Randomized, Open-Label Phase II Study Comparing Capecitabine-Cisplatin Every 3 Weeks with S-1-Cisplatin Every 5 Weeks in Chemotherapy-Naïve Patients with HER2-Negative Advanced Gastric Cancer: OGSG1105, HERBIS-4A Trial.

LESSONS LEARNED: Evidence has suggested that capecitabine-cisplatin is similar or possibly superior to S-1-cisplatin in terms of safety and efficacy for Japanese patients with advanced gastric cancer (AGC).As far as we are aware, our study is the first randomized trial of two regimens consisting of an oral fluoropyrimidine plus cisplatin in human epidermal growth receptor 2-negative AGC patients with measurable lesions.
BACKGROUND: We performed a phase II study to evaluate the safety and efficacy of capecitabine plus cisplatin in comparison with S-1 plus cisplatin for first-line treatment of human epidermal growth receptor 2 (HER2)-negative advanced gastric cancer in Japan.
METHODS: Eligible patients were randomly assigned to receive either capecitabine at 1,000 mg/m2 twice daily for 14 days plus cisplatin at 80 mg/m2 on day 1 every 3 weeks (n = 43) or S-1 at 40-60 mg twice daily for 21 days plus cisplatin at 60 mg/m2 on day 8 every 5 weeks (n = 41). The primary endpoint of the study was response rate.
RESULTS: Response rate did not differ significantly between the capecitabine-cisplatin and S-1-cisplatin groups (53.5% vs. 51.2%, respectively, p > .999). S-1-cisplatin tended to confer a better progression-free survival (PFS; median of 5.9 vs. 4.1 months, p = .284), overall survival (OS; median of 13.5 vs. 10.0 months, p = .290), and time to treatment failure (TTF; median of 4.5 vs. 3.1 months, p = .052) compared with capecitabine-cisplatin. Common hematologic toxicities of grade 3 or 4 included anemia and neutropenia in both groups. However, anorexia, fatigue, and hyponatremia of grade 3 or 4 occurred more frequently in the capecitabine-cisplatin group.
CONCLUSION: Capecitabine-cisplatin failed to demonstrate superior efficacy compared with S-1-cisplatin. The higher incidence of severe adverse events with capecitabine-cisplatin suggests that S-1-cisplatin should remain the standard first-line chemotherapy for HER2-negative advanced gastric cancer in Japan. © AlphaMed Press; the data published online to support this summary is the property of the authors.

RCT Entities:   Population Interventions Outcomes

Discussion

The response rate was 51.2% (95% CI, 35.1%–67.1%) in the S‐1–cisplatin group and 53.5% (95% CI, 37.7%–68.8%) in the capecitabine‐cisplatin group (p > .999). The DCR for the FAS was higher in the S‐1–cisplatin arm (82.9%) than in the capecitabine‐cisplatin arm (67.4%). A waterfall plot analysis revealed that patients in the S‐1–cisplatin arm showed greater tumor shrinkage and that a larger proportion of patients in this arm experienced tumor shrinkage from baseline compared with the capecitabine‐cisplatin arm (Fig. 1).

Figure 1.

Waterfall plot of maximum percentage change in target lesion size according to RECIST. S‐1–cisplatin (A) and capecitabine‐cisplatin (B) groups, respectively.

For survival analysis, the median follow‐up time was 11.3 months. The median PFS was 5.9 months in the S‐1–cisplatin group and 4.1 months in the capecitabine‐cisplatin group (HR, 0.763; 95% CI, 0.462–1.259; p = .284) (Fig. 2A), whereas the corresponding values for median OS were 13.5 and 10.0 months (HR, 0.776; 95% CI, 0.485–1.244; p = .290) (Fig. 2B) and those for median TTF were 4.5 and 3.1 months (HR, 0.651; 95% CI, 0.421–1.006; p = .052) (Fig. 2C).

Figure 2.

Kaplan‐Meier estimates of survival. PFS (A), OS (B), and TTF (C). Red and green lines indicate S‐1–cisplatin (SP) and capecitabine‐cisplatin (XP) groups, respectively.

Abbreviations: OS, overall survival; PFS, progression‐free survival; TTF, time to treatment failure.

