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$2014-0223 Title: S-1 as Monotherapy or in Combination With Leucovorin as Second-Line Treatment in Gemcitabine-Refractory Advanced Pancreatic Cancer: A Randomized, Open-Label, Multicenter, Phase II$

1 Overview First Published Online October 1, 2014 DOI: /theoncologist Title: S-1 as Monotherapy or in Combination With Leucovorin as Second-Line Treatment in Gemcitabine-Refractory Advanced Pancreatic Cancer: A Randomized, Open-Label, Multicenter, Phase II Study Authors: Feijiao Ge, a Nong Xu, b Yuxian Bai, c Yi Ba, d Yanqiao Zhang, c Fei Li, e Huayan Xu, a Ru Jia, a Yan Wang, a Li Lin, a Jianming Xu a a Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing, People s Republic of China; b The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, People s Republic of China; c The Third Affiliated Hospital of Harbin Medical University, Harbin, People s Republic of China; d Cancer Hospital of Tianjin Medical University, Tianjin, People s Republic of China; e Xuanwu Hospital of Capital Medical University, Beijing, People s Republic of China ClinicalTrials.gov Identifier: NCT Sponsor(s): Taiho Pharmaceutical Company Limited Principal Investigator: Jianming Xu IRB Approved: Yes Disclosures The authors indicated no financial relationships. Author Summary: Abstract and Brief Discussion Background In this study, we compared the efficacy and safety of the oral fluoropyrimidine S-1 as monotherapy or in combination with leucovorin as the second-line treatment for patients with metastatic pancreatic cancer whose disease had progressed on gemcitabine treatment. Methods The study was a randomized, open-label, controlled study. Patients randomly received S-1 or S-1 in combination with leucovorin (SL arm) in 21-day cycles. The primary endpoint was the 6-month survival rate. Results A total of 92 patients were randomized to S-1 (n 5 47) and SL (n 5 45). No statistically significant differences were observed between the two arms with regard to 6-month survival rates (40% vs. 49%), median overall survival (5.5 vs. 6.3 months), median progression-free survival (1.9 vs. 3.0 months), and overall response rate (4.7% vs. 8.3%).The rate of major grade 3 4 adverse events of digestive toxicity was significantly higher in the SL arm than in the S-1 arm. Conclusion Compared with S-1, SL did not improve the survival of patients with metastatic pancreatic cancer who had failed to benefit from prior gemcitabine treatment, but SL had a higher adverse event rate. Discussion There is no standard second-line treatment regimen after failure of first-line therapy for patients with locally advanced or metastatic pancreatic cancer (PC), mainly because of the poor condition of the patients.

