Global Collaboration Is Key to Progress in Gastroesophageal Cancers

Johanna C. Bendell, MD

Gastroesophageal Cancer Outcomes: East Asia Versus Western Countries

The landscape for treating patients with gastroesophageal cancers is undergoing rapid change, and international cooperation among specialists is crucial to the advancement of care, according to a panel of experts who participated in a recent OncLive Peer Exchange^® program. The panel, which included experts from the United States, the United Kingdom, and Japan, provided a global perspective on how the management of gastroesophageal cancers is developing. Gastroesophageal cancer encompasses malignancies of the stomach, esophagus, and gastroesophageal junction. Historically, gastroesophageal cancers have posed a tremendous challenge and are associated with low rates of long-term survival.¹ New and emerging treatments have the potential to improve outcomes for patients, but limited information is available to guide clinicians on how to incorporate them into care models. “This is a quickly evolving field, and we will have new drugs [or] new treatment options for our patients, and we’ll need to be smart about how to sequence them,” said panel member Manish A. Shah, MD.Johanna C. Bendell, MD, who served as moderator for the panel, pointed out that the main subtypes—gastric, esophageal, and gastroesophageal junctional carcinoma (GEJC)—are distinctly different diseases. Shah said most cases of gastroesophageal cancer are caused by helicobacter pylori (H pylori), a bacterium found in the stomach lining that affects half the world’s population. Cigarette smoking is another major risk factor.¹ Identification and treatment of H pylori and declines in smoking rates have led to reductions in the incidence of gastric cancer in developed countries, but it remains a significant problem worldwide. Conversely, the incidence of GEJC continues to climb in developed and underdeveloped countries.²

“Depending on what part of the world you’re in, your gastroesophageal cancer may have a different prognosis, behavior, and response to therapy,” Bendell said. It is widely recognized that the prevalence of gastric cancer is much higher in East Asian countries such as Japan and China than in Western countries, yet survival outcomes are typically better in the East.³

Kohei Shitara, MD, said that despite the decrease in prevalence, “[Japan] still has 50,000 new gastric cancers, at best, annually.” As a result, Japan has implemented nationwide screening programs, which Shitara said means approximately 70% of gastric cancers are diagnosed at an early stage.

Ian Chau, MD, FRCP, said nationwide screening programs would not be cost effective in Europe or the United States, where gastric cancer is relatively uncommon. As a result, most patients in Western countries present with locally advanced disease, Shah said. Chau added that they are typically also older than Japanese patients at diagnosis and thus less able to tolerate intensive therapies.

“Historically, D2 gastrectomy is a standard surgical procedure for Japanese gastric cancer, and it achieves almost a 50% disease-free survival without any type of chemotherapy,” Shitara said. Shah said the survival rate with surgery alone is 30% or less in the United States and Europe, underscoring the differences in the disease between East Asian and Western countries.

Immunotherapy Trials

“It’s a completely different ball game,” said Yelena Y. Janjigian, MD. Because of the differences, drug trials in Asian patients are routinely considered inapplicable to Western populations. That perspective may be evolving, however, after reports from clinical trials of checkpoint inhibitors showed similar response rates and survival outcomes in East Asian and Western patients.In the phase III ONO-4538-12 (ATTRACTION-2) trial, patients from Japan, Korea, and Taiwan with advanced gastric cancer or GEJC were randomly assigned to salvage therapy (third or later line) with nivolumab (Opdivo) monotherapy (n = 330) or to placebo (n = 163) until unacceptable toxicity or disease progression.4 According to an interim analysis, the nivolumab arm had a significantly higher objective response rate (ORR) than the placebo arm (11.2% vs 0%, respectively; P <.0001) and a significantly longer median progression-free survival (PFS; 1.61 vs 1.45 months, respectively; P <.0001).⁴ The median duration of overall survival (OS) was 5.32 months in the nivolumab group versus 4.14 months in the placebo group, representing a 37% reduction in the risk of death with nivolumab (HR, 0.63; 95% CI, 0.50-0.78; P <.0001).

