Experts Dissect Key Findings for Progressive Gastric and GEJ Cancers

OncologyLive, Vol. 20/No. 18, Volume 29, Issue 18

Although chemotherapy combinations remain standard first-line therapy for advanced or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) cancer, strategies for progressive disease have shifted to include antiangiogenic agents and immunotherapy.

Johanna C. Bendell, MD

Although chemotherapy combinations remain standard first-line therapy for advanced or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) cancer, strategies for progressive disease have shifted to include antiangiogenic agents and immunotherapy.

Today, a preferred second-line regimen consists of the antiangiogenic agent ramucirumab (Cyramza) in combination with paclitaxel, and the immune checkpoint inhibitors (ICIs) pembrolizumab (Keytruda) and nivolumab (Opdivo) are increasingly used as third-line options. The limited success of some ICIs targeting patients with advanced gastric/ GEJ cancer and uncertainty surrounding PD-L1 expression as a biomarker has prompted exploration into whether these agents might act synergistically with other immunotherapies, including other ICIs, as well as with cytotoxic agents, angiogenesis inhibitors, and novel or traditional targeted antibodies.1

In an OncLive Peer Exchange® panel discussion, investigators involved in clinical trials of new or emerging approaches for progressive gastric/GEJ cancers discussed how recent findings—both positive and negative— have revealed the heterogeneity of these cancers. “Just like with all the other tumor types we have, we’re starting to divide gastric cancer into very specific populations that might have different treatment options,” said moderator Johanna C. Bendell, MD.

“Chemotherapy still plays a significant role in the treatment of advanced gastroesophageal cancers,” Bendell said. “However, progress with targeted therapies has extended survival and is expanding the options for patients.”

Angiogenesis in Gastric/GEJ Cancers

In the decades since Judah Folkman, MD, and others established that tumor cells depend on angiogenesis for growth and survival, several antiangiogenic agents have come to market for solid tumors.2 The monoclonal antibody bevacizumab (Avastin) was the first FDA-approved angiogenesis inhibitor. Because of gastric cancer’s high angiogenic potential and the importance of VEGF-mediated pathways in its pathogenesis and progression,2 investigators appeared surprised when the phase III AVAGAST trial found that adding bevacizumab to standard chemotherapy did not improve overall survival (OS) in patients with previously untreated gastric/GEJ cancer.2-4

However, the phase III REGARD and RAINBOW trials of ramucirumab in patients with previously treated gastric/GEJ cancers that progressed after chemotherapy observed significant survival benefits compared with placebo5 or placebo plus paclitaxel.6 Manish A. Shah, MD, an AVAGAST investigator, pointed out that “ramucirumab is a VEGFR2 inhibitor; it’s different from bevacizumab, which is a VEGF-A inhibitor.”

Although ramucirumab showed single-agent activity in the REGARD trial,5 David H. Ilson, MD, PhD, said its activity when combined with paclitaxel in the RAINBOW trial was “more clinically relevant.” In the combination arm, the objective response rate (ORR) was higher and median OS was 2 months longer than in the placebo—paclitaxel arm.6

“Median OS was extended past 9 months, which was unprecedented for second-line treatment, and there was improvement in progression-free survival [PFS], without any detriment in quality of life,” Ilson said.6,7 Shah said the recent randomized phase III RAINFALL trial in untreated gastric/GEJ cancer observed no improvement in OS or PFS when ramucirumab was combined with chemotherapy, and ramucirumab is not a recommended first-line option.8

For patients with advanced HER2-positive disease, trastuzumab (Herceptin) in combination with chemotherapy is the first-line choice, panelists noted. Ramucirumab is FDA approved as a single agent or in combination with paclitaxel for patients who have progressed on chemotherapy.