2 S-1 has been approved to treat patients with metastatic PC in Japan and Taiwan. In the GEST study, median overall survival (OS) in the gemcitabine monotherapy group (8.8 months) was significantly longer than that in previously reported phase III studies, possibly because in Japan, a higher proportion of patients (50.5%) received S-1-based therapy in second-line treatment. For patients with gemcitabine-resistant advanced PC, several phase II studies have shown that S-1 in second-line treatment could achieve promising efficacy and good tolerability. In this study, we evaluated a combination of S-1 and leucovorin (SL) because preclinical studies have confirmed that leucovorin could enhance the efficacy of S-1. Its main mechanism is thought to be the formation of more covalent triple complexes (ternary complex; i.e., TS-FdUMP-CH2FH4) with the addition of leucovorin. In this study, SL did not further enhance the overall response rate or the clinical benefit rate and did not prolong median OS and progression-free survival (PFS) compared with S-1. These results are different from previously reported results in metastatic colorectal cancer. It is possible that by enhancing the incidence of grade 3 4 adverse events compared with S-1 (57.8% vs. 31.1%), SL resulted in higher rates of dose reductions (40.0% vs. 14.9%) an observation that is similar to previous reports. In this study, the overall response rate in the two arms was lower than in previous phase II studies of S-1 monotherapy as second-line treatment for advanced PC. Through analysis, we concluded that the lower response rate may be explained by the poor general condition of the patients (53.7% with Karnofsky performance status 70 80) and the higher proportions of withdrawal (10.9%) and treatment at reduced dose levels (30.5%) due to adverse events. Compared with the S-1 arm, patients in the SL arm had significantly higher digestive toxicity but no significant increase in grade 3 or 4 bone marrow toxicity; however, in the SL arm, after reducing the dose level of S-1, 83.3% (15 of 18) of patients could tolerate it. OS and PFS in the two arms were similar to the results of previously reported studies that enrolled some locally advanced PC, whereas in this study, most patients had metastatic PC and poor prognosis. Patients with metastasis in two or more organs accounted for 71.4% of the S-1 arm and 65% of the SL arm, showing that S-1 or SL after dose adjustment had some effect for patients with metastatic PC. Trial Information Disease Pancreatic cancer Disease Advanced cancer/solid tumor only Stage of disease / treatment Metastatic / Advanced Prior Therapy 1 prior regimen Type of study - 1 Phase II Type of study - 2 Randomized Overall Response Rate p =.503, HR: PFS p =.860, HR: Primary Endpoint Correlative endpoint Secondary Endpoint Overall survival Secondary Endpoint Progression-free survival Secondary Endpoint Overall response rate Secondary Endpoint Correlative endpoint Additional Details of Endpoints or Study Design The primary endpoint was the 6-month survival rate. Survival time was calculated from the date of randomization to the date of death from any cause. The secondary endpoints were OS, PFS, overall response rate, clinical benefit response, and safety. PFS was defined as the time from randomization to the time of progression or death from any cause. CBR was evaluated according to the Rothenberg definition. Investigator s Analysis Correlative endpoints not met but clinical activity observed Drug Information Drug 1 Generic/Working name Company name Drug class TS-1 Taiho Pharmaceutical Company Limited Antimetabolite

3 Dose Route Schedule of Administration Drug 2 Generic/Working name Drug type Drug class Dose Route Schedule of Administration 20 mg Oral (po) S-1 was orally administered 80 mg/m2 per day, twice a day, continued for 14 days and with rest for 7 days, fora 21-daycycle.The specific dosages for patients whose body surface areas were,1.25, , and.1.5 m2 were 80, 100, and 120 mg, respectively. Leucovorin Other Other Milligrams per Oral (po) Leucovorin was orally administered 25 mg with S-1 simultaneously, twice a day for 14 days. Patient Characteristics Number of patients, male 61 Number of patients, female 31 Stage Stage III (2 patients) and stage IV (90 patients) Age Median (range): 58 Number of prior systemic therapies Median (range): 1 Performance Status: ECOG unknown 0 Other Cancer Types or Histologic Subtypes Adenocarcinoma 92 Most patients in both arms had a KPS score of 80 or more (83% and 95.6%), of which patients with a Karnofsky performance status score of 90 or above accounted for 46.8% (22 of 47) of the S-1 arm and 51.1% (23 of 45) of the SL arm. In the S-1 arm, two cases were locally advanced PC and 45 cases were metastatic PC. Among the patients with metastatic PC, there were more than two metastatic organs in 32 cases (71.1%). In the SL arm, all patients had metastatic PC, with morethan two metastaticorgans in 30 cases(66.7%). By the time of this analysis, 79.3% (73 of 92) of patients had died, 1.1% (1 of 92) of patients were lostto follow-up, and 6 patients were still under study treatment. In the S-1 arm, the median follow-up time was 21 months, with 37 deaths(78.7%). In the SL arm, the median follow-up time was 20.7 months, with 36 deaths (80%). Primary Assessment Method Experimental Arm: Total Patient Population Number of patients screened: 45 Number of patients enrolled: 45 Number of patients evaluable for toxicity: 45 Number of patients evaluated for efficacy: 36 Evaluation method: RECIST 1.0 Response assessment CR: 0% Response assessment PR: 8.3% Response assessment SD: 52.8% Response assessment PD: 38.9% (Median) duration assessments PFS: 3.0 months, CI:

