More than 20,000 adults in the United States are diagnosed with esophageal cancer every year.

 Although the incidence, location, and histology of esophageal cancer vary globally, patients in the Western World typically develop esophageal cancer in the distal esophagus or at the gastroesophageal junction (

 The most common disease type is esophageal adenocarcinoma (EAC), which may point to obesity as a factor.

Rising obesity rates across the United States have led to increasing reflux disease, Barrett esophagus, and esophageal adenocarcinoma.

 Overall survival for esophageal cancer remains poor, especially for metastatic disease with a median survival of slightly over 1 year from the time of diagnosis.

 Metastatic EAC is typically managed with chemotherapy and immunotherapy, but many patients eventually develop resistance to these therapies, leading to poor outcomes.

Exploring and targeting the underlying mechanisms of therapeutic resistance are critical for improving the outlook for esophageal cancer. Therefore, it is of utmost importance to identify new treatment options or repurpose commonly used drugs in novel combinations to improve outcomes in this difficult-to-treat patient population.

Targeting the Role of Stress in Therapeutic Resistance

Study results have recently discovered that adrenergic stress hormones produced during the fight-or-flight response are key players in psychological stress, such as anxiety or depression, which are significantly increased following a cancer diagnosis. Our team at Roswell Park Comprehensive Cancer Center in Buffalo, New York, led by Elizabeth Repasky, PhD, discovered that stress can reduce the efficacy of chemotherapy and the immune system’s power to control tumor growth.

 Interestingly, our work has also revealed a solution to this problem.

Propranolol, a type of beta-blocker, is commonly prescribed for heart problems such as hypertension or arrhythmia and management of anxiety and migraines. Propranolol blocks the β-adrenergic receptors by which stress hormones act on both tumors and immune cells. Using propranolol in mice enhances long-term immune control of tumor growth by reducing the accumulation of myeloid-derived suppressor cells.

 Moreover, the resistance to cytotoxic chemotherapy caused by stress can be reversed by using propranolol.

 The same phenomenon might be possible in humans.

A team of researchers at Roswell Park Comprehensive Cancer Center, led by Anurag Singh, MD, showed that patients undergoing chemoradiation for esophageal cancer who took β-blockers for high blood pressure did better than those patients not taking β-blockers.

 Our previous clinical trial in advanced melanoma patients, led by Shipra Gandhi, MD, showed that combining immunotherapy (pembrolizumab [Keytruda]) with propranolol produces an unprecedented response rate, one not seen historically with immunotherapy alone without significantly increased adverse effects (AEs).

 Therefore, we hypothesize that adding propranolol to standard chemotherapy and immunotherapy for esophageal cancer will significantly improve outcomes and not cause additional AEs.

Based on these premises, our team at Roswell Park is conducting a multicenter, nonrandomized, single-arm, phase 2 clinical trial (NCT05651594). Patients with advanced or metastatic EAC will be treated with a combination of standard chemotherapy-immunotherapy and propranolol (

Propanolol for Advanced Esophageal Cancers

We aim to enroll a total of 40 patients over 2 years, with at least 20 patients enrolled at our site. The study’s primary end point is the overall response rate (ORR) as determined by RECIST 1.1 criteria. Secondary end points include safety (toxicities and AEs) assessed as per Common Terminology Criteria for Adverse Events Version 5.0, progression-free survival, overall survival, and ORR as determined by immune-based RECIST criteria. The correlative studies will analyze blood- and tissue-based biomarkers, including immune markers. Perceived stress and the chronotropic effect of exercise will be correlated with clinical outcomes to determine the efficacy of the study treatment combination.

Survival with standard chemotherapy- immunotherapy for esophageal cancer remains very poor. Propranolol is affordable and very well tolerated. If the study results are favorable, propranolol could be quickly and widely implemented in clinical practice.

Sarbajit Mukherjee, MD, MS, is an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Cancer stat facts: esophageal cancer. National Cancer Institute. Accessed January 3, 2022. https://seer.cancer.gov/statfacts/html/ esoph.html

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Eng JWL, Reed CB, Kokolus KM, et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through beta-adrenergic receptor activation. 

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Propranolol in combination with pembrolizumab and standard chemotherapy for the treatment of unresectable locally advanced or metastatic esophageal or gastroesophageal junction adenocarcinoma. ClinicalTrials.gov. Updated December 19, 2022. Accessed January 3, 2022. https://clinicaltrials.gov/ct2/show/NCT05651594

Articles

Although the incidence, location, and histology of esophageal cancer vary globally, patients in the Western World typically develop esophageal cancer in the distal esophagus or at the gastroesophageal junction. 