A subgroup analysis of HER2-positive patients in the RAINBOW trial associated ramucirumab plus paclitaxel with a higher ORR and longer median OS and PFS than paclitaxel alone but was underpowered to assess significance.9 Among ramucirumab-treated patients, median OS was longer for HER2-positive individuals than for the overall population, which Shah said supports using ramucirumab plus paclitaxel as second-line therapy for all patients, regardless of HER2 status. He advised against using “the other second-line drugs that are available—a single-agent taxane or irinotecan.”

Bendell asked Kohei Shitara, MD, whether he shared concerns raised by AVAGAST data that Asian patients might not benefit from angiogenic inhibitors. Shitara was lead author of a subgroup analysis from the RAINBOW trial that he said observed “doubling of response rate and PFS even in the Japanese patient population.”10 He attributed the lack of improvement in OS with ramucirumab to the control arm’s unusually prolonged median survival.

Other subgroup analyses from the REGARD and RAINBOW trials support the efficacy of ramucirumab in Asian populations.11 Shitara, whose practice is in Japan, said oncologists there “use paclitaxel and ramucirumab as standard treatment; it is recommended in the Japanese guidelines.” He sometimes pairs ramucirumab with nab-paclitaxel (Abraxane) to reduce the risk of infusion-related reaction. Shitara said a phase II trial of the combination reported “more than a 50% response rate in the second-line setting.”12

Ilson praised ramucirumab’s tolerability and said it does not appear to increase the risks of bleeding and perforation like bevacizumab, but he expressed concern about neuropathy when using ramucirumab with paclitaxel, especially in patients previously treated with FOLFOX, which is composed of fluorouracil, leucovorin, and oxaliplatin.

He said he occasionally uses single-agent ramucirumab as maintenance therapy in patients who are “still responding to ramucirumab— paclitaxel and have neuropathy.” Shah agreed that continuing ramucirumab while pausing taxane therapy might help with neuropathy, a condition he frequently treats with duloxetine (Cymbalta) or an alpha-lipoic acid supplement.

Regorafenib (Stivarga) and apatinib are other antiangiogenic compounds evaluated for chemorefractory advanced gastric cancer. Regorafenib is a multikinase inhibitor whose angiogenic targets include VEGFR1, VEGFR2, and TIE2.13 Ilson said phase II data suggested regorafenib might have disease-stabilizing effects but that it produced few responses.13 He said Chinese trials of the VEGFR2 inhibitor apatinib established its superiority over standard chemotherapy or placebo14 and that it is “approved in China as a late-line treatment option.”

Immune Checkpoint Inhibition

The panel reviewed data from several clinical trials of ICIs in gastric/GEJ cancer, including trials that led to the approval of the PD-1 inhibitors pembrolizumab in the United States and nivolumab in Japan as third-line or later options for advanced or metastatic gastric or esophageal tumors.

The phase III ATTRACTION-2 trial randomly assigned 493 heavily pretreated Asian patients to nivolumab or placebo every 2 weeks or until disease progression or intolerance. Shitara said, “Nivolumab clearly showed a survival benefit. The hazard ratio was 0.63, and this resulted in the Japanese approval of nivolumab.”15 He said a biomarker analysis showed a survival benefit with nivolumab regardless of PD-L1 expression, so it was approved without restrictions.

“In contrast, pembrolizumab is approved by the FDA for patients with a combined positive score (CPS) of 1 or more based on KEYNOTE-059,” Shitara said. KEYNOTE-059 was a phase II trial of pembrolizumab monotherapy in patients with progression after at least 2 lines of therapy.16 Preliminary data showed a significantly higher ORR and duration of response in PD-L1—positive patients than in those who were PD-L1 negative.16 Longterm data presented at the 2019 American Society of Clinical Oncology (2019 ASCO) annual meeting confirmed pembrolizumab’s enhanced efficacy in PD-L1—positive disease.17

Shitara was an investigator for KEYNOTE-061, a phase III study that compared pembrolizumab versus paclitaxel as second-line therapy in patients with advanced gastric/GEJ cancer.18 He said KEYNOTE-061 failed to meet its primary endpoint of improved OS in pembrolizumab- treated patients with a CPS ≥1,18 which was “very disappointing,” but that post hoc analyses observed greater efficacy with pembrolizumab in subsets of patients with a CPS ≥10, good performance status, a high PD-L1 score, and microsatellite instability (MSI)—high tumors.18 “This subgroup analysis may support the use of pembrolizumab in MSI-high tumors even in the second-line setting,” Shitara said.

