Advances in the treatment of gastric cancer: 2020–2021

Abstract

Purpose of review

To review studies from 2020 to 2021 in esophagogastric cancer.

Recent findings

After up front D2 gastrectomy for lymph node-positive gastric cancer, 6 months of adjuvant chemotherapy with S-1 and oxaliplatin achieved superior disease-free survival (DFS) compared with 1 year of S-1. The addition of adjuvant radiotherapy, however, added no benefit. After chemoradiotherapy and surgery in esophageal and gastroesophageal junction cancer, in patients with residual disease found at surgery, 1 year of adjuvant nivolumab substantially improved DFS compared with observation alone, leading to regulatory approval for adjuvant nivolumab. In metastatic esophagogastric cancer, the addition of either pembrolizumab or nivolumab to first-line chemotherapy improved response, disease free, and overall survival with the greatest survival benefit dependent on programmed death receptor ligand, programmed death receptor ligand −1 status, leading to regulatory approval for these agents. A preliminary report of a phase 3 trial adding pembrolizumab to first-line chemotherapy with trastuzumab in HER2-positive gastric cancer reported a significant improvement in response, leading to regulatory approval for pembrolizumab. The fibroblast growth factor receptor appears to be a promising new target in gastroesophageal cancer based on phase 2 data for bemarituzumab.

Summary

Optimal adjuvant chemotherapy after D2 resection of node-positive gastric cancer is 6 months of a fluorinated pyrimidine and oxaliplatin, with no benefit for adjuvant radiotherapy. Adjuvant nivolumab after resection of esophageal cancer after chemoradiotherapy improves DFS and is a new care standard. Pembrolizumab added to first-line chemotherapy in both HER2-positive and negative esophagogastric cancer improves outcome and is a new standard of care. Nivolumab added to first-line chemotherapy in HER2-negative gastric cancer improves treatment outcome and is a new care standard.

INTRODUCTION

Collectively esophageal and gastric cancer account for over 1.3 million cases annually with a high rate of fatality. In patients with gastric cancer, a D1 surgery is defined as gastrectomy and resection of group 1 (perigastric) lymph nodes. D2 gastrectomy involves resection of group 1 and group 2 lymph nodes (i.e., lymph nodes around the left gastric artery, common hepatic artery, celiac axis, splenic artery, and proper hepatic artery). Perioperative chemotherapy with FLOT (infusional 5-fluorourical, leucovorin, oxaliplatin, and docetaxel), or adjuvant chemotherapy after D2 resection with a fluorinated pyrimidine with or without a platinum drug, improves survival. Postoperative adjuvant radiation therapy is reserved for patients undergoing less than a D1 resection. In metastatic gastric cancer, chemotherapy combines a fluorinated pyrimidine with a platinum agent, and if patients are HER2-positive trastuzumab is included. Adding a third agent (epirubicin or docetaxel) increases toxicity without clearly improving survival. Paclitaxel and ramucirumab is standard second-line chemotherapy. For thirdline therapy, trifluridine tipiracil is typically used. After initial approval of immune checkpoint inhibitors for patients with chemotherapy refractory metastatic esophagogastric cancer who test programmed death receptor ligand, programmed death receptor ligand −1 (PDL-1) positive or are microsatellite instability (MSI) high, recent first-line trials discussed below now have established an earlier role for these agents.

SURGERY AND ADJUVANT THERAPY

Gastric cancer

In Asia upfront surgery with D2 gastrectomy in gastric cancer is followed by 6 months to a year of adjuvant chemotherapy. Korean investigators recently reported the results of the ARTIST 2 trial in patients with node-positive gastric cancer after D2 gastrectomy, randomizing patients to 1 year of adjuvant S-1 or 6 months of S-1/oxaliplatin, with a third arm of S-1/oxaliplatin combined with postoperative radiation therapy [1]. S-1 is an orally active combination of tegafur (a prodrug that is converted by cells to fluorourical), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorourical), and oteracil. Oteracil inhibits phosphorylation of fluorourical in the gastrointestinal tract, thereby reducing its gastrointestinal toxicity. Although the trial was prematurely closed due to accrual issues, the interim analysis was felt to meet the trial endpoints. The median age in the 546 patients was 61, 68% had stage III and 32% had stage II disease, and most had diffuse histology (48%) followed by intestinal (30%) or mixed/unknown (22%). The radiotherapy arm received 45 Gray (Gy) of radiation combined with S-1 daily during radiotherapy in addition to S-1/oxaliplatin.