Investigators Seek Simpler Solution to Treatment Resistance in Esophageal Cancer

Gastroesophageal cancers (GEC), which consist of esophageal, gastroesophageal junction (GEJ), and gastric cancers, are the most prevalent gastrointestinal cancers worldwide. Globally, more than 600,000 new esophageal cancer cases are detected annually, claiming 544,000 lives.

 On the other hand, more than 1 million new gastric cancer cases are detected annually worldwide, leading to an estimated 769,000 deaths. 

In 2021, several new FDA approvals involving the use of immune checkpoint inhibitors changed the treatment landscape in GEC. Nivolumab (Opdivo) was approved as the first adjuvant treatment in patients with completely resected esophageal/GEJ cancer following chemoradiation therapy (CRT) who had residual pathologic disease. Furthermore, pembrolizumab (Keytruda) and nivolumab were also approved for the frontline treatment of patients with met-astatic GEC. These immune checkpoint inhibitors have a manageable toxicity pro-file while significantly improving clinical outcomes in patients. 

However, not all patients benefit similarly from using this class of agents. PD-L1 expression has been commonly used as a biomarker, and patients with higher PD-L1 expression seem to benefit more from checkpoint inhibitors. Therefore, it is crucial to understand and interpret the results from the landmark clinical trials in the context of recent FDA approvals.

Defining the Role of Immunotherapy as Adjuvant Treatment of Gastroesophageal Cancers 

Neoadjuvant CRT followed by surgery is a widely used treatment strategy for patients with resectable esophageal or GEJ cancer.

Studies in murine models show that radiotherapy and chemotherapy can exert immunomodulatory effects, resulting in synergistic treatment responses when combined with immunotherapy.

CheckMate 577 (NCT02743494) was a global, randomized, double-blind, placebo-controlled phase 3 trial that evaluated nivolumab vs placebo as an adjuvant treatment after neoadjuvant CRT and surgery for patients with esophageal or GEJ cancer with residual pathological disease.

 Results showed that nivolumab was associated with a significant improvement in disease-free survival at 22.4 months (95% CI, 16.6-34.0) compared with 11.0 months (95% CI, 8.3-14.3) with placebo, leading to a 31% reduction in the risk of recurrence or death (HR, 0.69; 96.4% CI, 0.56-0.86; 

 < .001). Overall survival (OS) data favored nivolumab over placebo across most prespecified subgroups and regardless of PD-L1 status.

 Regarding safety, serious adverse events (AE) related to nivolumab that led to discontinuation of the trial regimen were reported in less than 10% of patients. 

The data served as the basis for the May 2021 FDA approval of nivolumab for the adjuvant treatment of completely resected esophageal or GEJ cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy. Currently, the global, randomized, phase 3 KEYNOTE-585 trial (NCT03221426) is investigating the role of both neoadjuvant and adjuvant pembrolizumab and chemotherapy in patients with localized gastric or GEJ adenocarcinoma.

Given the positive results of CheckMate 577, an important question in the field is whether the adjuvant use of checkpoint inhibitor therapy may improve outcomes in patients undergoing definitive CRT without surgery. This is being investigated in the ongoing KEYNOTE-975 study (NCT04210115).

 Use of immune checkpoint inhibitors in the neoadjuvant setting is also being investigated.

Immunotherapy as a New First-line Therapy: Lessons Learned From KEYNOTE-590, CheckMate 649, CheckMate 648, AND KEYNOTE-811

A combination of fluoropyrimidine plus platinum-based chemotherapy is used as the standard first-line treatment for patients with advanced or metastatic GEC. Several studies, including KEYNOTE-059 (NCT02335411), KEYNOTE-181 (NCT02564263), Check-Mate 032 (NCT01928394), ATTRACTION-2 (NCT02267343), and ATTRACTION-3 (NCT02569242), demonstrated the activity of immune checkpoint inhibitors in refractory GEC. However, results of a chemoimmunotherapy approach in the frontline setting have not been inspiring until just recently.