While cautioning about the weakness of crosstrial comparisons, Shitara observed that the findings from ONO-4538-12 were similar to the findings from CheckMate 032, a phase I/II trial in Western patients with gastric cancer or GEJC who had received at least 1 prior chemotherapy regimen (n = 160).5 In CheckMate 032, participants were randomly assigned to nivolumab alone or with ipilimumab. In the nivolumab monotherapy arm (n = 59), the ORR was 12% and median OS was 6.2 months.⁵ Janjigian, who was a lead investigator for CheckMate 032, said PFS and OS in the nivolumab trials were not impressive, although a subset of patients clearly benefited from the checkpoint inhibitor.

KEYNOTE-059 was a sizable phase II trial testing the checkpoint inhibitor pembrolizumab (Keytruda). It included 3 cohorts of patients with metastatic gastric cancer or GEJC: chemotherapyresistant patients assigned to single-agent pembrolizumab, newly diagnosed patients treated with pembrolizumab plus chemotherapy, and newly diagnosed patients with PD-L1—positive tumors, who were assigned to single-agent pembrolizumab.⁶ Only 13% of patients in cohort 1 were Asian.⁷ According to updated data presented in September at the 2017 ESMO Congress, the ORR for cohort 1’s heavily pretreated patients was 12%. Chau suggested the results of KEYNOTE-059 show that nivolumab and pembrolizumab perform similarly in chemotherapy-resistant patients and in East Asian and Western populations.⁸ Therefore, it may be reasonable to extrapolate trial data for checkpoint inhibitors in East Asian patients to Western patients.⁸

On September 22, the FDA granted an accelerated approval for pembrolizumab for patients with recurrent locally advanced or metastatic gastric cancer or GEJC whose tumors express PD-L1. Patients must have received 2 or more prior systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy

Biomarkers

Bendell said although the ORR with single-agent checkpoint inhibitors in previously treated patients is only 10%, that subset responds very well. “The important part is finding out who is at the tail end of the curve,” she said.

“We don’t know how to identify these patients who are going to respond,” Shah said. The panel then discussed the importance of molecular profiling for all patients with metastatic disease. Certain biomarkers appear to influence response, including microsatellite instability (MSI), which is determined using immunohistochemistry and PD-L1 positivity.

“The MSI-high tumors clearly have benefit from single-agent therapy,” Shah said. He described the FDA’s decision in May to approve pembrolizumab “across the board for all MSI-high solid tumors” that are unresectable or metastatic and that progress after treatment as practice changing. Chau said that while the FDA’s approval of pembrolizumab for MSI-high solid tumors was exciting, data from KEYNOTE-059 suggest that only 4% of patients with gastric cancer/GEJC are MSI-positive and only half of the MSI-positive patients responded to pembrolizumab.

Janjigian agreed that MSI-high gastric cancer is rare but expressed her view that clinicians should still test for it in their metastatic patients because “it could have a significant impact on their outcome for treatment.”

Shah said the value of PD-L1 positivity in the third-line setting is also unclear. Although data suggest previously treated patients with PD-L1—positive tumors are more likely to respond to checkpoint inhibitors or to have more durable responses, he said several patients with PD-L1–negative tumors have responded and have equally durable responses.

Returning to differences between Asian and Western patients, Shitara noted that studies suggest there are no large differences in genomic or immunological profiles between the populations. He said all patients with metastatic gastric cancer should be tested for HER2 amplification and Epstein-Barr virus status in addition to biomarkers that might predict response to checkpoint inhibitors. Janjigian agreed. “In 2017, we really should plan on doing a multiplexed assay,” she said. “Generally, in these next-generation sequences— which should be considered standard in these patients—you can assess HER2 and you can assess MSI in a prospective and standardized manner.”