Bendell questioned whether KEYNOTE-061 used the right comparator. “They should have been using paclitaxel plus ramucirumab,” she said. Shah pointed out that pembrolizumab is not approved as second-line therapy in the United States except for patients with mismatch repair—deficient or MSI-high disease. “That’s not unique to gastric cancer but [applies to] all solid tumors,” he said. “In the first line…should we combine immunotherapy with chemotherapy? The answer is a resounding no—there’s no evidence to say that’s effective,” Shah said.

Although investigators for the KEYNOTE-062 trial observed no survival benefit with a first-line regimen of pembrolizumab plus chemotherapy in PD-L1—positive patients, even in those with a CPS ≥10, Shah said data indicated pembrolizumab monotherapy was noninferior to chemotherapy alone.19 He said he would not use pembrolizumab alone as frontline therapy for patients with advanced gastric cancer, who tend to be very ill, because nonresponders may be unable to receive subsequent treatment.

“I have a bit of an issue with this noninferiority claim of pembrolizumab monotherapy,” Ilson said. “If you look at the PFS, 70% to 80% of patients get a few doses of pembrolizumab, fail it, and go on and get chemotherapy. Arguably, you’re comparing chemotherapy with chemotherapy,” he said. The panel agreed that if pembrolizumab received a first-line indication, its use should be limited to patients with MSI-high tumors who are asymptomatic and have a high CPS.

Ilsen said efforts to combine PD-1 and CTLA-4 inhibitors have not met with the same success in gastric cancer as they have in melanoma. In the phase II CheckMate 032 study, the combination of nivolumab plus the CTLA-4 inhibitor ipilimumab (Yervoy) failed to improve OS or PFS compared with nivolumab alone, and it significantly increased toxicity.20

“I think at the current time, the combination of CTLA-4 and PD-1 [inhibitors] is on the back burner,” he said. Ilsen added that the novel CTLA-4 inhibitor tremelimumab is being investigated in gastric cancer and could prove to be a better partner for nivolumab. Shitara said other immunotherapy mechanisms are also being studied, including adoptive cell therapy, oncolytic virotherapy, CD4-positive T-cell depletion, and HSP90 inhibition.

Novel Agents and Combinations

Table. Select Clinical Trials Testing Immunotherapy Combinations in Gastric or GEJ Cancer1 (Click to Enlarge)

In a review of current and emerging strategies for esophageal and gastric cancers, de Mello and colleagues noted several major clinical trials that are testing novel combinations of ICIs and targeted therapies (Table).1 One approach being investigated combines antiangiogenic agents with immunotherapy.

At 2019 ASCO, Shitara presented data from a phase I trial that evaluated the combination of regorafenib and nivolumab in patients with advanced gastric or colorectal cancer.21 He said 44% of the 25 patients with gastric cancer responded to the regimen. The investigators hypothesized that using regorafenib to reduce the regulatory T-cell population might decrease resistance to PD-1 inhibition.21 “The biopsy before and after treatment showed a clear reaction of regulatory T cells,” he said.

Shah also was an investigator for the phase III BRIGHTER trial, which evaluated napabucasin, a stemness inhibitor, plus paclitaxel as second-line treatment for gastric/GEJ cancer.22 “Unfortunately, that was a negative study,” he said. “We also did a phase II study of [napabucasin] with immunotherapy. We haven’t seen much effect,” he said.

