Advances in immunotherapy for metastatic esophageal cancer

INTRODUCTION

Cancers of the esophagus (EC), including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), are among the most fatal cancers in the world. ESCC, being more common in Southeast Asian and African regions, is very aggressive and occurs in the middle or upper one-third of the esophagus. EAC, more common in European and North American regions, usually occurs in the lower third of the esophagus and originates from glandular lining near the stomach. EC is the 8^th most common cause of cancer worldwide and 6^th most common cause of cancer mortality.^[1] Half of EC cases present at an advanced stage. Conventionally, systemic chemotherapy (CT) has been the mainstay of treatment in such cases, yielding a median survival of only around 12 months. Recently, immune checkpoint inhibitors (ICIs) have been extensively studied for the treatment of advanced EC. Several phase III trials have demonstrated benefits in response and survival as compared to CT along with a manageable safety profile in advanced EC.^[2] There are more data on esophagogastric junction (EGJC) or gastric cancers rather than on isolated EC. Limited literature on EC urged us to write this review.

RATIONALE OF ICIs

The immune system of human body is a complex interaction between cells and biochemical signals that orchestrate the detection and damage from external antigens, while avoiding autoimmune damage. Cancer cells are not foreign cells; hence, they are not so easily detected by immune cells. As per newly proposed “cancer-immunity cycle” model, dead cancer cells emit antigens recognizable by antigen-presenting cells. This leads to the recruitment of CD 4 and CD 8+T-cells at the tumor sites. Cancer cells manipulate signals to escape from immune surveillance. By overcoming this, the immune system can be used as a potential weapon against cancer. This forms the rationale of ICIs, where we use either agonists of stimulatory receptors or antagonists of inhibitory signals to immune cells. Nonetheless, as of now, only a subset of EC patients benefit from ICIs. Biomarker research is underway, to select the potential patients most likely to benefit from therapy and spare others from side effects (e.g., inflammation of skin, intestines, endocrine system, and liver) and failure of treatment.^[3]

ROLE OF BIOMARKER TESTING

Any targeted therapy, including ICIs, does not equally benefit all patients. Hence, predictive biomarkers are needed to select potential patients most likely to benefit from these agents. Key biomarkers proposed for ICIs in EC include microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) expression.^[4] Four subtypes of esophagogastric cancers can be distinguished at the molecular level: Tumors with chromosomal instability (50%), MSI-high (MSI-H) tumors (22%), Epstein–Barr virus-positive (8%), and genomically stable tumors (20%).^[5] PDL1 is the ligand that blocks the programmed death receptor 1 (PD-1), leading to immune tolerance. PD-L1 testing is available by various immunohistochemistry (IHC) methods, and rates of positivity in clinical trials are reported as tumor proportion score (TPS) only or as combined positive score (CPS) for the tumor cells, lymphocytes, and macrophages. The CPS appears to be a better as it looks at many cells constituting tumor microenvironment. In patients with EC undergoing ICIs treatment, testing for a mutation or DNA MMR deficiency is routinely checked. A high MSI is a surrogate marker of MMR deficiency and it results from failure of repair to mismatched nucleotides during DNA replication. Thus, a higher tumor mutational burden (TMB) results in increased neoantigens load. Testing can be done by IHC, by polymerase chain reaction, or by next-generation sequencing (NGS). MSI is seen in <1% of ECs.^[6] A high TMB, recently defined as the presence of 10 or more mutations per megabase detected by NGS, is another potential biomarker of ICIs benefit.^[7] Other potential biomarkers of response to ICIs include detection of the Epstein–Barr virus, in which tumors can lead to enhanced expression of both PD-L1 and PD-L2,^[8] and other germline and somatic mutations that may increase the TMB including mutations in POLE.^[9]

ICIs IN FIRST LINE

The results of three recent positive Phase 3 trials have established a new standard-of-care practice for the use of ICIs in combination with first-line (1L) CT in EGJC. Results of these trials are outlined in [Table 1]. These trials have demonstrated remarkable accomplishment of a benchmark overall survival (OS) exceeding 12 months for the 1^st time in this disease.

ICIs IN SECOND LINE

IO IN SUBSEQUENT LINES

The large Phase 2 expansion cohort of the KEYNOTE-059 trial reported results for pembrolizumab in 259 patients with gastric or EGJ adenocarcinoma. This international multicenter trial enrolled equal proportions of patients with gastric (48.3%) and EGJ cancers (51.4%). Half of the patients had received 2 prior regimens (51.7%), and half had received ≥3 regimens (48.3%). A total of 24.3% were human epidermal growth factor receptor 2 (HER2)positive, 57% had a CPS of at least 1%, and a small minority had MSI-H tumors (4.0% with tissue available for testing). The RR in all patients, which was the primary endpoint, was 11.6%, and it was superior in PD-L1-positive patients (15.5%) versus PD-L1-negative patients (6.4%). In addition, the DoR was superior in PD-L1-positive patients versus PD-L1-negative patients (16.3 vs. 6.9 months). The RR was 57.1% in MSI-H patients. In the KEYNOTE-059 trial, pembrolizumab in the 3L setting (or later) in non-Asian patients showed RR of 12% with a median OS of 5.6 months.^[27] The effect of nivolumab monotherapy in esophagogastric cancer refractory to or intolerant of ≥2 previous CT regimens is comparable to that of pembrolizumab, but the impact of PD-L1 expression on efficacy is contradictory. In the ATTRACTION-2 study, nivolumab monotherapy increased the 12-month OS in an Asian collective to 27 versus 11% with placebo (HR0.63, P < 0.0001), independently of the PD-L1 status, Lauren classification, and localization of the tumor.^[28]

