**3. Seeking the best regimen of second-line therapy**

Several randomized trials have been released to explore the optimal combination and doses for second-line therapy using the currently active agents or those deemed active. The agents investigated by these trials include chemotherapeutic drugs [17-20], a molecular targeting agent [21], and their combinations [22-26].

The efficacy of chemotherapy as a second-line setting has been investigated in several RCTs. In the TCOG GI-0801 trial [17], median PFS was significantly longer (3.8 months, n=64) by biweekly irinotecan plus cisplatin than by irinotecan alone (2.8 months, n=63), but median OS did not differ between the arms (10.7 months versus 10.1 months). Notably, the proportion of patients receiving third-line therapy was the same (75%) in both groups. The results of another randomized trial (ECRIN) have been reported in the abstract form [18], in which irinotecan plus cisplatin (n=84) was compared with irinotecan alone (n=84) in patients refractory to an S-1 containing regimen. WJOG 4007 [19] is a RCT comparing weekly paclitaxel (n=108) with biweekly irinotecan (n=111) in GC patients refractory to fluoropyrimidines plus cisplatin. Although there are no statistically significant differences between weekly paclitaxel and biweekly irinotecan for median OS (9.5 months vs 8.4 months, p=0.38), median PFS (3.6 months vs 2.3 months, p=0.33), or response rate (20.9% vs 13.6%, p=0.24), the median OS of both arms are equally longer than those of the previous second-line studies (Table 1, Figure 2). Several explanations are possible for the longer median OS in this study. One explanation is the lower proportion of patients with severe peritoneal metastasis in this study (25.6%) as compared with those in the AIO [10] (45%) and Kang [11] (45%) studies. Another explanation is that the proportion of patients receiving third-line therapy in this study was substantial, being 89.8% in the paclitaxel arm and 72.1% in the irinotecan arm. Interestingly, the third-line therapy was an irinotecan-containing regimen in 75% of patients of the paclitaxel arm and a taxanecontaining regimen in 60% of the irinotecan arm. Including later lines, 81% patients in the paclitaxel arm received irinotecan and 68% of patients in the irinotecan arm received paclitaxel. The more prolonged median OS in both arms of the WJOG 4007 than those of the previous studies implies that both irinotecan and paclitaxel in second- and further-line settings could potentially contribute to prolonged survival. The ongoing fourth RCT (JACCRO GC05) [20] has been comparing irinotecan plus S-1 with irinotecan alone to GC patients refractory to S-1. Since the standard regimen in adjuvant and advanced settings in Japan is respectively S-1 and S-1 plus cisplatin, this study will provide one answer to the clinically important question of whether the prolonged use of S-1 is effective even to the S-1 resistant patients whom the clinicians face.


proved QOL than those in the placebo arm. Finally, apatinib, a tyrosine-inhibitor agent targeting VEGFR with an anticipated anti-angiogenesis effect, has been now tested in a clinical trial (NCT 01512745) [15]. This study aims to determine whether apatinib can improve PFS or

Subsequently, a metaanalysis has very recently elucidated a 36% reduction in the risk of death (p<0.0001) by second-line therapy [16], suggesting that second-line therapy is effective and should be considered in some segments of GC patients refractory to first-line therapy.

Several randomized trials have been released to explore the optimal combination and doses for second-line therapy using the currently active agents or those deemed active. The agents investigated by these trials include chemotherapeutic drugs [17-20], a molecular targeting