Disease-free survival (DFS) at 3 years was superior for S-1/oxaliplatin with (72.8%, hazard ratio (HR) 0.724, P = 0.074) and without radiation therapy (74.3%, HR 0.693, P = 0.042) compared with S-1 alone (64.8%). Radiation therapy had no impact on DFS (HR 0.971, P = 0.879). ARTIST 2 makes two key observations in node-positive gastric cancer that will impact practice after up front gastrectomy for node-positive gastric cancer. Adjuvant radiation therapy after D2 resection adds no survival benefit, and combination chemotherapy with a fluorinated pyrimidine and oxaliplatin for 6 months appears superior to 1 year of fluorinated pyrimidine alone.

Esophageal and gastroesophageal junction cancer

The standard treatment for locally advanced esophageal squamous cell and adenocarcinoma in the United States is chemoradiotherapy alone or chemoradiotherapy followed by surgery. In patients with residual disease remaining at surgery, recurrence is common and there has been no proven benefit for any additional adjuvant therapy.

The recently reported CheckMate 577 trial, a global double-blind placebo-controlled industry sponsored phase 3 trial compared adjuvant treatment with nivolumab versus placebo in patients with esophageal and gastroesophageal junction (GEJ) cancer after chemoradiotherapy and surgery [2^■■]. Patients had to have evidence of either residual disease in the primary or lymph nodes at surgery. Patients were randomized 2: 1 to placebo or to 1 year of adjuvant nivolumab 240 mg every 2 weeks for 16 weeks, followed by 480 mg every 4 weeks for a total of 1 year. Therapy was started 4–16 weeks after surgery. Most patients had adenocarcinoma (71%), pT3–4 (55%) or pN1–2 disease (58%), and 40% had primary GEJ tumors.

Median DFS was substantially improved comparing placebo (11.0 months) with adjuvant nivolumab (22.4 months, HR 0.69, P < 0.001). The benefit was seen across treatment subgroups including squamous cancer (HR 0.61) and adenocarcinoma (HR 0.75), node-negative (0.71) and node-positive disease (0.67), and in tumors testing PDL-1 positive (HR 0.75) and negative (HR 0.73). Quality of life was similar in patients treated with placebo or nivolumab, and no new safety concerns were identified. Therapy discontinuation due to serious treatment-related adverse events was rare (5%).

CheckMate 577 establishes adjuvant nivolumab as a new standard of care in patients with esophageal cancer who after preoperative chemoradiotherapy have residual disease found at surgery. Overall survival (OS) data are pending, but the substantial difference in DFS will likely translate into an OS benefit. Whether the addition of checkpoint inhibitor therapy will improve outcome in patients receiving neoadjuvant chemotherapy without radiation therapy, or in the nonoperative chemoradiotherapy setting, is the subject of ongoing clinical trials.