JAVELIN Gastric 300 was a negative trial in patients with previously treated advanced disease. In this open-label Phase 3 trial, 371 patients with previously treated gastric or GEJ adenocarcinoma received avelumab or physician’s choice of CT with either paclitaxel or irinotecan. PD-L1 positivity, defined as a TPS of ≥1%, was present in 26.8% of the 317 patients tested. Superiority for OS, the primary endpoint, was not achieved with avelumab (4.6 months) versus CT (5.0 months; HR, 1.1; P = 0.81). PFS and the RR favored CT (2.7 months, 4.3%) over avelumab (1.4 months, 2.2%). No difference in survival outcome was observed as a function of PD-L1 status or the CT administered. However, the control arm of this trial received active therapy as compared nivolumab trial and Phase 2 expansion cohort data for pembrolizumab where control arms received placebo or no therapy [Table 2].^[29]

IO+CHEMO+HER2

Recent advances, including the inclusion of trastuzumab in the 1L treatment of metastatic HER2-positive disease and the inclusion of ramucirumab in 2L treatment, have now been surpassed by the advent of ICIs.^[8] Another trial, leading to regulatory approval of 1L ICI in esophagogastric cancer, was KEYNOTE-811. This randomized, placebo-controlled Phase 3 trial evaluated trastuzumab CT with or without pembrolizumab in HER2-positive esophagogastric cancer. In a planned interim analysis of the first 264 patients treated, most were HER2 positive, with an IHC score of 3+ (79–82%) and a CPS of at least 1% (85–88%). The RR was significantly higher with pembrolizumab (74.4%) than with placebo (51.9%; P = 0.0001), as was the complete RR (11% vs. 3%). Based on these interim results, the combination of pembrolizumab with 1L CT in HER2-positive esophagogastric cancer was granted accelerated approval.^[30]

FDA APPROVALS

• (a) Based on CheckMate 649, the FDA approved on April 16, 2021, nivolumab (Opdivo, Bristol-Myers Squibb Company) in combination with fluoropyrimidine- and platinum-containing CT for 1L treatment of advanced or metastatic gastric cancer, GEJ junction cancer, and esophageal adenocarcinoma.^[14]

• (b) On March 22, 2021, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck Sharp, and Dohme Corp.) in combination with platinum- and fluoropyrimidine-based CT for patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1–5 cm above the GEJ junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation. On the basis of the KEYNOTE-590 study, in March 2021, the FDA approved a combined CT and pembrolizumab treatment protocol for primary inoperable or metastatic esophageal and gastroesophageal junction cancers, which is not reliant on PD-L1 expression or histological type.^[31]

• (c) On June 10, 2020, the Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for patients with unresectable advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.^[32]

• (d) On July 30, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced, or metastatic, ESCC whose tumors express PD-L1 (CPS ≥ 10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.^[33]

• (e) On May 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck and Co.) for adult and pediatric patients with unresectable or metastatic, MSI-H, or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This is the FDA’s first tissue/site-agnostic approval.^[34]

• (f) On June 16, 2020, the Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck and Co., Inc.) for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high (TMB-H) (≥10 mutations/ megabase [mut/Mb]) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.^[35]

FUTURE PERSPECTIVES

Looking at the wide applicability of ICIs in EC, their requirement is likely to rise further. More specific, reliable, economical, and easily reproducible biomarkers are needed for cost-effective and safe use of ICIs. In a resource-constrained setting like India, efforts are needed to reduce the cost of these drugs to benefit a maximum number of patients. Based on the results of a study from China, camrelizumab is a cost-effective option compared with docetaxel or irinotecan CT in patients with advanced ESCC as 2L therapy from the perspective of Chinese society. Although the price of nivolumab in China is lower than that in several other countries, camrelizumab still has a 68.35% lower price than nivolumab.^[4] A high degree of response that is durable is seen in most patients, and the initially approved indication for the later-line use of these agents in MSI-H esophagogastric cancers will likely be changed to include earlier-line therapy.^[4]

CONCLUSION

The incorporation of ICIs in therapeutic landscape of EC has brought a new ray of hope. The three pivotal positive trials have brought the use of ICIs in first-line setting in combination with CT. Nivolumab added to 1L CT in gastric and GEJ adenocarcinoma is now the treatment of choice. Pembrolizumab with 1L CT is new standard therapy in esophageal and GEJ adenocarcinoma and squamous cancer. In addition, in HER2-positive esophagogastric adenocarcinoma, pembrolizumab added to trastuzumab and CT is now the gold standard. The judicious use of ICIs in the light of available biomarkers at various treatment levels may enable an astute oncologist to provide significantly better results to the cancer patients.