Chao Discusses Impact of RAINBOW, TAGS, and KEYNOTE Trials in Gastric/GEJ Cancer

The RAINBOW and TAGS trials have demonstrated strong evidence to support the use of ramucirumab and TAS-102 in patients with advanced gastric or gastroesophageal cancer who have progressed on first-line therapy.

Joseph Chao, MD

THE RAINBOW AND TAGS trials have demonstrated strong evidence to support the use of ramucirumab (Cyramza) and TAS-102 (trifluridine/tipiracil; Lonsurf) in patients with advanced gastric or gastroesophageal (GEJ) cancer who have progressed on first-line therapy. However, additional data suggest that with proper patient selection, immunotherapy will become equally as valuable to patients with progressive disease.

In a presentation during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Cancers, Joseph Chao, MD, an assistant clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, discussed the impact of these trials on the field and highlighted other recent updates in the space.

One of the more provocative trials to come from the 2019 Gastrointestinal Cancers Symposium was the phase III KEYNOTE- 181 trial, which examined the use of second-line pembrolizumab (Keytruda) versus investigator’s choice of chemotherapy in patients with advanced/metastatic esophageal cancer.

Patients had to have advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, Siewert type 1 GEJ adenocarcinoma, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1, to be eligible for participation. A total of 628 patients were randomized 1:1 to receive either 200 mg of pembrolizumab monotherapy (n = 314) every 3 weeks for up to 35 cycles, or investigator’s choice of chemotherapy (n = 314), which consisted of 80 to 100 mg/m2 of paclitaxel on days 1, 8, and 15 of 4-week cycles, or 75 mg/m2 of docetaxel every 3 weeks, or 180 mg/m2 of irinotecan every 2 weeks.

The primary endpoint of the study was overall survival (OS) in 3 subgroups: intent-to-treat (ITT) population in addition to those with a PD-L1 combined positive score (CPS) ≥10, and those with squamous cell histology. In the PD-L1 CPS ≥10 cohort, the median OS was 9.3 months (range, 6.6-12.5) in the pembrolizumab arm and 6.7 months (range, 5.1-8.2) in the chemotherapy arm (HR, 0.69; 95% CI, 0.52-0.93; P = .0074).1 These patients also experienced the greatest benefit in progression-free survival (PFS) and objective response rate (ORR) with pembrolizumab monotherapy compared with other subgroups, said Chao.

The median OS in the squamous cell subset was 8.2 months (range, 6.7-10.3) in the pembrolizumab arm and 7.1 months (range, 6.1-8.2) in the chemotherapy arm (HR, 0.78; 95% CI, 0.63-0.96; P = .0095); this failed to reach statistical significance per a pre-specified statistical plan, explained Chao. Pembrolizumab also failed to demonstrate significance in the ITT population with a median OS of 7.1 months observed in both arms (HR, 0.89; 95% CI, 0.75-1.05; P = .0560).

“[Results suggest] that without biomarker selection, there’s dilution in terms of the response rates with pembrolizumab,” added Chao. The rate of grade ≥3 toxicities was lower in the immunotherapy arm (18.2%) than in the chemotherapy arm (40.9%); however, 23.2% of patients experienced an immune-related adverse event.

“It’s a practice-changing regimen for patients with advanced or metastatic esophageal squamous cell carcinoma with PD-L1 expression ≥10,” said Chao. In terms of advanced gastric/GEJ adenocarcinoma, ramucirumab is typically reserved for use in second-line therapy based on positive data from the phase III RAINBOW trial, noted Chao. Data presented at the 2014 Gastrointestinal Cancers Symposium demonstrated the superiority of the combination of ramucirumab and paclitaxel in OS and PFS compared with paclitaxel alone, resulting in the FDA’s decision to approve the combination later that year.2

Given the potential of VEGF inhibition in the second-line setting, ramucirumab in combination with cisplatin and capecitabine was also investigated in treatment-naïve patients, explained Chao.3

The median PFS in the ITT population was 5.85 months and 5.55 months in the experimental arm and control arms, respectively (HR, 0.75; 95% CI, 0.63-0.91; P = .0024). The median OS was 11.17 months with the ramucirumab combination versus 10.74 months with placebo (HR, 0.96; 95% CI, 0.80-1.16; P = .68), which was not statistically significant.

