The efficacy, safety, and QOL data of this phase III study (SOPP) were reported. In patients with MRGC, SOX was significantly non-inferior but not superior to SP3 in terms of PFS (median 5.6 versus 5.7 months). Additionally, the OS in both groups did not differ (median 12.9 versus 11.4 months). ORRs were similar between SOX and SP3 (58% versus 60%). The two regimens were well tolerated with different toxicity profiles. The influence of both regimens on QOL showed no significant difference during the treatment period.
For MRGC, palliative chemotherapy improves OS compared with the best supportive care alone. The combination of intravenous 5-fluorouracil and cisplatin (± epirubicin) has been considered the standard first-line chemotherapy in MRGC [2, 5, 6]. Recent trials have shown that oral fluoropyrimidine (capecitabine and S-1) can replace intravenous 5-fluorouracil [5,6,7] and oxaliplatin can replace cisplatin [4, 5]. Considering convenience and safety profiles, oral fluoropyrimidine and oxaliplatin are being extensively used in MRGC.
S-1 has demonstrated different safety profiles between East Asian and Caucasian patients . According to ethnicity and geographical area, diverse dosing schedules of SP have been used. Based on the result of the SPIRITS trial , 5-weekly SP [SP5; S-1 80–120 mg/day (days 1–21) and cisplatin 60 mg/m2 (day 8)] is widely used as first-line chemotherapy for MRGC in Japan. However, 3-weekly SP [SP3; S-1 80 mg/m2/day (days 1–14) and cisplatin 60 mg/m2 (day 1)] is popular in Korea . Interestingly, in the Japanese SP5 regimen, the S-1 dose is capped at 120 mg/day if BSA ≥ 1.5 m2; however, in the Korean SP3 regimen, the S-1 dose (80 mg/m2/day) is not capped and can be increased to 160 mg/day if BSA ≥ 2.0 m2 (Supplementary Table 1). In the Korea–Japan collaborative phase III S-1 Optimal Schedule Study (SOS), SP3 was not only non-inferior but was superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; HR 0.82 (95% CI, 0.68–0.99)]. However, because the PFS improvement was small and no difference in OS was observed, the Korean and Japanese investigators concluded that both SP3 and SP5 can be recommended as first-line chemotherapy for MRGC . In contrast, considering inter-ethnic variabilities in S-1 tolerability, a 4-weekly regimen was established [S-1 50 mg/m2/day (days 1–21) and cisplatin 75 mg/m2 (day 1)] in Western countries .
As S-1 has been popularly used in East Asian patients rather than Western patients, the safety and efficacy of SOX have been actively investigated in East Asian countries. However, the tested dosages and schedules of SOX were diverse in several phase II trials for MRGC [10, 12,13,14,15]. In the Japanese G-SOX phase III study (N = 685), the oxaliplatin dose was chosen as 100 mg/m2 (day 1) in SOX and the SP5 regimen was used in the reference arm. S-1 was used with the dosage cap at 120 mg/day if BSA ≥ 1.5 m2 in both SOX and SP5. The investigators demonstrated that SOX is non-inferior to SP5 in terms of PFS [5.5 versus 5.4 months (median); HR 1.004, 95% CI 0.840–1.199; predefined non-inferiority margin 1.30] in the per-protocol population (N = 642). The OS [14.1 versus 13.1 months (median)] and ORRs (56% versus 52%) did not significantly differ between SOX and SP5 . In this SOPP study, different dosage of oxaliplatin (130 mg/m2; day 1) in the SOX was used and SP3 was chosen as the reference arm. In both SOX and SP3 arms, the S-1 dose (80 mg/m2/day) was not capped and could be increased to 160 mg/day according to the subject’s BSA. This study also demonstrated that SOX is non-inferior to SP3 in terms of PFS [5.6 versus 5.7 months (median); HR 0.85, 95% CI 0.67–1.07]; when both predefined non-inferiority margins of 1.4 and 1.25 were used, SOX was proven to be non-inferior to SP3. OS and ORR did not differ between SOX and SP3 [OS (median), 12.9 versus 11.4 months; ORR, 58% versus 60%]. Therefore, regarding efficacy, although different dosages and treatment schedules of SOX and SP regimens were evaluated, both SOPP and G-SOX studies arrived at the same conclusion.
In terms of severe AEs (≥ grade 3), anemia (11% versus 5%), leucopenia (10% versus 2%), neutropenia (40% versus 16%), and febrile neutropenia (5% versus 0.6%) were more common in SP3 than in SOX; conversely, peripheral sensory neuropathy was more common with SOX than SP3 (9% versus 4%). Although thrombocytopenia of all grades was more frequent with SOX than SP3 (71% versus 58%), the frequency of severe thrombocytopenia (≥ grade 3) was similar between the 2 arms (8% versus 5%). In this study, nausea and vomiting (all grades) were more common with SOX than SP3. However, in the G-SOX study, nausea (all grades) was more frequent with SP5 than SOX. This differential pattern in the incidence of nausea and vomiting could be attributed to the different oxaliplatin doses used in the two studies. Although some differences exist in the pattern of developing treatment-related AEs between the SOPP and G-SOX studies, the overall differences in the AE profiles observed with SOX and SP in this SOPP study were consistent with those observed in the G-SOX study .