The most common all‐grade hematologic adverse events were anemia (79% in the S‐1–cisplatin group, 74% in the capecitabine‐cisplatin group) and neutropenia (54% and 60%), each of which occurred at a similar frequency in the two groups. In contrast, anemia and neutropenia of grade 3 or 4 were more common in the capecitabine‐cisplatin group than in the S‐1–cisplatin group. With regard to nonhematologic toxicities, anorexia (67% and 72%) and malaise (46% and 49%) were common all‐grade adverse events in both treatment groups. Anorexia, fatigue, and hyponatremia of grade 3 or 4 were more frequent in the capecitabine‐cisplatin group (23%, 14%, and 16%) than in the S‐1–cisplatin group (13%, 0%, and 5%). Peripheral neuropathy and hand‐foot syndrome of grade 3 or 4 were apparent in the capecitabine‐cisplatin arm (5% and 2%) but not in the S‐1–cisplatin arm. One death in the capecitabine‐cisplatin group (2%, 1 of 43) was due to brain infarction, which was considered to be treatment related by the investigators.

Trial Information

Gastric cancer

Metastatic/advanced

None

Phase II

Randomized

Overall response rate

Progression‐free survival

Overall survival

Safety

Time to treatment failure

Drug Information for Phase II S‐1 + CDDP

S‐1

TS‐1

Taiho Pharmaceutical, Co, Ltd.

80–120 mg/m2

p.o.

S‐1 at 40–60 mg twice daily for 21 days every 5 weeks

Cisplatin (CDDP)

Platinum compound

60 mg/m2

IV

Cisplatin at 60 mg/m2 on day 8, every 5 weeks

Drug Information for Phase II Capecitabine + CDDP

Capecitabine

Xeloda

Chugai Pharmaceutical, Co, Ltd.

2,000 mg/m2

p.o.

Capecitabine at 1,000 mg/m2 twice daily for 14 days every 3 weeks

Cisplatin (CDDP)

Platinum compound

80 mg/m2

IV

Cisplatin at 80 mg/m2 on day 1 every 3 weeks

Patient Characteristics for Phase II S‐1 + CDDP

Patient Characteristics for Phase II Capecitabine + CDDP

Primary Assessment Method for Phase II S‐1 + CDDP

Total patient population

41

39

39

41

RECIST 1.1

n = 0 (0%)

n = 21 (51%)

n = 13 (32%)

n = 3 (7%)

n = 4 (10%)

179 days, confidence interval (CI): 136–225

412 days, CI: 340–701

Secondary Assessment Method for Phase II S‐1 + CDDP

Total patient population

179 days, CI: 136–225

412 days, CI: 340–701

Primary Assessment Method for Phase II Capecitabine + CDDP

Total patient population

43

43

43

43

RECIST 1.1

n = 0 (0%)

n = 23 (53%)

n = 6 (14%)

n = 10 (3%)

n = 4 (10%)

124 days, CI: 108–200

305 days, CI: 218–474

Secondary Assessment Method for Phase II Capecitabine + CDDP

Total patient population

124 days, CI: 108–200

305 days, CI: 218–474

Phase II S‐1 + CDDP Adverse Events

Serious Adverse Events

Phase II Capecitabine + CDDP Adverse Events

Assessment, Analysis, and Discussion

Study completed

Inactive because results did not meet primary endpoint

Gastric cancer is the fifth most common malignant disease and the second leading cause of cancer deaths worldwide [1], with an especially high incidence in East Asia. Individuals newly diagnosed with gastric cancer often present with unresectable or metastatic disease, known as advanced gastric cancer (AGC). Trastuzumab in combination with chemotherapy has been found to confer a significantly better overall survival (OS) compared with chemotherapy alone in patients with AGC positive for human epidermal growth receptor 2 (HER2) [2]. On the other hand, for individuals with HER2‐negative disease, who account for most cases of AGC, treatment options are largely restricted to conventional therapy such as doublet or triplet combination chemotherapy. The outcome for such patients thus remains poor, with a global standard regimen for treatment of HER2‐negative AGC remaining to be established.

In East Asia, including Japan and Korea, the combination of a fluoropyrimidine plus a platinum agent has been adopted as standard therapy for HER2‐negative AGC [3], [4]. S‐1 is a fluoropyrimidine preparation that includes tegafur, gimeracil, and oteracil potassium in a molar ratio of 1:0.4:1 and was designed to minimize gastrointestinal toxicity and maximize antitumor activity [5]. The SPIRITS phase III trial showed that S‐1 in combination with cisplatin conferred a significant survival benefit (median survival time of 13.1 months) compared with S‐1 alone, resulting in this combination being accepted as a standard first‐line regimen for AGC in East Asia [3]. In Western countries, regimens containing a fluoropyrimidine plus a platinum compound and either docetaxel [6] or epirubicin [7] have improved survival in patients with AGC. However, the combination of a fluoropyrimidine plus a platinum agent has been widely accepted as a standard treatment option for such patients in practice, given that the addition of docetaxel or epirubicin was associated with a limited improvement in survival but substantial hematologic toxicity [6], [7].