The global, phase 3 KEYNOTE-590 trial (NCT03189719) compared pembrolizumab and chemotherapy against placebo plus chemotherapy in patients with unresectable, locally advanced, or metastatic esophageal cancer or GEJ adenocarcinoma in the first-line setting. OS was significantly improved with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in all randomized patients at 12.4 months vs 9.8 months (HR, 0.73; 95% CI, 0.62-0.86;

In patients with a PD-L1 combined positive score (CPS) of 10 or higher, the median OS was 13.5 months vs 9.4 months (HR, 0.62; 95% CI, 0.49-0.78; 

 < .0001). Specifically in esophageal squamous cell carcinoma (ESCC), the median OS was 12.6 months and 9.8 months, respectively (HR, 0.72; 95% CI, 0.60-0.88; 

 = .0006), leading to the March 2021 FDA approval of pembrolizumab in this setting. However, further analysis showed that the benefit was less prominent in esophageal adenocarcinoma (EAC; HR, 0.74; 95% CI, 0.54-1.02) and in patients with a PD-L1 CPS of less than 10 (HR, 0.86; 95% CI, 0.68-1.10).

CheckMate 649 (NCT02872116) was a global, open-label, phase 3 trial that randomized previously untreated patients with unresectable, advanced, or metastatic gastric/GEJ/EAC with no known HER2 positivity to nivolumab and ipilimumab (Yervoy), nivolumab and chemotherapy, or chemotherapy alone. Nivolumab and chemotherapy improved OS in patients with a PD-L1 CPS of 5 or higher at 14.4 months (95% CI, 13.1-16.2) vs 11.1 months (95% CI, 10.1-12.1) with chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; 

 < .0001]. In all randomized patients, the median OS was 13.8 months vs 11.6 months, respectively (HR, 0.77; 99.3% CI, 0.68-0.94; 

 < .0001) but the combination of nivolumab and ipilimumab did not significantly improve survival compared with chemotherapy. 

Based on the results of this study, nivolumab was approved by the FDA in April 2021 for use in this patient population, regardless of PD-L1 status. Interestingly, in a subgroup analysis, patients with a CPS of less than 5 did not seem to benefit from the addition of nivolumab (HR, 0.94; 95% CI, 0.78-1.13). These results seem to suggest that, at least for metastatic/unresectable HER2-negative GEC, patients with a higher CPS are likely to benefit more from the addition of immune checkpoint inhibitors.

CheckMate 648 (NCT03143153) was the first, global, phase 3 study to evaluate a combination immunotherapy regimen consisting of nivolumab and ipilimumab and nivolumab and chemotherapy against standard chemotherapy as first-line treatment in patients with unresectable advanced, recurrent, or metastatic ESCC. In all randomized patients, the combination immunotherapy regimen improved OS over chemotherapy at 12.8 months (95% CI, 11.3-15.5) vs 10.7 months (95% CI, 9.4-11.9), respectively (

 = .011). This study also found improved outcomes in terms of OS when combining nivolumab with chemotherapy compared with chemotherapy alone at 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9), respectively (

 No new safety signals were observed. This study presented nivolumab and chemotherapy as a new potential treatment option in the frontline treatment of metastatic ESCC, and the results also suggest that some patients with ESCC may benefit from a chemotherapy-free approach (

Overall Survival Benefits With Frontline Immunotherapy GEC Cancers13-15

Since the ToGA trial (NCT01041404), trastuzumab (Herceptin) plus chemotherapy has been the standard first-line treatment for patients with metastatic or unresectable HER2-positive gastric or GEJ adenocarcinoma.

 Because some recent phase 2 studies showed great antitumor activity and a manageable safety profile of pembrolizumab combined with trastuzumab and chemotherapy,

KEYNOTE-811 (NCT03615326) was conducted to assess the efficacy of this regimen.

 This was a randomized, double-blind, placebo-controlled trial in patients with metastatic HER2-positive gastric or GEJ adenocarcinoma who did not receive prior systemic treatment for their metastatic disease. Patients were randomized to receive pembrolizumab or placebo in combination with trastuzumab and chemotherapy. Patients in the pembrolizumab arm had an objective response rate of 74.4% (95% CI, 66.2%-81.6%) compared with 51.9% (95% CI, 43.0%-60.7%) in those in the placebo arm. The duration of response was also improved in the pembrolizumab arm, and the AEs were manageable. Based on these data, the FDA granted an accelerated approval in May 2021 to pembrolizumab in combination with trastuzumab and chemotherapy in this patient population. 

The current biomarkers validated for use in the clinical setting are the PD-L1 score, agnostic biomarkers such as mismatch repair or micro-satellite instability (MMR/MSI), and tumor mutational burden (TMB).