Another study to which Shah contributed assessed the efficacy of andecaliximab, a novel inhibitor of matrix metalloproteinase 9 in the tumor microenvironment, added to first-line chemotherapy for patients with gastric/GEJ cancer.23 He said the phase III study’s findings were negative, as were results of a phase II study that added andecaliximab to nivolumab for previously treated patients.24 Despite the negative results, Shah said, “We’re assessing a lot of pharmacodynamic markers to see how we can understand the immune microenvironment.”

The panel discussed data for trifluridine/ tipiracil (Lonsurf), which US and Japanese regulatory agencies approved in 2019 for treatment of gastric/GEJ cancer in the third line and beyond.25 “We conducted the TAGS study as a global trial, which compared trifluridine/tipiracil with placebo in patients who were refractory to 2 or more previous lines of chemotherapy,” Shitara said. Median OS was 5.7 months in the trifluridine/tipiracil arm versus 3.6 months in the placebo arm (HR, 0.69), which reflected significant improvement.26 Ilson expressed the view that trifluridine/tipiracil should be the new standard third-line treatment for patients with PD-L1—negative disease.

Bendell asked the group whether PARP inhibitors were being considered for gastric cancer and noted that “a plenary session looking at the use of PARP inhibitors in patients with BRCA mutations and pancreas cancer was big news at ASCO.” Ilson described results of a phase III trial that combined olaparib (Lynparza) with paclitaxel for second-line therapy of advanced gastric cancer that he said were disappointing and showed no clear survival benefit.27 He said ongoing trials were evaluating olaparib in combination with ICIs and tyrosine kinase inhibitors.

“A whole host of other targets and approaches are in development for later-line therapy,” Ilson said. Some of the novel agents mentioned included drugs targeting FGFR3 and claudin 18.2. Shah stressed the need for a global approach to drug development due to the heterogeneity of gastric cancer in different populations.

“In the last 10 years, 10,000 patients have actually been enrolled on clinical trials in gastric cancer,” Shah said. “There are new drugs, and I think with the combination of immunotherapy and targeted agents, we’re going to redefine how we treat this disease,” he concluded.

Shah emphasized that because ICIs have only modest activity in gastric/GEJ cancer, with a typical response rate of 10% to 15%, investigators are “doing a lot of work…to try to combine drugs to improve the efficacy of the immunotherapy.” Ilson said there is a need for combinations that can make a cold immune environment hot and thus more susceptible to immunotherapy.


