Zaid M, Hanna N, El-Kouri N, Einhorn LH, Albany C. Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann Oncol. 2017;28:2670–9. Article PubMed PMC
4. Milowsky MI, Rumble RB, Booth CM, Gilligan T, Eapen LJ, Hauke RJ, et al. Guideline on muscle-invasive and metastatic bladder cancer (European Association of Urology Guideline): American Society of Clinical Oncology clinical practice gui-deline endorsement. J Clin Oncol. 2016;34:1945–52. Article PubMed
5. Mathew Thomas V, Jo Y, Tripathi N, Roy S, Chigarira B, Narang A, et al. Treatment patterns and attrition with lines of therapy for advanced urothelial carcinoma in the US. JAMA Netw Open. 2024;7:e249417Article PubMed PMC
6. 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. Article PubMed
7. Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, 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. Article PubMed
8. Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27:4454–61. Article PubMed
9. Joly F, Houede N, Noal S, Chevreau C, Priou F, Chinet-Charrot P, et al. Do patients with advanced urothelial carcinoma benefit from weekly paclitaxel chemotherapy? A GETUG phase II study. Clin Genitourin Cancer. 2009;7:E28–33. Article PubMed
10. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15:1853–7. Article PubMed
11. Papamichael D, Gallagher CJ, Oliver RT, Johnson PW, Waxman J. Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter. Br J Cancer. 1997;75:606–7. Article PubMed PMC PDF
12. Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007;25:265–70. Article PubMed PDF
13. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006;24:3451–7. Article PubMed
14. Choi YJ, Lee SH, Lee JL, Ahn JH, Lee KH, You D, et al. Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17). Br J Cancer. 2015;112:260–5. Article PubMed PMC PDF
15. Galsky MD, Moshier E, Krege S, Lin CC, Hahn N, Ecke T, et al. Posttreatment prognostic nomogram for patients with metastatic urothelial cancer completing first-line cisplatin-based chemotherapy. Urol Oncol. 2014;32:48.Article
16. Akaza H, Naito S, Usami M, Miki T, Miyanaga N, Taniai H, et al. Efficacy and safety of gemcitabine monotherapy in patients with transitional cell carcinoma after Cisplatin-containing therapy: a Japanese experience. Jpn J Clin Oncol. 2007;37:201–6. Article PubMed
17. Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, et al. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer. Eur J Cancer. 1998;34:1208–12. PubMed
18. Kim H, Lee SH, Kim DH, Lee JY, Hong SH, Ha US, et al. Gemcitabine maintenance versus observation after first-line chemotherapy in patients with metastatic urothelial carcinoma: a retrospective study. Transl Androl Urol. 2020;9:2113–21. Article PubMed PMC
19. Beer TM, Goldman B, Nichols CR, Petrylak DP, Agarwal M, Ryan CW, et al. Southwest Oncology Group phase II study of irinotecan in patients with advanced transitional cell carcinoma of the urothelium that progressed after platinum-based chemotherapy. Clin Genitourin Cancer. 2008;6:36–9. Article PubMed
20. Witte RS, Elson P, Bono B, Knop R, Richardson RR, Dreicer R, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997;15:589–93. Article PubMed
21. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383:1218–30. PubMed
22. Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullen A, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN bladder 100 trial after ≥ 2 years of follow-up. J Clin Oncol. 2023;41:3486–92. Article PubMed PMC
23. Garcia-Donas J, Font A, Perez-Valderrama B, Virizuela JA, Climent MA, Hernando-Polo S, et al. Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial. Lancet Oncol. 2017;18:672–81. Article PubMed
24. Bellmunt Molins J, Garcia-Donas Jimenez J, Valderrama BP, Virizuela Echaburu JA, Hernando-Polo S, Climent Duran MA, et al. Final overall survival analysis of the SOGUG phase 2 MAJA study: maintenance vinflunine versus best supportive care after first-line chemotherapy in advanced urothelial carcinoma. Clin Genitourin Cancer. 2020;18:452–60. Article PubMed
25. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390:875–88. PubMed
26. Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Duran I, Lee JL, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125–35. Article PubMed PMC
27. Chen MC, Hung MY, Pan CM, Huang SW, Jan CI, Li YH, et al. Pemetrexed combined with dual immune checkpoint blockade enhances cytotoxic T lymphocytes against lung cancer. Cancer Sci. 2023;114:2761–73. Article PubMed PMC
28. Lu CS, Lin CW, Chang YH, Chen HY, Chung WC, Lai WY, et al. Antimetabolite pemetrexed primes a favorable tumor microenvironment for immune checkpoint blockade therapy. J Immunother Cancer. 2020;8:e001392Article PubMed PMC
29. Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35:485–90. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-Line Platinum-Based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05)

Cancer Res Treat. 2025;57(4):1167-1177. Published online December 27, 2024

DOI: https://doi.org/10.4143/crt.2024.1003

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-Line Platinum-Based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05)

Fig. 1. Patient flowchart.