 The PD-L1 CPS is the most common method of assessing PD-L1 expression in GEC. It is a qualitative immunohistochemistry assay where PD-L1 protein levels are detected in tumor tissues, and CPS was developed to consider the expression of PD-L1 on tumor cells and immune cells combined. Although CPS 10 appears to correlate to some degree with response to pembrolizumab, its utility is limited in PD-L1–negative tumors, and other biomarkers are needed.

Mutations in genes encoding MMR and epigenetic silencing of 

 lead to an inability of cells to repair mismatched nucleotides during DNA replication, resulting in MMR deficiency.

Consequently, this increases neoantigen burden and a heightened response to immune check-point inhibition in various tumors. MSI-H is a robust biomarker of immunotherapy response with predictability across various solid tumors and is approved as an agnostic biomarker for pembrolizumab. Nonetheless, a significant 40% to 60% proportion of patients with GEC who have MMR-deficient/MSI-high tumors still do not respond to immune checkpoint inhibitors, suggesting that there are additional immuno-suppressive mechanisms in effect in the tumor microenvironment.

TMB is another biomarker. High TMB is defined as at least 10 nonsynonymous somatic mutations per megabase of the tumor genome. In a phase 1/2 trial (NCT02915432) of toripalimab, a humanized PD-1 antibody, in patients with advanced gastric cancer who progressed on at least 1 prior systemic therapy, high TMB was associated with greater OS.

Epstein-Barr virus (EBV) is a human herpesvirus associated with multiple cancer types such as lymphomas, nasopharyngeal carcinomas, and gastric adenocarcinomas. EBV-associated gastric cancers (EBVaGC) show intense intratumoral and peritumoral immune cell infiltration, making these tumors potentially more responsive to immune checkpoint blockade. However, the prevalence of EBVaGC is low in the Western population, and regular testing is not used for routine oncology care.

Gene expression profiles can be used as biomarkers. For example, the KEYNOTE-059 study used a novel 18-gene T-cell–inflamed gene expression profiling score as a biomarker, whereas higher gene expression profiling score was associated with improved response.

 Our group used a targeted gene expression analysis in GEC to reveal that inflammation in the tumor-immune microenvironment is associated with improved OS in all patients. Furthermore, it was associated with improved OS and progression-free survival in patients treated with immune-modulating drugs.

 Tumor inflammation needs to be investigated further as a biomarker, perhaps in conjunction with other established biomarkers such as PD-L1. 

Finally, circulating biomarkers, including circulating tumor DNA, which may be better reflective of the status of the tumor as compared with archival tissue-based biomarkers like PD-L1, should be evaluated in this context.

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It  is  crucial  to  understand  and  interpret  the  results from the landmark clinical trials in the context of recent FDA approvals in gastroesophageal cancers.

Immunotherapy Paves Path for New Standards of Care in Gastroesophageal Cancers

Sarbajit Mukherjee, MD, MS, assistant professor of oncology, Department of Medicine, member, Tumor Immunology and Immunotherapy Program, Roswell Park Comprehensive Cancer Center, clinical assistant professor, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses considerations to inform when to initiate immunotherapy in gastroesophageal cancer. 

Now that several immunotherapeutic agents are approved for use in gastroesophageal cancer, the field is working to determine when immunotherapy should be initiated for patients, Mukherjee says.

On May 20, 2021, the FDA approved nivolumab (Opdivo) for patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease who have received neoadjuvant chemoradiation. The regulatory decision was based on findings from the phase 3 CheckMate 577 trial (NCT02743494), which demonstrated a statistically significant improvement in disease-free survival with nivolumab vs placebo in this patient population.

Notably, the approval of adjuvant nivolumab is not dependent on tumor histology or biomarker status, so patients with adenocarcinoma and squamous cell disease are eligible for this treatment irrespective of PD-L1 status, Mukherjee explains.

Other immunotherapeutic agents are included in the National Comprehensive Center Network (NCCN) guidelines as recommended frontline therapies in the metastatic setting. However, certain drugs are included in the NCCN guidelines with specific PD-L1 cutoffs. As such, this discordance complicates treatment selection with immunotherapy, Mukherjee concludes.

Videos

Sarbajit Mukherjee, MD, MS, discusses considerations to inform when to initiate immunotherapy in gastroesophageal cancer. 

Sarbajit Mukherjee, MD, MS

Articles

Investigators Seek Simpler Solution to Treatment Resistance in Esophageal Cancer

Immunotherapy Paves Path for New Standards of Care in Gastroesophageal Cancers

Dr. Mukherjee on Determining When to Initiate Immunotherapy in Gastroesophageal Cancer