Adverse Effects

In KEYNOTE-059, the overall incidence of grade 3 to 5 treatment-related adverse events (TRAEs) in the previously treated cohort was 18%.⁶ In the ONO-4538-12 trial, 12% of patients in the nivolumab arm developed a TRAE ≥grade 3.⁴ CheckMate 032 reported that the most frequent grade 3/4 TRAEs associated with nivolumab use were diarrhea and elevated liver function test results.⁵ Chau cautioned that while investigators for the gastric cancer trials found the checkpoint inhibitors were well tolerated, patients receiving their third or fourth line of therapy probably did not remain in the study long. “We know immune-related side effects come a bit later...You’re not going to see those side effects kick in,” he warned. Chau also expressed concern that gastrointestinal oncologists who have not participated in clinical trials of pembrolizumab or nivolumab may not know how to manage their adverse effects.

Conclusions

Bendell agreed. “Some people can be off the treatment and come in months later with autoimmune side effects from the study,” she said. Chau said he expects checkpoint inhibitors will eventually be used earlier in gastric cancer, which will make it even more critical for oncologists to understand how to manage immune-related adverse effects.“Many new immune combinations are coming,” Bendell said. She noted that tumor vaccines may be on the horizon in gastric cancer and that data had already been reported from combinations of immunotherapy agents and antiangiogenic agents. Bendell cautioned, however, that it is important to continue to look for options beyond immunotherapy. “We have to remember that 80% to 90% of patients aren’t going to respond to immunotherapy,” she said.

The panel agreed that global collaboration offered the best opportunity to help patients. Janjigian noted that gastric cancer is 4 or 5 different molecularly driven diseases, each with a narrow population of affected patients. “These small subsets of patients are very difficult to study if we don’t come together and make sure to enroll patients in clinical trials,” she said. Janjigian also called for greater sharing of data “across the globe.”

Evidence from immunotherapy trials that gastric cancer may be more similar in Eastern Asian and Western patients than previously thought could open the door to faster progress. Chau concluded that better collaboration means “we can actually move some of these new treatments quicker and earlier to our patients’ benefit.”

References

1. Shah MA. Update on metastatic gastric and esophageal cancers. J Clin Oncol. 2015;33(16):1760-1770. doi: 10.1200/JCO.2014.60.1799.
2. Buas MF, Vaughan TL. Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat Oncol. 2013;23(1):3-9. doi: 10.1016/j.semradonc.2012.09.008.
3. Lin Y, Ueda J, Kikuchi S, et al. Comparative epidemiology of gastric cancer between Japan and China. World J Gastroenterol. 2011;17(39):4421-4428. doi: 10.3748/wjg.v17.i39.4421.
4. Kang YK, Satoh T, Ryu MH, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized, phase III trial. J Clin Oncol. 2017;35(suppl 4; abstr 2). http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.4_suppl.2.
5. Janjigian YY, Ott PA, Calvo E, et al. Nivolumab ± ipilimumab in pts with advanced (adv)/metastatic chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or gastroesophageal junction (GEJ) cancer: CheckMate 032 study. J Clin Oncol. 2017;35(suppl; abstr 4014). http://meetinglibrary.asco.org/record/153619/abstract.
6. Wainberg ZA, Jalal S, Muro K, et al. KEYNOTE-059 update: efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal (G/GEJ) cancer. Paper presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA28_PR. http://cslide.ctimeetingtech.com/library/esmo/browse/search/2bDq#2Bb5i02Fh.
7. Janjigian YY. Immune therapy in non-CRC GI cancer. Presented at: ESMO World Congress on Gastrointestinal Cancer 2017; June 28—July 1, 2017; Barcelona, Spain. http://cslide.ctimeetingtech.com/library/esmo/browse/search/2sEG#2HMa02z.
8. Pembrolizumab: promising response rate in pretreated metastatic gastric cancer [news release]. Madrid, Spain: European Society for Medical Oncology; September 8, 2017. www.esmo.org/Conferences/ESMO-2017-Congress/Press-Media/Press-Releases/Keynote-059-Gastric-Wainberg-Chau. Accessed September 18, 2017.