Phase II Study of the Triple Combination Chemotherapy of SOXIRI (S-1/Oxaliplatin/Irinotecan) in Patients with Unresectable Pancreatic Ductal Adenocarcinoma.

LESSONS LEARNED: The triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic ductal adenocarcinoma was an effective treatment that appeared to be better tolerated than the widely used FOLFIRINOX regimen.SOXIRI regimen may provide an alternative approach for advanced pancreatic cancer.
BACKGROUND: In our previous phase I study, we determined the recommended dose of a biweekly S-1, oxaliplatin, and irinotecan (SOXIRI) regimen in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). This phase II study was conducted to assess the safety and clinical efficacy in patients with unresectable PDAC.
METHODS: Patients with previously untreated metastatic and locally advanced PDAC were enrolled. The primary endpoint was response rate (RR). Secondary endpoints were adverse events (AEs), progression-free survival (PFS), and overall survival (OS). Patients received 80 mg/m2 of S-1 twice a day for 2 weeks in alternate-day administration, 150 mg/m2 of irinotecan on day 1, and 85 mg/m2 of oxaliplatin on day 1 of a 2-week cycle.
RESULTS: Thirty-five enrolled patients received a median of six (range: 2-15) treatment cycles. The RR was 22.8% (95% confidence interval [CI]: 10.4-40.1); median OS, 17.7 months (95% CI: 9.8-22.0); and median PFS, 7.4 months (95% CI: 4.2-8.4). Furthermore, the median OS in patients with distant metastasis was 10.1 months, whereas that in patients with locally advanced PDAC was 22.6 months. Major grade 3 or 4 toxicity included neutropenia (54%), anemia (17%), febrile neutropenia (11%), anorexia (9%), diarrhea (9%), and nausea (9%). There were no treatment-related deaths.
CONCLUSION: SOXIRI is considered a promising and well-tolerated regimen in patients with unresectable PDAC. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

Since Conroy et al. reported the significant efficacy in OS and quality of life with FOLFIRINOX compared with gemcitabine (GEM) in patients with metastatic pancreatic cancers, this regimen has been one of the most effective current standard treatments for unresectable PDAC [1]. However, this treatment carries significantly more adverse events and cannot be used in all patients with advanced pancreatic cancer [2], [3]. We previously performed a phase I study to determine the recommended dose of a biweekly S‐1, oxaliplatin, and irinotecan (SOXIRI) regimen, using S‐1 in alternate‐day administration instead of 5‐fluorouracil (5‐FU), potentially more feasible than FOLFIRINOX in patients with unresectable PDAC [4]. The recommended dose of S‐1, oxaliplatin, and irinotecan is 80, 85, and 150 mg/m2, respectively.

S‐1 is a drug combination comprising three agents at a 1:0.4:1 molar ratio: tegafur, a prodrug of 5‐FU; 5‐chloro‐2,4‐dihydroxypyridine, which blocks dihydropyrimidine dehydrogenase, the first step in 5‐FU metabolism; and potassium oxonate, which blocks the enzyme orotate phosphoribosyltransferase, thereby reducing the gastrointestinal toxicity of 5‐FU. S‐1 has regulatory approval in Japan and in Europe.

This phase II study was carried out to investigate the efficacy and safety of a SOXIRI regimen in chemotherapy‐naïve patients with unresectable PDAC. The RR, which was the primary endpoint of this study, was 22.8% (95% CI: 10.4–40.1) with the lower limit of the 95% CI being above the threshold RR of 10%. The disease control rate (74.0%) was similar to the findings of the former FOLFIRINOX phase II/III study (70.2%) [1] and the FOLFIRINOX phase II study in Japanese patients (69.4%) [3]. In addition, the median OS (17.7 months) and the median PFS (7.4 months) were also favorable (Fig. 2). Accordingly, we consider the SOXIRI regimen to be effective in patients with unresectable PDAC.

Figure 2.

OS in the locally advanced cohort (solid line) and in the metastatic cohort (dotted line).

Abbreviation: OS, overall survival.

The incidences of grade 3–4 neutropenia and febrile neutropenia in this study were lower (54% and 11%) than those in the FOLFIRINOX phase II study for Japanese patients (vs. 78% and 22%, respectively) [3] and similar to the FOLFIRINOX phase II/III study (vs. 46% and 5%, respectively) [1]. With regard to nonhematologic events, the incidence of grade 3 or 4 fatigue, nausea, neuropathy (6%, 9%, 0%) was similar to that in the FOLFIRINOX phase II study for Japanese patients (vs. 0%, 0%, 5.6%, respectively) [3] and lower than in the Conroy et al. FOLFIRINOX phase II/III study (vs. 5.6%, 23.6%, 9%, respectively) [1]. Taken together, the toxicities including hematological and nonhematological events are relatively mild compared with previous studies.

In summary, our present findings suggest that the SOXIRI regimen appears comparable efficacy with acceptable AEs in patients with unresectable PDAC. Thus, the SOXIRI regimen could be an optional regimen for the FOLFIRINOX in patients with unresectable PDAC.

Trial Information

Pancreatic cancer

Advanced cancer

Metastatic/advanced

None

Phase II

Single arm

Overall response rate

Safety

Progression‐free survival

Overall survival

Active and should be pursued further

Drug Information

S‐1

Small molecule

Antimetabolite

80 mg/m2

p.o.