4 (Median) duration assessments OS: 6.3 months, CI: (Median) duration assessments duration of treatment: 6 weeks Control Arm: Total Patient Population Number of patients screened: 47 Number of patients enrolled: 47 Number of patients evaluable for toxicity: 47 Number of patients evaluated for efficacy: 41 Evaluation method: RECIST 1.0 Response assessment CR: 0% Response assessment PR: 4.9% Response assessment SD: 53.7% Response assessment PD: 41.4% (Median) duration assessments PFS: 1.9 months, CI: (Median) duration assessments OS: 5.5, CI: (Median) duration assessments duration of treatment: 6 weeks Assessment, Analysis, and Discussion Completion: Pharmacokinetics / Pharmacodynamics: Investigator s Assessment: Study completed Not Collected Correlative endpoints not met but clinical activity observed Discussion There is no standard second-line treatment regimen after failure of first-line therapy for patients with locally advanced or metastatic pancreatic cancer (PC), mainly because of the poor condition of the patients. In clinical practice, less than 50% of patients can accept second-line treatment [1].There have been a number of studies of second-line treatment for metastatic PC, such as irinotecan, 5-fluorouracil (5-FU) combined with oxaliplatin, 5-FU combined with paclitaxel, and 5-FU combined with celecoxib and irinotecan [2 6]. One meta-analysis of second-line treatment for metastatic PC [7] included 33 clinical studies, 1,269 patients, and different single-agent or combination therapies including 5-FU, cisplatin, taxanes, and erlotinib. The results showed that, compared with best supportive treatment, the second-line treatment could have a survival benefit (6 months vs. 2.8 months, p 5.013); however, most of the studies were single-arm or nonrandomized phase II studies, mainly using response rate (RR) or progression-free survival (PFS) as the primary endpoints. S-1 has been approved to treat patients with metastatic PC in Japan and Taiwan. In first-line treatment, it showed similar efficacy and better tolerability compared with gemcitabine (GEM) [8], and in postoperative adjuvant therapy, it was also noninferior to GEM [9]. The GEST study [8] is currently the sole large-scale phase III study and proved that S-1 as first-line treatment of advanced PC was noninferior compared with GEM alone. Median overall survival (OS) for GEM combined with S-1 was 10.1 months, which was prolonged compared with the median OS of the GEM treatment group (8.8 months) but showed no statistical difference. Median OS in the GEM monotherapy group was significantly longer than that of the previously reported phase III studies, and it is possible that, in Japan, a higher proportion of patients (50.5%) in the GEM monotherapygroup received S-1 monotherapyor S-1-based combination therapy in second-line treatment. For the patients with GEM-resistant advanced PC, several phase II studies have shown that S-1 in second-line treatment could achieve promising efficacy, and its overall RR could be up to 15% 37%, especially with good tolerability. In this study, we designed S-1 combined with leucovorin (SL) therapy because preclinical studies have confirmed that SL could enhance the efficacy of S-1 [10]. Its main mechanism is that leucovorin could promote the formation of more covalent triple complexes (ternary complex; i.e., TS-FdUMP-CH2FH4). Several recent clinical studies on patients with metastatic colorectal cancer (mcrc) also showed that SL could enhance efficacy [11, 12]. Generally, the S-1 monotherapy regimen is continuous oral administration for 4 weeks and rest for 2 weeks (6-week regimen). In a phase I studyof SL [12],three regimens were designed: (a) a 6-week regimen, with oraladministration of SL for