The efficacy of chemotherapy as a second-line setting has been investigated in several RCTs. In the TCOG GI-0801 trial [17], median PFS was significantly longer (3.8 months, n=64) by biweekly irinotecan plus cisplatin than by irinotecan alone (2.8 months, n=63), but median OS did not differ between the arms (10.7 months versus 10.1 months). Notably, the proportion of patients receiving third-line therapy was the same (75%) in both groups. The results of another randomized trial (ECRIN) have been reported in the abstract form [18], in which irinotecan plus cisplatin (n=84) was compared with irinotecan alone (n=84) in patients refractory to an S-1 containing regimen. WJOG 4007 [19] is a RCT comparing weekly paclitaxel (n=108) with biweekly irinotecan (n=111) in GC patients refractory to fluoropyrimidines plus cisplatin. Although there are no statistically significant differences between weekly paclitaxel and biweekly irinotecan for median OS (9.5 months vs 8.4 months, p=0.38), median PFS (3.6 months vs 2.3 months, p=0.33), or response rate (20.9% vs 13.6%, p=0.24), the median OS of both arms are equally longer than those of the previous second-line studies (Table 1, Figure 2). Several explanations are possible for the longer median OS in this study. One explanation is the lower proportion of patients with severe peritoneal metastasis in this study (25.6%) as compared with those in the AIO [10] (45%) and Kang [11] (45%) studies. Another explanation is that the proportion of patients receiving third-line therapy in this study was substantial, being 89.8% in the paclitaxel arm and 72.1% in the irinotecan arm. Interestingly, the third-line therapy was an irinotecan-containing regimen in 75% of patients of the paclitaxel arm and a taxanecontaining regimen in 60% of the irinotecan arm. Including later lines, 81% patients in the paclitaxel arm received irinotecan and 68% of patients in the irinotecan arm received paclitaxel. The more prolonged median OS in both arms of the WJOG 4007 than those of the previous studies implies that both irinotecan and paclitaxel in second- and further-line settings could potentially contribute to prolonged survival. The ongoing fourth RCT (JACCRO GC05) [20] has been comparing irinotecan plus S-1 with irinotecan alone to GC patients refractory to S-1. Since the standard regimen in adjuvant and advanced settings in Japan is respectively S-1 and S-1 plus cisplatin, this study will provide one answer to the clinically important question of whether the prolonged use of S-1 is effective even to the S-1 resistant patients whom the

**3. Seeking the best regimen of second-line therapy**

agent [21], and their combinations [22-26].

OS compared to placebos.

106 Updates on Cancer Treatment

clinicians face.

**Table 1.** Published results of randomized controlled trials of second-line therapy versus best supportive care or placebo.

The RCT comparing a molecular targeting agent with a chemotherapeutic agent has been ongoing. HER2-positive advanced GC patients have been allocated to either trastuzumab emtansine or taxane (GATSBY, NCT01641939) [21].

A combination of molecular targeting agents and chemotherapy agents has been investigated in several RCTs. First, paclitaxel with or without lapatinib, which binds to the intracellular tyrosine kinase domains of ERBB1 and ERBB2 (HER2), was compared in HER2-positive advanced GC (TYTAN) [22]. Neither median OS nor median PFS were prolonged by lapatinib plus paclitaxel (n=132) as compared to paclitaxel alone (n=129). Second, the results of the RAINBOW trial [23,24], which compared ramucirumab plus paclitaxel with placebo plus paclitaxel, have been very recently reported in the abstract form. Sixty hundred and sixty-five GC patients, who were refractory to cisplatin and fluoropyrimidine-containing regimens, were randomized in a 1:1 ratio to receive paclitaxel plus ramucirumab or paclitaxel plus a placebo. The paclitaxel and ramucirumab arm showed a significant benefit in median OS (HR=0.807, p=0.0169) and median PFS (HR=0.635, p<0.0001). The subsequent geographical regionstratified analysis elucidated that the advantage of median PFS and median OS was more evident in Western patients than in Japanese patients (Figure 2). Such a regional difference could partly explained by a higher use of post-discontinuation treatment in Japan (75% of patients) than in Western countries (36-38% of patients), which may eventually mask any potential OS benefit of ramucirumab plus paclitaxel in Japan. Two other RCT trials [25,26] are now ongoing. Paclitaxel with or without everolimus has been compared in patients with advanced GC refractory to fluoropyrimidine containing regimens [25]. Patients will be randomized in a 1:1 ratio for a total of 240 patients per treatment arm. Nimotuzumab plus irinotecan versus irinotecan monotherapy as second-line therapy has been investigated in Figure 2

**Figure 2.** Comparisons of median OS between the previous RCTs. The percentage indicates the proportion of patients receiving further therapy in each trial. The reference numbers are expressed in brackets. \*; first-line trials, BSC; best supportive care, PBO; placebo, Cape; capecitabine, Ox; oxaliplatin, EOC; epirubicin, oxaliplatin, and capecitabine, ND; not described.

patients with ERBB1 overexpressed advanced GC [26]. This is a Japan and Korea collaborative RCT allocating patients at 1:1 ratio for a total of approximately 400 patients per arm.

The results of some trials have been published; however, at present, trials in which the primary endpoint has been met have been unfortunately very limited. The positive results hitherto obtained include a prolonged PFS by a combination of irinotecan and cisplatin after the failure of S-1 based first-line chemotherapy, and prolonged PFS and OS by ramucirumab in combi‐ nation with weekly paclitaxel. The results of other studies, especially using molecular targeting agents, are awaited.