Twice a day every 2 weeks

Oxaliplatin

Small molecule

Platinum compound

85 mg/m2

IV

Day 1 of a 2‐week cycle

Irinotecan

Small molecule

Topoisomerase I

150 mg/m2

IV

Day 1 of a 2‐week cycle

19

16

Locally advanced only: 15; metastatic disease: 20

Median (range): 65 (42–75)

Median (range): none

0 — 28

1 — 7

2 —

3 —

Unknown —

Additional details for patient and treatment characteristics can be found in Table 1 and 2.

Table 1.

Tumor response (n = 35)

Abbreviations: CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease.

Table 2.

Patient characteristics

Abbreviations: CA19‐9, carbohydrate antigen 19‐9; ECOG, Eastern Cooperative Oncology Group.

Primary Assessment Method

35

35

35

34

RECIST 1.1

n = 0 (0%)

n = 8 (23%)

n = 18 (51%)

n = 8 (23%)

n = 1 (3%)

7.4 months, CI: 4.2–8.4

17.7 months, CI: 9.8–22.0

Maximum percentage changes from baseline in size of target lesions according to the RECIST criteria (n = 34).

Adverse Events

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

In 2011, FOLFIRINOX was compared with GEM in a phase II/III study involving patients with metastatic pancreatic ductal adenocarcinoma (PDAC) [1]. FOLFIRINOX exhibited a significant improvement in overall survival (OS) and quality of life versus GEM. The FOLFIRINOX regimen requires close monitoring and must be limited to patients with good performance status because of significant toxicity [2]. In a phase II study conducted in Japan, febrile neutropenia occurred during the first cycle in 22.2% of patients [3]. Because of the high incidence of severe neutropenia and febrile neutropenia, the relative dose intensity of bolus 5‐fluorouracil (5‐FU) was only 15.9% [3]. These significant toxicities in Japan, as well as in Western countries, resulted in modification of the FOLFIRINOX regimen; several studies using reduced irinotecan or omitting the bolus fluorouracil have been reported [5], [6], [7].

S‐1 (TS‐1; Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) is an oral fluoropyrimidine derivative in which tegafur is combined with two 5‐chloro‐2, 4‐dihydroxypyridine modulators and oteracil potassium, a potentiator of 5‐FU's antitumor activity that also decreases gastrointestinal toxicity [8]. In Japan, clinical studies of S‐1 have reported promising results in various cancer [9], [10]. With respect to pancreatic cancer, combination chemotherapy with GEM plus S‐1 is reportedly well tolerated and active against advanced PDAC [11], [12]. In addition, S‐1 is often used as a substitute of 5‐FU in various combination chemotherapies such as 5‐FU and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) for metastatic colorectal cancer [13], [14]. Although S‐1 is associated with various nonhematologic toxicities, including anorexia, nausea, vomiting, stomatitis, and diarrhea [10], [15], [16], we adopted the alternate‐day dosage of S‐1 as a substitute for 5‐FU in this study because previous studies about gastric cancer reported that this method of administration reduced adverse effects without compromising efficacy [17], [18]. Although a multicenter, randomized, phase II study comparing S‐1 alternate‐day therapy with the standard daily regimen in patients with unresectable advanced PDAC failed to demonstrate noninferiority to the daily treatment (9.4 months, 95% confidence interval 7.6–11.1 vs. 10.4 months, 7.9–12.8) in OS rate. On the other hand, the incidence of anorexia, fatigue, neutropenia, pigmentation, and pneumonitis was significantly lower in alternate‐day treatment compared with daily treatment and comparable median OS (9.4 months) [19]. Considering the comparable effectiveness and the improved safety of SOXIRI in this study, the S‐1 alternate‐day treatment instead of 5‐FU in the FOLFIRINOX regimen may be of value in the treatment of pancreatic cancer.

There are several limitations in this study. First, the current study included a relatively high population of patients with locally advanced pancreatic cancer, which might lead to the favorable OS when we compared all cohorts with previous studies using FOLFIRINOX. However, the median survival time of patients with metastatic PDAC (10.1 months) in this study was comparable to previous studies [1], [3], [7] (Figure 2). Therefore, we thought the SOXIRI regimen was not inferior to the original regimen. Second, although this study was conducted at dual institutions in Japan, almost the entire study population comprised an only Asian population, that is, Japanese patients. With respect to the applicability of this regimen in white patients, it should be noted that there are some pharmacogenomic differences regarding S‐1 metabolism between Asians and whites. The most important component of S‐1, tegafur, is converted to cytotoxic fluorouracil by cytochrome P450 (CYP) enzyme [20]. One of the CYP family, CYP2A6, plays a central role in this conversion process [21]. Because of the different polymorphisms in the CYP2A6 gene among Asians and whites [22], [23], the efficacy of CYP2A6 in whites is higher than that in Asians. Therefore, the area under the curve of fluorouracil in whites is higher than that in Asians [24] and the tolerability against the same dose of S‐1 in whites is lower. However, the alternate‐day administration of S‐1, which is milder than the usual administration, may reduce AEs in white populations. Furthermore, the study population is relatively small. Further larger studies are needed to confirm our findings.

In conclusion, the substitution of S‐1 for infusional 5‐fluorouracil, in combination with irinotecan and oxaliplatin, retained the efficacy with good tolerability in the first‐line treatment of unresectable PDAC. Our findings may provide an alternative approach for reducing patient burden with comparable efficacy to the original FOLFIRINOX for advanced PDAC.

Kaplan‐Meier curves for overall survival and progression‐free survival. (A): Overall survival. (B): Progression‐free survival.

See http://www.TheOncologist.com for supplemental material available online.

Adverse events across all cycles, and occurring in at least 10% of patients.

Abbreviation: NC/NA, no change from baseline/no adverse event.