TREATMENT OF METASTATIC DISEASE

Immune checkpoint inhibitors

The key advance in systemic therapy for advanced esophagogastric cancer in the past year was the elevation of immune checkpoint inhibitor therapy to first-line treatment, despite some initial negative trials in first-line therapy. Initial approval for nivolumab and pembrolizumab in chemotherapy refractory gastric cancer has now been expanded to earlier line usage. Results from the KEYNOTE-181 trial were reported in 2020, an international, open label industry sponsored randomized trial in esophageal and GEJ adenocarcinoma or squamous cell cancer, comparing second-line treatment with either pembrolizumab 200 mg every 3 weeks or investigators’ choice chemotherapy (irinotecan, docetaxel, or paclitaxel) [3]. Most of the 628 patients had squamous cancers (61%), and one-third had combined positive scores of PD-L1 staining cells (tumor cells, lymphocytes, and macrophages) of at least 10% (34–37%). OS was superior for pembrolizumab compared with chemotherapy in patients with combined PDL-1 score (CPS) at least 10% (9.3 versus 6.7 months, HR 0.69, P = 0.0074), with a superior 12-month survival (43 versus 20.4%). OS in all squamous cancers trended but did not achieve the criterion for superiority for pembrolizumab (8.2 versus 7.1 months, HR 0.78). In all patients, pembrolizumab was not superior to chemotherapy. The greatest benefit was seen in patients with squamous cancer with PDL-1 CPS at least 10%. Response rate (RR) in CPS at least 10% was superior for pembrolizumab over chemotherapy (21.5 versus 6.1%) and response duration was also superior (9.3 versus 7.7 months). Pembrolizumab had fewer grade 3/4 treatment-related adverse events compared with chemotherapy (18 versus 40.9%). Based on KEYNOTE-181, the Food and Drug Administration approved pembrolizumab as second-line therapy for squamous cancers with CPS at least 10%.

A salient-negative phase 3 trial in gastric adenocarcinoma preceded the recent reports of positive first-line trials. The KEYNOTE-62 trial compared pembrolizumab alone, the combination of pembrolizumab and chemotherapy, or chemotherapy alone with cisplatin and capecitabine or infusional fluorourical in 763 patients with PDL-1 CPS score 1% or higher [4]. Adding pembrolizumab to first-line chemotherapy failed to improve OS (12.5 months) compared with chemotherapy (11.1 months, HR 0.85, P = 0.05), even in patients with PD-L1 CPS score 10% or higher (12.3 versus 10.8 months, HR 0.85, P = 0.16). In an analysis for noninferiority for pembrolizumab versus chemotherapy, allowing a HR of 1.2, pembrolizumab achieved noninferior OS compared with chemotherapy (10.6 versus 11.1 months). However, patients treated with first-line pembrolizumab had a higher initial death rate and more rapid early disease progression (median 2.0 months) compared with chemotherapy (6.4 months). In the small group of patients with MSI high cancers (6.5%), pembrolizumab alone or combined with chemotherapy achieved superior survival (median not reached) compared with chemotherapy (8.5 months, HR 0.29), irrespective of PDL-1 CPS score. These results support first-line use of pembrolizumab with or without chemotherapy in MSI high cancers.

Two potentially practice-changing trials were presented at the 2020 European Society for Medical Oncology virtual meeting evaluating checkpoint inhibitors in the first-line treatment of esophagogastric cancers. CheckMate 649 trial, an industry sponsored open label randomized phase 3 trial treated 1581 patients with advanced gastric and GEJ adenocarcinoma with FOLFOX or capecitabine/oxaliplatin, with or without nivolumab [5^■■]. Progression-free survival (PFS) and OS focusing on patients with a PDL-1 CPS of 5% or higher were coprimary endpoints. Improvement in PFS (7.7 versus 6.0 months, HR 0.68, P < 0.0001) and OS (14.4 versus 11.1 months, HR 0.71, P < 0.001) were achieved with nivolumab. Nivolumab also increased RR (60 versus 45%) and response duration (9.5 versus 7.0 months). Secondary endpoints were also positive with improved survival in patients with PDL-1 CPS 1% or higher (HR 0.74) or all patients (HR 0.77). Nivolumab was recently approved in the United States to combine with first-line chemotherapy in in esophagogastric adenocarcinoma irrespective of PDL-1 CPS score. Although not yet published, data included in the product package insert indicate uncertain benefit in the 606 patients with CPS less than 5% (median OS was 12.4 months with versus 12.3 months without nivolumab, HR 0.94), or the 265 CPS-negative patients (median OS 13.1 months with versus 12.5 months without nivolumab, HR 0.85).