Fig. 2. Kaplan-Meier curves for progression-free survival (PFS) (A) and overall survival (OS) (B).

Fig. 3. Forest plot of progression-free survival (A) and overall survival (B) subgroup analysis. CI, confidence interval; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LLB, liver, lung, and bone; LTUC, lower tract urothelial carcinoma; OBS, observation; PEM, pemetrexed maintenance; PR, partial response; SD, stable disease; UTUC, upper tract urothelial carcinoma.

Fig. 1.

Fig. 2.

Fig. 3.

Pemetrexed Maintenance versus Observation in Patients with Advanced Urothelial Carcinoma Who Completed First-Line Platinum-Based Chemotherapy without Disease Progression (PREMIER, KCSG GU16-05)

	Pemetrexed (n=49)	Observation (n=48)
Age (yr)	69 (43-90)	66 (33-82)
Male sex	31 (63.3)	35 (72.9)
ECOG PS
0	6 (12.2)	7 (14.6)
1	42 (85.7)	39 (81.2)
2	1 (2.0)	2 (4.2)
Disease status
Recurrent	19 (38.8)	18 (37.5)
Locally advanced	1 (2.0)	6 (12.5)
Initially metastatic	29 (59.2)	24 (50.0)
First-line regimen
GP	41 (83.7)	40 (83.3)
Classic MVAC	2 (4.1)	1 (2.1)
Dose-dense MVAC	0	4 (8.3)
GC	6 (12.2)	3 (6.2)
No. of first-line treatments	6 (4-7)	6 (3-6)
Response to first-line therapy
CR	4 (8.2)	9 (18.8)
PR	34 (69.4)	32 (66.7)
SD	11 (22.4)	7 (14.6)
Location of disease
Bladder	20 (40.8)	25 (52.1)
Ureter	13 (26.5)	12 (25.0)
Renal pelvis	12 (24.5)	8 (16.7)
Urethra	1 (2.0)	2 (4.2)
Multifocal	3 (6.1)	0
Metastatic site
Abdomen–pelvis LN	30 (61.2)	31 (64.6)
Lung	18 (36.7)	14 (29.2)
Thoracic LN	10 (20.4)	10 (20.8)
Bone	6 (12.2)	11 (22.9)
Liver	5 (10.2)	5 (10.4)
Galsky score	52 (4-142.5)	48 (0-110)
0-60	30 (61.2)	32 (66.7)
61-120	18 (36.7)	16 (33.3)
121 or higher	1 (2.0)	0

	Pemetrexed (n=49)	Observation (n=48)
Any subsequent treatment^a)	31 (63.3)	29 (60.4)
Subsequent treatment unknown^b)	5 (10.2)	5 (10.4)
Immunotherapy	25 (51.0)	25 (52.1)
Platinum-based chemotherapy	17 (34.7)	14 (29.2)
Taxane	10 (20.4)	9 (18.8)
Pemetrexed	1 (2.0)	6 (12.5)
Enfortumab vedotin	2 (4.1)	1 (2.1)
Sacituzumab govitecan	2 (4.1)	1 (2.1)

	All grades	Grade 3	Grade 4
Hematological adverse events
Anemia	15 (30.6)	3 (6.1)	0
Neutropenia	6 (12.2)	2 (4.1)	0
Thrombocytopenia	1 (2.0)	0	0
Febrile neutropenia	0
Non-hematological adverse events
Fatigue	9 (18.4)	1 (2.0)	0
Anorexia	5 (10.2)	0	0
Neuropathy	6 (12.2)	0	0
Creatinine increased	5 (10.2)	0	1 (2.0)
Nausea	4 (8.2)	1 (2.0)	0
Edema	4 (8.2)	0	0
Rash	4 (8.2)	0	0
Vomiting	2 (4.1)	1 (2.0)	0
Constipation	2 (4.1)	0	0
ALT increased	2 (4.1)	0	0
AST increased	1 (2.0)	0	0
Alopecia	1 (2.0)	0	0
Bleeding	3 (6.1)	1 (2.0)	0
Mucositis, oral	1 (2.0)	0	0
Infection	2 (4.1)	1 (2.0)	0

Table 1. Baseline characteristics of patients (n=97)

Table 2. Subsequent anticancer treatment in study population (n=97)

Values are presented as number (%).

Some patients received > 1 category of subsequent therapy,

Subsequent treatment data could not be collected in patients who were lost to follow-up or withdrawn from the study.

Table 3. Adverse event in patients who were allocated into pemetrexed group (n=49)

Values are presented as number (%). ALT, alanine aminotransferase; AST, aspartate aminotransferase.