5 4 weeks and restfor 2weeks; (b) a5-week regimen,with oraladministration ofsl for 3 weeks andrestfor 2weeks; and (c) a4- week regimen, with oral administration of SL for 2 weeks and rest for 2 weeks. The results showed that there was a higher incidence of grade 3 4 adverse events (AEs) in the 6-week regimen, reaching maximum tolerated dose; therefore, the 4-week SLregimen wasrecommended.the main dose-limitingtoxicity wastoxicityto the digestive system(stomatitis, anorexia, diarrhea). In this study, to guarantee parallel dose intensity in the two groups of treatment regimens, we followed results reported by Tsukuda et al. [13] showing that the patient s tolerability in the 3-week S-1 monotherapy regimen for head and neck tumors (taken orally for 2 weeks and rest for 1week) was significantly higher than that of the 6-week regimen. Consequently, we selected the 3-week dosing regimen in the two arms and indicated in the protocol that for grade 3 4 hematologic toxicity or grade 2 or worse nonhematological toxicity, the investigator could reduce S-1 dose levels.the results showed that median OS in the SL and S-1 arms was 6.3 and 5.5 months, respectively, which was similar to the survival benefit obtained in the previous phase II studies of S-1 monotherapy and further validated the feasibility of S-1 use in the second-line setting of metastatic PC. In this study, SL did not further enhance the overall RR or clinical benefit response and did not prolong median OS and PFS compared with S-1, different from the previously reported result in mcrc that SL could enhance the efficacy of S-1 [11]. It is possible that SL may significantly enhance the incidence of grade 3 4 AEs compared with S-1 (57.8% vs. 31.1%), and the rate of AEs at a lower dose level was significantly enhanced (40.0% vs. 14.9%), which is similar to previous reports. In this study, the overall RR in the two arms was lower than previous phase II study results of S-1 monotherapy as second-line treatment for patients with advanced PC.Through analysis, we concluded that it is possible that patients in the present study had poor general conditions (53.7% with Karnofsky performance status of points) and had higher proportions of withdrawal (10.9%) and treatment at reduced dose levels (30.5%) due to AEs. Compared with the S-1 arm, patients in the SL arm had significantly higher digestive toxicity (stomatitis, diarrhea, anorexia) but no significant increase in bone marrow toxicity of grade 3 4, similar to the phase II study results in patients with mcrc, whose major dose-limiting toxicity was digestive toxicity; however, in the SL arm, after reducing the dose level of S-1, 83.3% (15 of 18) of patients could tolerate it. OS and PFS in the two arms were similar to the results of the previously reported two-drug combination regimens, but patients with locally advanced PC were included in the previous studies, whereas in this study, most patients had metastatic PC with poor prognosis.patientswithmetastasisintwoormoreorgansaccountedfor71.4%ofthes-1armand65%oftheslarm,showing that S-1 or SL after dose adjustment had some effect for patients with metastatic PC. Acknowledgment Feijiao Ge and Nong Xu contributed equally to this work. References 1. Louvet C, Labianca R, Hammel P et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005;23: Pelzer U, Schwaner I, Stieler J et al. Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: A phase III-study from the German CONKO-study group. Eur J Cancer 2011;47: Yi SY, Park YS, Kim HS et al. Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer. Cancer Chemother Pharmacol 2009;63: Oettle H, Arnold D, Esser M et al. Paclitaxel as weekly second-line therapy in patients with advanced pancreatic carcinoma. Anticancer Drugs 2000;11: Milella M, Gelibter A, Di Cosimo S et al. Pilot study of celecoxib and infusional 5-fluorouracil as second-line treatment for advanced pancreatic carcinoma. Cancer 2004;101: Jacobs AD, Burris HA, Rivkin S et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study. J Clin Oncol 2004;22(suppl 14):4013a. 7. Rahma OE, Duffy A, Liewehr DJ et al. Second-line treatment in advanced pancreatic cancer: A comprehensive analysis of published clinical trials. Ann Oncol 2013;24: Ueno H, Ioka T, Ikeda M et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013;31: Maeda A, Boku N, Fukutomi A et al. Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC-01). Jpn J Clin Oncol 2008;38: Tsukioka S, Uchida J, Tsujimoto H et al. Oral fluoropyrimidine S-1 combined with leucovorin is a promising therapy for colorectal cancer: Evidence from a xenograft model of folate-depleted mice. Mol Med Rep 2009;2: Koizumi W, Boku N,Yamaguchi Ketal. PhaseII studyofs-1 plus leucovorin in patients with metastatic colorectal cancer. Ann Oncol 2010;21: Hyodo I, Nishina T, Boku N et al. Phase I study of oral fluoropyrimidine S-1 plus oral leucovorin in patients with metastatic colorectal cancer. Ann Oncol 2006;17(suppl 120):347Pa. 13. Tsukuda M, Kida A, Fujii M et al. Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer. Br J Cancer 2005;93:

6 Figures and Tables Figure 1. Flow diagram for eligible patients at each point of treatment. Abbreviation: SL, S-1 plus leucovorin. Figure 2. Percentage change from baseline in size of target lesion. Abbreviations: PD, progressive disease; PR, partial response; SD, stable disease; SL, S-1 plus leucovorin.

