Key Trials Show Utility of Agents Across Therapeutic Classes in Gastric/GEJ Cancer

Hope E. Uronis, MD, MHS

Although there has been an increase in the incidence of esophageal and gastroesophageal junction (GEJ) adenocarcinoma, physicians have seen an improvement in overall survival (OS) over the last 40 years, due to strides made with VEGF inhibitors, TAS-102 (trifluridine/tipiracil; Lonsurf), and checkpoint inhibition.

“It’s pretty exciting—after a long time of not much happening in gastric and esophageal cancer, we’re moving somewhere,” said Hope E. Uronis, MD, MHS, in a presentation during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies.

VEGF Inhibition

During her lecture, Uronis shed light on these therapeutic classes and the trials that have demonstrated their utility and refined their applicability across settings, subpopulations, and histologies of gastric/GEJ cancer.Bevacizumab (Avastin) was the first VEGF inhibitor to be tested in combination with chemotherapy as frontline therapy in patients with advanced gastric cancer in the phase III AVAGAST trial. However, the combination of bevacizumab, fluoropyrimidine, and cisplatin failed to demonstrate a statistically significant benefit in OS over placebo, said Uronis.

Ramucirumab (Cyramza) is perhaps the most commonly utilized VEGF inhibitor in gastric/GEJ cancer, explained Uronis. The agent operates as a fully human IgG1 antibody that binds to the extracellular domain of VEGF receptor 2, thereby blocking binding of VEGF-A, VEGF-C, and VEGF-D.

The VEGF inhibitor was tested in combination with chemotherapy as frontline therapy in both the phase III RAINFALL¹ and phase II RAINSTORM² trials. Notably, the population was predominantly Western in the RAINFALL trial, said Uronis. However, regardless of the chemotherapy backbone, both trials were negative.

In the United States, ramucirumab was also tested in combination with FOLFOX in a phase II trial in patients with metastatic esophageal, GEJ, and gastric adenocarcinoma, and again, resulted in negative findings, said Uronis.

“The question of first-line VEGF therapy is answered, and it doesn’t add anything,” said Uronis. “It doesn’t make sense biologically.”

In terms of second-line VEGF inhibition, investigators compared the use of ramucirumab with placebo in the phase III REGARD trial.³ In the study, patients with metastatic gastric/GEJ adenocarcinoma were randomized to receive either ramucirumab or placebo. The trial enrolled a predominantly Western population. The trial met the study endpoint of OS, with a hazard ratio of 0.776. Ramucirumab resulted in a 5.2-month OS compared with 3.8 months in the placebo arm. Progression-free survival (PFS) and response rates were also superior with ramucirumab, ultimately leading to its FDA approval in 2014 for second-line use following prior exposure to a fluoropyrimidine or platinum, said Uronis.

Ramucirumab was also paired with paclitaxel in the phase III RAINBOW trial.⁴ Patients with advanced gastric/GEJ cancer were randomized to receive either 80 mg/m² of paclitaxel on days 1, 8, and 15 and ramucirumab once every 2 weeks, or paclitaxel and placebo. The median OS indicated a survival benefit of approximately 2 months with ramucirumab, said Uronis (HR, 0.807; 95% CI, 0.678-0.962; P =.0169). Approximately 70% of the population was Western, noted Uronis, cautioning against the study’s generalizability across all patients with gastric/GEJ cancer.

TAS-102

“The bottom line is, there are no candidate biomarkers identified, although there is an ongoing analysis with the ramucirumab studies,” explained Uronis. “Those remain to be seen.”In the refractory setting, patients with ≥2 prior lines of therapy and an ECOG performance status of 0 or 1 were randomized 2:1 to receive either 35 mg/m² of twice daily TAS-102 on days 1 to 5 and 8 to 12 of every 28-day cycle or placebo in the phase III TAGS trial.⁵ Patients were stratified by prior gastrectomy, representing approximately 44% of patients in both arms, said Uronis. Patients were further stratified by ECOG performance status, region of the world, and prior exposure to ramucirumab. Gastric cancer represented the predominant primary site, at 71% in both arms, said Uronis.

“This was a positive study with an OS of 5.7 months versus 3.6 months for those patients who received TAS-102 [and placebo, respectively],” said Uronis. “This is impressive in a third-line refractory population.”

PFS served as a secondary endpoint of the trial, although no difference was reported between arms. Moreover, prior gastrectomy did not seem to impact the observed benefit in OS, added Uronis. Toxicities were consistent with expectations, although approximately one-fifth of patients experienced grade 3 anemia and neutropenia.