Capecitabine is an oral fluoropyrimidine prodrug that manifests high antitumor activity in association with low toxicity, given that it is converted to 5‐fluorouracil (5‐FU) by thymidine phosphorylase, which is present at much higher concentrations in tumor cells than in normal cells [8]. As capecitabine plus cisplatin was found to be noninferior to 5‐FU plus cisplatin in terms of progression‐free survival (PFS) for the first‐line treatment of AGC, the former combination is now considered an effective alternative to the latter [4]. Moreover, capecitabine‐cisplatin has been adopted as a standard backbone chemotherapy for combination with trastuzumab [2] or other molecularly targeted agents such as bevacizumab [9] or cetuximab [10] in global phase III trials for AGC.

In Japan, capecitabine was approved for AGC in 2011, and the safety and efficacy of capecitabine‐cisplatin in the Japanese population have been demonstrated in two global phase III trials—the AVAGAST [9] and ToGA [2] studies—in which 94 Japanese AGC patients of unknown HER2 status and 50 Japanese patients with HER2‐positive AGC, respectively, received this combination alone [11]. In these two studies, the median OS, median PFS, and overall response rate (RR) were 14.2–17.7 months, 5.6–5.7 months, and 49.2%–58.5%, respectively. Adverse events were generally mild, with the most common events of grade 3 or 4 being neutropenia, anemia, anorexia, and nausea. Similar efficacy and safety profiles for capecitabine‐cisplatin in Japanese AGC patients were also apparent in a retrospective study [12]. These data have suggested that capecitabine‐cisplatin is similar or possibly superior to S‐1‐cisplatin in terms of safety and efficacy for Japanese patients with AGC. However, capecitabine‐cisplatin has not been prospectively compared with S‐1‐cisplatin in patients with HER2‐negative AGC to date. We have therefore now conducted a phase II study to assess the efficacy and safety of capecitabine‐cisplatin versus S‐1‐cisplatin in Japanese patients with HER2‐negative AGC.

In our trial, however, capecitabine‐cisplatin failed to show a superior efficacy relative to S‐1‐cisplatin. Although RR, the primary endpoint of our trial, did not differ significantly between the two treatment groups, disease control rate (DCR) was higher in the S‐1‐cisplatin arm, with this benefit being confirmed by waterfall analysis. The benefit of S‐1‐cisplatin with regard to its high DCR likely reflects the observed trend toward a better PFS and OS in the S‐1‐cisplatin arm than in the capecitabine‐cisplatin arm.

With respect to adverse events, both regimens in the present study showed similar hematologic toxicity profiles, with anemia and neutropenia being most frequently observed. In contrast, the overall incidence of nonhematologic toxicities of grade 3 or 4 was higher in the capecitabine‐cisplatin group than in the S‐1‐cisplatin group. A meta‐analysis comparing S‐1 with capecitabine in AGC found no overall difference in terms of serious adverse events [13]. In the present study, however, anorexia, fatigue, and hyponatremia of grade 3 or 4 occurred more frequently in the capecitabine‐cisplatin arm than in the S‐1‐cisplatin arm. Moreover, brain infarction of grade 5 occurred in one patient of the capecitabine‐cisplatin group, possibly as a result of the high dose intensity of cisplatin, which is known to be associated with venous thromboembolism [14]. Indeed, most of the differences in nonhematologic toxicity between the two groups were likely due to the higher dose of cisplatin administered in the capecitabine‐cisplatin arm, which was also associated with a shorter time to treatment failure. Together, our findings suggest that, at least in the setting of the present trial, administration of cisplatin at 80 mg/m2 every 3 weeks in combination with capecitabine did not increase efficacy but was more toxic compared with that at 60 mg/m2 every 5 weeks in combination with S‐1.

In conclusion, although our study was a phase II trial and our results thus need confirmation, capecitabine‐cisplatin failed to demonstrate superior efficacy over S‐1‐cisplatin. The higher incidence of severe nonhematologic adverse events observed with capecitabine‐cisplatin suggests that S‐1‐cisplatin should remain the standard first‐line chemotherapy for HER2‐negative AGC with measurable lesions, at least in Japan.

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

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