7 Figure 3. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) in the two arms. Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; SL, S-1 plus leucovorin. Table 1. Baseline clinical characteristics of patients (N 5 92) Clinical data S-1 (n 5 47) SL (n 5 45) p value a Sex, n (%) Male 35 (74.5) 26 (57.8).123 Female 12 (25.5) 19 (42.2) Age, years, median (range) 58 (30 76) 57 (36 76).592 KPS score, n (%) $80 39 (82.9) 43 (95.6).091,80 8 (17.0) 2 (4.4) Neoplasm staging, n (%) Stage III (locally advanced) 2 (4.3) Stage IV (metastatic) 45 (95.7) 45 (100) Pancreatectomy, n (%) Yes 21 (44.7) 21 (46.7) 1.0 No 26 (55.3) 24 (53.3) Primary lesion site, n (%) Head of pancreas 20 (42.6) 17 (37.8) Body of pancreas 6 (12.8) 5 (11.1) Tail of pancreas 13 (27.7) 9 (20.0).615 Head and body of pancreas 1 (2.1) 2 (4.4) Body and tail of pancreas 7 (14.9) 12 (26.7) Pathological pattern, n (%) High differentiation 3 (6.4) 5 (11.1) Moderate differentiation 15 (31.9) 14 (31.1) Low to moderate differentiation 8 (17.0) 9 (20.0).897 Low differentiation 17 (36.2) 13 (28.9) Indeterminate 4 (8.5) 4 (8.9) Reasons for ineffective GEM treatment, n (%) Disease progression 42 (89.4) 38 (84.4).386 Intolerant 5 (10.6) 8 (18.8) CA199, n (%) Normal 8 (17.0) 7 (15.6) 1.0 Elevated 39 (82.9) 38 (84.4) Median CA199 1,001 ( ) ( ).392 a Chi-square test. Abbreviations: GEM, gemcitabine; KPS, Karnofsky performance status; SL, S-1 plus leucovorin.

8 Table 2. Cox proportional hazards analysis of overall survival Parameter HR 95% CI p value Therapy (S-1 vs. SL) Age (,65 vs. $65 years) KPS ($80 vs.,80) ,.01 Sex (female vs. male) Primary lesion excised (no vs. yes) Primary lesion site (not head of pancreas vs. head of pancreas) Baseline CA199 (normal vs. elevated) Abbreviations: CI, confidence interval; HR, hazard ratio; KPS, Karnofsky performance status; SL, S-1 plus leucovorin. Table 3. Common adverse events in the safety population Adverse reactions All grades, (%) S-1 (n 5 47) SL (n 5 45) Grade 3, Grade 4, Grade 5, All grades, (%) Grade 3, Grade 4, Grade 5, p value a Granulocytopenia 11 (23.4) (24.4) Anemia 16 (34.0) (35.6) Thrombocytopenia 10 (21.3) (28.9) Transit elevation of 10 (21.3) (20.0) transaminase Elevation of serum 11 (23.4) (20.0) bilirubin Diarrhea 16 (34.0) (35.6) Anepithymia 23 (48.9) (62.2) Stomatitis 10 (21.3) (35.6) Hyperpigmentation 18 (38.3) (44.4) Emesis 9 (19.1) (15.6) Fatigue 24 (51.1) (66.7) Rash 2 (4.3) (14.9) Abdominal distension 2 (4.3) (4.4) Alimentary tract hemorrhage (2.2) Intestinal obstruction (2.1) Overall adverse reactions 45 (95.7) (100) a Chi-square test: comparison between the two groups occurrence rates of adverse reactions at all levels (N 5 92). Abbreviation: SL, S-1 plus leucovorin. Click here to access other published clinical trials.

Reference No: Author(s) 12/05/16. Approval date: committee. June Operational Date: Review:

Reference No: Author(s) 12/05/16. Approval date: committee. June Operational Date: Review: Reference No: Title: Author(s) Systemic Anti-Cancer Therapy (SACT) Guidelines for Pancreatic Adenocarcinoma Dr Colin Purcell, Consultant Medical Oncologist & on behalf of the GI Oncologists Group, Cancer