Checkpoint Inhibition

Based on these results, the FDA approved TAS-102 on February 25, 2019, for adult patients with metastatic gastric or GEJ adenocarcinoma previously treated with ≥2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and, if appropriate, HER2/neu-targeted therapy.Pembrolizumab (Keytruda) is the only checkpoint inhibitor with indications in patients with recurrent locally advanced or metastatic gastric/GEJ cancer whose tumors express PD-L1 with a combined positive score (CPS) ≥1, said Uronis. Additionally, patients have to have progression on or after ≥2 prior lines of therapy, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.

However, two second-line trials have compared pembrolizumab with chemotherapy and had mixed findings. In the KEYNOTE-061 trial,⁶ patients with metastatic gastric/GEJ cancer were randomized 1:1 to receive either 200 mg of pembrolizumab once every 3 weeks or 80 mg/m² of paclitaxel on days 1, 8, and 15 of every 4-week cycle. Among patients, 489 were unselected, after which an additional 104 patients were enrolled with a CPS score ≥1. Regarding patient demographics, the predominant region that was represented in the trial was Western, although Asian patients comprised approximately one-third of the study population. Patients were in their early-60s, and similar to previous trials, the predominant primary site in the experimental and control arms was gastric, at 68% and 63%, respectively.

Notably, more than half of patients had a time to progression on frontline therapy of <6 months. Among patients with a CPS score ≥1, the median OS was not statistically significant, although pembrolizumab monotherapy resulted in a median OS of 9.1 months versus 8.3 months with paclitaxel (HR, 0.82; 95% CI; 0.66-1.03; P =.0421).

“In looking at the curves, it makes me wonder if median survival is a really good way to look at this, because the responses are delayed in patients who get immunotherapy and in those who it works in,” said Uronis.

Moreover, the comparator arm was not the doublet paclitaxel/ramucirumab physicians tend to use in practice—–another aspect of the trial that may dissuade physicians from considering these results too heavily, explained Uronis.

However, a posthoc analysis in patients with a CPS score ≥10 revealed a median OS of 10.4 months and 8.0 months in those treated with pembrolizumab and paclitaxel, respectively (HR, 0.64; 95% CI, 0.41-1.02).

The second trial to examine pembrolizumab as a single agent was the KEYNOTE-181 trial,⁷ in which patients with metastatic Siewert Type 1 GEJ adenocarcinoma or squamous cell esophageal cancer were randomized to receive 200 mg of pembrolizumab once every 2 weeks for up to 35 cycles or physician’s choice chemotherapy, consisting of paclitaxel, docetaxel, or irinotecan.

The intention-to-treat population showed no benefit in OS with the PD-1 inhibitor. However, in patients with squamous and adenocarcinoma and a CPS score ≥10, the use of pembrolizumab resulted in a 31% reduction in the risk of progression or death, with 26% of patients still alive at 18 months. The rates of median OS were 9.3 months and 6.7 months in the pembrolizumab and chemotherapy arms, respectively.

Pembrolizumab also demonstrated a nonstatistically significant benefit in the squamous cell cohort, with an HR of 0.78 and a median OS of 8.2 months versus 7.1 months with chemotherapy (P = .0095). Notably, the subgroup analysis of patients with a CPS ≥10 seemed to be driven by those with squamous cell histology, said Uronis.

“This, again, shows that you need to pay attention to the CPS score and think carefully when you’re treating patients,” she concluded.

In terms of investigational trials, Uronis highlighted several combinatorial approaches including VEGF-directed therapy in combination with trastuzumab (Herceptin) or immunotherapy, as well as chemotherapy and immunotherapy—–all of which are enrolling at Duke Cancer Institute.

References

1. Fuchs CS, Shitara K, Di Bartolomeo M, et al. RAINFALL: a randomized, 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(suppl 4; abstr 5). doi: 10.1200/JCO.2018.36.4_suppl.5.
2. Muro K, Yoshikawa T, Shitara K, et al. Randomized, double-blind, phase 2 study of S-1 plus oxaliplatin (SOX) with or without ramucirumab (RAM) as first-line therapy followed by paclitaxel plus RAM as second-line therapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma (AGC). J Clin Oncol. 2018;36(suppl 15; abstr. 4036). doi: 10.1200/JCO.2018.36.15_suppl.4036.
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5. Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase III, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Ann Oncol. 2018;29(suppl 8; abstr LBA25). doi: 10.1093/annonc/mdy424.027.
6. Shitara K, Özgü&#287;rolu M, Bang YJ, et al. KEYNOTE-061: phase 3 study of pembrolizumab vs paclitaxel for previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer. In: Proceedings from the 2018 World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. Abstract LBA-005.
7. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase III KEYNOTE-181 study. J Clin Oncol. 2019;37(suppl 4; abstr 2). doi: 10.1200/JCO.2019.37.4_suppl.2.