  1. de Mello RA, Lordick F, Muro K, Janjigian YY. Current and future aspects of immunotherapy for esophageal and gastric malignancies. Am Soc Clin Oncol Educ Book. 2019;39:237-247. doi: 10.1200/EDBK_236699.
  2. Nienhüser H, Schmidt T. Angiogenesis and anti-angiogenic therapy in gastric cancer. Int J Mol Sci. 2018;19(1):e43. doi: 10.3390/ijms19010043.
  3. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29(30):3968-3976. doi: 10.1200/jco.2011.36.2236.
  4. Hironaka S. Anti-angiogenic therapies for gastric cancer. Asia Pac J Clin Oncol. 2019;15(4):208-217. doi: 10.1111/ajco.13174.
  5. Fuchs CS, Tomasek J, Yong CJ, et al; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39. doi: 10.1016/S0140-6736(13)61719-5.
  6. Wilke H, Muro K, Van Cutsem E, et al; RAINBOW Study Group. 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.
  7. Al-Batran SE, Van Cutsem E, Oh SC, et al. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016;27(4):673-679. doi: 10.1093/annonc/mdv625.
  8. Fuchs CS, Shitara K, Di Bartolomeo M, et al; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2019;20(5):e242. doi: 10.1016/S1470-2045(19)30244-X]. Lancet Oncol. 2019;20(3):420-435. doi: 10.1016/S1470-2045(18)30791-5.
  9. De Vita F, Borg C, Farina G, et al. Ramucirumab and paclitaxel in patients with gastric cancer and prior trastuzumab: subgroup analysis from RAINBOW study. Future Oncol. 2019;15(23):2723-2731. doi: 10.2217/fon-2019-0243.
  10. Shitara K, Muro K, Shimada Y, et al. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. Gastric Cancer. 2016;19(3):927-938. doi: 10.1007/s10120-015-0559-z.
  11. Yen C-J, Bai L-Y, Cheng R, et al. Ramucirumab in patients with advanced gastric and gastroesophageal junction cancer: learnings from East Asian data. J Cancer Res Pract. 2018;5(2):43-46. doi: 10.1016/j.jcrpr.2018.03.001.
  12. Bando H, Shimodaira H, Fujitani K, et al. A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. Eur J Cancer. 2018;91:86-91. doi: 10.1016/j.ejca.2017.11.032.
  13. Pavlakis N, Sjoquist KM, Martin AJ, et al. Regorafenib for the treatment of advanced gastric cancer (INTEGRATE): a multinational placebo-controlled phase II trial. J Clin Oncol. 2016;34(23):2728-2735. doi: 10.1200/JCO.2015.65.1901.
  14. Chen J, Wang J. Efficacy and safety assessment of apatinib in patients with advanced gastric cancer: a meta-analysis. Onco Targets Ther. 2018;11:4149-4158. doi: 10.2147/OTT.S157466.
  15. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461-2471. doi: 10.1016/S0140-6736(17)31827-5.
  16. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. doi: 10.1001/jamaoncol.2018.0013.
  17. Wainberg ZA, Yoon HH, Catenacci DVT, et al. Efficacy and safety of pembrolizumab (pembro) alone or in combination with chemotherapy (chemo) in patients (pts) with advanced gastric or gastroesophageal (G/GEJ) cancer: long-term follow up from KEYNOTE-059. J Clin Oncol. 2019;37(suppl 15; abstr 4009). doi: 10.1200/JCO.2019.37.15_suppl.4009.
  18. Shitara K, Özgüroğlu M, Bang Y-J, et al; KEYNOTE-061 investigators. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123-133. doi: 10.1016/S0140-6736(18)31257-1.
  19. Tabernero J, Cutsem EV, Bang Y-J, et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study. J Clin Oncol. 2019;37(suppl 18; abstr LBA4007). doi: 10.1200/JCO.2019.37.18_suppl.LBA4007.
  20. Janjigian YY, Bendell J, Calvo E, et al. CheckMate-032 Study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J Clin Oncol. 2018;36(28):2836-2844. doi: 10.1200/JCO.2017.76.6212.
  21. Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): an open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603). J Clin Oncol. 2019;37(suppl 15; abstr 2522). doi: 10.1200/JCO.2019.37.15_suppl.2522.
  22. Shah MA, Shitara K, Lordick F, et al. The BRIGHTER trial: a phase 3 randomized double-blind study of napabucasin (NAPA) plus paclitaxel (PTX) versus placebo (PBO) plus PTX in patients (pts) with pretreated advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2018;36(suppl 15; abstr 4010). doi: 10.1200/JCO.2018.36.15_suppl.4010.
  23. Shah MA, Yañez Ruiz EP, Bodoky G, et al. A phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of andecaliximab combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma (GAMMA-1). J Clin Oncol. 2019;37(suppl 1; abstr 4). doi: 10.1200/JCO.2019.37.4_suppl.4.
  24. Shah MA, Metges J-P, Cunningham D, et al. A phase II, open-label, randomized study to evaluate the efficacy and safety of andecaliximab combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2019;37(suppl 4; abstr 75). doi: 10.1200/JCO.2019.37.4_suppl.75.
  25. Lonsurf [prescribing information]. Princeton, NJ: Taiho Oncology, Inc., 2019. Accessed September 4, 2019.
  26. Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2018;19(12):e668. doi: 10.1016/S1470-2045(18)30843-X]. Lancet Oncol. 2018;19(11):1437-1448. doi: 10.1016/S1470-2045(18)30739-3.
  27. Bang YJ, Xu RH, Chin K, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1637-1651. doi: 10.1016/S1470-2045(17)30682-4.