Because the third-line setting of metastatic gastric/GEJ cancer remains undefined, said Chao, investigators launched the phase III TAGS registration trial. In this trial, patients who had received ≥2 prior lines of therapy were randomized 2:1 to receive either 35 mg/m2 of TAS-102 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle plus best supportive care (n = 337), or placebo plus best supportive care (n = 170).4 The majority of participants had gastric cancer (n = 142) and had received platinum chemotherapy or fluoropyrimidine, although one-third of patients had been exposed to ramucirumab, noted Chao.

The median OS was 5.7 months and 3.6 months with TAS-102 and placebo, respectively (HR, 0.69; 95% CI, 0.56-0.85; P = .0006). Further, the median PFS was 2.0 months with TAS-102 and 1.8 months with placebo (HR, 0.57; 95% CI, 0.47-0.70; P <.0001).

Grade ≥3 treatment-related toxicities were higher in the TAS-102 arm at 53% compared with the placebo arm at 13%. “Because of the experience in metastatic colorectal cancer (mCRC), many treating physicians were familiar with managing toxicities, specifically neutropenia,” said Chao. “It certainly appears to be a well-tolerated agent in line with what our experience is in mCRC.”

Although ramucirumab retains its role in the second-line setting, immune checkpoint inhibitors are also of interest in this setting, noted Chao. Specifically, single-agent pembrolizumab is being examined in the phase III KEYNOTE-061 trial in patients with advanced gastric/GEJ cancer, he said.

Patients in the trial were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for 35 cycles or until progressive disease or intolerance or 80 mg/mg2 of paclitaxel on days 1, 8, and 15 of 4-week cycles. Results revealed a median OS of 9.1 months and 8.3 months with pembrolizumab monotherapy and chemotherapy, respectively, in patients with PD-L1 ≥1% (HR, 0.82; 95% CI, 0.66-1.03; P = .04205).

As expected, the OS benefit was heightened in patients with PD-L1 expression ≥10 with a median OS of 10.4 months in the immunotherapy arm compared with 8.0 months in the chemotherapy arm (HR, 0.64; 95% CI, 0.41-1.02).

“In terms of PFS, over half of patients demonstrate disease progression with pembrolizumab at the 2-month mark versus standard of care chemotherapy with paclitaxel, even with PD-L1 expression ≥1,” emphasized Chao. “Given our knowledge that paclitaxel and ramucirumab result in an 80% disease control rate, I would argue that you have to exercise caution in using pembrolizumab in the second-line setting.”

“There are many new directions we can move forward in to continue to improve use of immune checkpoint inhibitors in this disease setting,” concluded Chao.


  1. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as sec- ond-line therapy for advanced esophageal cancer: phase III KEYNOTE-181 study. J Clin Oncol. 2019;37(4 suppl; abstr 2). doi: 10.1200/JCO.2019.37.4_suppl.2.
  2. WilkeH,MuroK,VanCutsemE,etal;RAINBOWStudyGroup.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi: 10.1016/S1470-2045(14)70420-6.
  3. FuchsCS,ShitaraK,DiBartolomeoM,etal.RAINFALL:arandomized,double-blind, placebo-controlled phase III study of cisplatin (Cis) plus capecitabine (Cape) or 5FU with or without ramucirumab (RAM) as first-line therapy in patients with metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma. J Clin Oncol. 2018;36 (4 suppl; abstr 5). doi: 10.1200/JCO.2018.36.4_suppl.5.
  4. ArkenauH-T,TaberneroJ,ShitaraK,etal.TAGS:aphase3,randomised,double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory met- astatic gastric cancer. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA25. ESMO-2018-Congress/TAGS-a-phase-3-randomised-double-blind-study-of-trifluridine- tipiracil-TAS-102-versus-placebo-in-patients-with-refractory-metastatic-gastric-cancer.
  5. Fuchs CS, Ozguroglu M, Bang Y-J, et al. Pembrolizumab (pembro) vs paclitaxel (PTX) for previously treated advanced gastric or gastroesophageal junction (G/ GEJ) cancer: phase 3 KEYNOTE-061 trial. J Clin Oncol. 2018;36(15 suppl; abstr 4062). doi: 10.1200/JCO.2018.36.15_suppl.4062.