The second practice changing trial, KEYNOTE-590, compared first-line chemotherapy with infusional 5-fluorourical and cisplatin and pembrolizumab or placebo in 740 patients with esophageal or GEJ adenocarcinoma or squamous cell cancer [6^■■]. On this industry sponsored multicenter trial, OS was improved with pembrolizumab in PDL-1 CPS 10% or higher patients (13.5 versus 9.4 months, HR 0.62, P < 0.0001), in squamous cancer patients with CPS 10% or higher (13.9 versus 98.8 months, HR 0.57, P < 0.0001), and in all squamous cancer patients (12.6 versus 9.8 months, HR 0.72, P = 0.0006). A coprimary endpoint of improved OS in all patients was also achieved (12.4 versus 9.8 months, HR 0.73, P < 0.001), although in patients with PDL-1 CPS lower than 10% a lesser benefit was seen (HR 0.86). PFS benefits were also seen across these subgroups, and both a higher RR (45 versus 29.3%) and response duration (8.3 versus 6.0 months) were achieved with pembrolizumab. Based on these positive results, pembrolizumab was also recently approved to combine with first-line chemotherapy in esophageal and GEJ adenocarcinoma and squamous cancer.

Approval for first-line use of pembrolizumab was also recently extended to HER2-positive esophagogastric cancer. A single-center phase 2 trial combining pembrolizumab with trastuzumab, a fluorinated pyrimidine, and a platinum agent reported encouraging rates of response, PFS and OS [7^■], and prompted the phase 3 trial KEYNOTE-811 trial. A planned interim analysis indicated a significantly higher RR for pembrolizumab arm compared with placebo. This led to regulatory approval for pembrolizumab in first-line treatment of HER2-positive esophagogastric cancers.

With these pivotal trials, pembrolizumab and nivolumab and chemotherapy are now standard treatment in metastatic esophagogastric squamous cell and adenocarcinoma. Pembrolizumab combined with trastuzumab and chemotherapy in HER2-positive esophagogastric cancer is also now standard of care. These new treatment standards will form the foundation for the next generation of clinical trials studying new agents.

Targeting the fibroblast growth factor receptor

The fibroblast growth factor receptor (FGFR) has emerged as another promising target in esophagogastric adenocarcinoma based on positive results from an industry-sponsored, placebo-controlled randomized phase 2 trial targeting the FGFR2b receptor with the receptor-blocking antibody bemarituzumab [8]. Patients were screened either by immunohistochemistry (IHC) for overexpression of FGFR2b, or by circulating tumor DNA for FGFR gene amplification. FGFR overexpression by IHC was common and seen in 30% of patients. In the 156 patients treated with FOLFOX plus placebo or FOLFOX plus bemarituzumab, PFS, the primary endpoint, was superior with bemarituzumab (9.5 months) versus placebo (7.4 months; HR, 0.68; P = 0.07). Survival was also superior (not reached versus 12.9 months; HR, 0.58; P = 0.03), and RR was increased (53 versus 40%). Patients treated with bemarituzumab had more corneal toxicities and stomatitis. A phase 3 trial is being planned.

CONCLUSION

After up front D2 gastrectomy for node-positive gastric cancer, adjuvant chemotherapy with S-1 and oxaliplatin improves survival and radiation therapy adds no benefit. Adjuvant therapy with nivolumab improves DFS in patients with esophageal and GEJ cancer who have residual disease found at surgery after preoperative chemoradiotherapy. Immune checkpoint inhibitors should be combined with first-line chemotherapy in metastatic esophagogastric cancer. Pembrolizumab is approved to combine with first-line chemotherapy in esophageal and GEJ squamous cell and adenocarcinoma, and in patients with HER2-positive esophagogastric cancer. Nivolumab is approved to combine with first-line chemotherapy in esophagogastric adenocarcinoma.

KEY POINTS.

• After D2 resection of node-positive gastric cancer 6 months of a fluorinated pyrimidine and oxaliplatin is appropriate adjuvant chemotherapy.

• Adjuvant nivolumab significantly improves DFS after chemoradiotherapy and surgery in esophageal cancer.

• Pembrolizumab and nivolumab improve response, disease free, and overall survival in esophagogastric cancer when added to first-line chemotherapy.

• In HER2-positive gastric cancer, the addition of pembrolizumab to first-line chemotherapy substantially improves response rate.