Interestingly, PFS and OS curves of SOX and SP3 tended to separate at about 7 and 10 months after randomization, respectively. This trend was not observed in the G-SOX study. At the end of this study, the study treatment was still ongoing in 16 subjects (9%) in SOX and 5 (3%) in SP3 (Fig. 1). Between the two regimens, there was no difference in the delivery of platinum agents. However, although there was no statistical difference, S-1 in SOX was delivered longer than S-1 in SP3 [median treatment cycles of S-1, 6 (range 1–45) in SOX versus 5 (range 1–35) in SP3; mean treatment cycles of S-1, 8.6 in SOX versus 7.2 in SP3 (Supplementary Table 2)]. When looked into the causes of study treatment discontinuation (Fig. 1), the proportion of subjects who were dropped out of study treatment owing to adverse events or refusal of treatment due to toxicity was numerically higher in SOX (9%) than in SP3 (5%). However, unexpectedly, subjects in SP3 rejected the study treatment more frequently for reasons other than identified toxicities (9%) than those in SOX (3%). Although the exact reasons of more treatment refusal in SP3 than in SOX was not clear, it is thought that there is still a possibility that treatment compliance decreased more in SP3 than in SOX due to unrecognized adverse events or other reasons. In addition, it was found that 13 subjects received conversion gastrectomy (9 in SOX and 4 in SP3) after study treatment (Supplementary Table 5); all these subjects had favorable OS outcomes and the median OS of these subjects did not reach. It is thought that the role of conversion surgery after palliative chemotherapy is not yet established in MRGC, so more researches are necessary. Although these explanations may not be enough, more conversion gastrectomy and more prolonged administration of S-1 in SOX group than in SP3 group may have contributed to the separation of PFS and OS curves after the observed time points between SOX and SP3.
In this study, subgroup analyses indicated no overall differences in PFS and OS between SOX and SP3. However, patients with a BMI ≥ 25 or age ≥ 60 years demonstrated longer PFS or OS with SOX than with SP3 (Supplementary Fig. 1). In the G-SOX study, the investigators have reported that patients with peritoneal metastasis had significantly longer OS with SOX than with SP5; the investigators could not observe any other subgroups with significantly improved OS with either SOX or SP5. The G-SOX investigators did not include BMI as one of the parameters for subgroup analyses of survival. In contrast, organs (such as the liver, lungs, or peritoneum) involved by metastasis were not included as parameters for subgroup analyses of PFS or OS in our study. Therefore, a direct comparison of subgroup analyses is not feasible between G-SOX and the current studies.
This study has some limitations. First, the study treatments were not blinded and 49% of enrolled subjects (164/337) had no measurable target lesion. The fact that only investigators, without the confirmation of independent central reviewers, determined tumor progression might be a limitation. Second, some experts may criticize the non-inferiority margin 1.4 as the basis for sample size calculation in this study was too wide. However, since non-inferiority margins of both 1.4 and 1.25 were satisfied through the two-step tests, it is thought that SOX was sufficiently proven non-inferior in terms of PFS compared to SP3. Third, some experts may question whether it is appropriate to set the primary endpoint to PFS in a phase III clinical trial of first-line chemotherapy in MRGC. In a meta-analysis of the GASTRIC group, the investigators showed that chemotherapy effects on PFS and OS were only moderately correlated, and thus they could not confirm the validity of PFS as a surrogate endpoint for OS in MRGC . It is agreed that PFS is not a good surrogate endpoint for OS in superiority trials for MRGC. However, as in other tumors, OS is greatly influenced by salvage chemotherapy after first-line chemotherapy, and the salvage chemotherapy is influenced by regional difference and practice pattern of the attending physicians . In addition, as the efficacy of salvage chemotherapy has been recently demonstrated in MRGC, the frequency of using second-line or later-line chemotherapy is increasing [22,23,24]. Therefore, it is believed that PFS as a primary endpoint is practically acceptable in non-inferiority trials of first-line chemotherapy in MRGC. For example, PFS was previously used as a primary endpoint in a phase III trial (ML17032), which had shown the non-inferiority of capecitabine/cisplatin compared to 5-fluorouracil/cisplatin in MRGC .
In conclusion, this SOPP study demonstrated that SOX is non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. Considering the SOPP and Japanese G-SOX studies, the SOX regimen can be recommended as a first-line treatment of MRGC in East Asian countries.