Immunotherapy Makes Major Strides for First-line Treatment of Unresectable Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma

Esophageal cancers are histologically classified as either esophageal adenocarcinoma or esophageal squamous cell carcinoma (ESCC), with the latter associated with a poorer prognosis.¹ Traditionally, first-line systemic therapy for advanced esophageal cancer consists of 2 cytotoxic agents (often a fluoropyrimidine and a platinum agent), with the potential for 3 cytotoxic agents for medically fit patients with excellent performance status and easy access to frequent toxicity evaluations.^2-4 Advanced esophageal adenocarcinoma that is HER2 overexpression positive may be supplemented with trastuzumab (Herceptin; Genentech, Inc), a HER2- targeting agent.⁵ The addition of specific immune checkpoint inhibitors to first-line chemotherapy in unresectable locally advanced or metastatic ESCC has resulted in improvements in survival outcomes and has transformed modern clinical practice.

Pembrolizumab Immunotherapy

Pembrolizumab (Keytruda; Merck & Co, Inc) is a PD-1–blocking monoclonal antibody that was initially FDA approved on July 30, 2019, as subsequent monotherapy for patients with recurrent, locally advanced, or metastatic ESCC with tumors expressing PD-L1 (combined positive score [CPS] ≥ 10), as determined by an FDA-approved test, with disease progression after 1 or more prior lines of systemic therapy.⁶ Pembrolizumab monotherapy is a category 1, preferred second-line treatment for patients with unresectable locally advanced, recurrent, or metastatic ESCC (when local therapy is not indicated) and a PD-L1 CPS of 10 or greater in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Esophageal and Esophagogastric Junction Cancers.⁴

In the first-line setting, pembrolizumab in combination with fluoropyrimidine-based and platinum-based chemotherapy received FDA approval on March 22, 2021, for the treatment of locally advanced or metastatic esophageal or gastroesophageal carcinoma that is not amenable to surgical resection or definitive chemoradiation.⁷ This approval was based on the double-blind, randomized, phase 3 KEYNOTE-590 trial (NCT03189719), in which 749 patients with previously untreated, unresectable locally advanced or metastatic esophageal cancer or gastroesophageal junction cancer were randomly assigned 1:1 to receive either pembrolizumab plus chemotherapy (5-fluorouracil and cisplatin) or chemotherapy alone for up to 35 cycles. Approximately 73% of all patients included in the trial specifically had ESCC (n = 548), 51% of all patients had a PD-L1 CPS of 10 or greater (n = 383), and 38% had both ESCC and PD-L1 CPS 10 or greater (n = 286).⁸

In KEYNOTE-590, the coprimary end point of overall survival (OS) in all major prespecified subgroups and the overall study population was met. In patients with both ESCC and a PD-L1 CPS of 10 or greater, the pembrolizumab-plus-chemotherapy treatment arm had an improved median OS of 13.9 months compared with 8.8 months in the chemotherapy-alone treatment arm (HR, 0.57; 95% CI, 0.43-0.75; P<.0001). In all patients with ESCC, pembrolizumab plus chemotherapy improved median OS compared with chemotherapy alone (12.6 months vs 9.8 months; HR, 0.72; 95% CI, 0.60-0.88; P = .0006). In all patients with a PD-L1 CPS of 10 or greater, pembrolizumab plus chemotherapy similarly improved median OS (13.5 months vs 9.4 months; HR, 0.62; 95% CI, 0.49-0.78; P < .0001). In the overall study population, pembrolizumab plus chemotherapy demonstrated clinical superiority (12.4 months vs 9.8 months; HR, 0.73; 95% CI, 0.62-0.86; P < .0001).⁸

Additionally, the coprimary end point of progression-free survival (PFS) in all major prespecified subgroups and the overall study population was met. In all patients with ESCC, there was an improvement in median PFS with pembrolizumab plus chemotherapy vs chemotherapy alone (6.3 months vs 5.8 months; HR, 0.65; 95% CI, 0.54-0.78; P < .0001). In all patients with a PD-L1 CPS of 10 or greater, there was similarly a substantial PFS benefit with pembrolizumab plus chemotherapy vs chemotherapy alone (7.5 months vs 5.5 months; HR, 0.51; 95% CI, 0.41-0.65; P < .0001). In the overall study population, pembrolizumab plus chemotherapy demonstrated clinical superiority (6.3 months vs 5.8 months; HR, 0.65; 95% CI, 0.55-0.76; P < .0001). However, a PFS analysis for the subgroup of patients with both ESCC and a PD-L1 CPS of 10 or greater was not reported.⁸

Based on the results of the KEYNOTE-590 trial, pembrolizumab in combination with a fluoropyrimidine (5-fluorouracil or capecitabine) and a platinum-based agent (cisplatin or oxaliplatin) is a preferred first-line therapy for HER2 overexpression–negative patients with unresectable locally advanced, recurrent, or metastatic ESCC (when local therapy is not indicated) in the NCCN Guidelines. Cisplatin-containing pembrolizumab regimens have a category 1 recommendation for a PD-L1 CPS of 10 or greater, and oxaliplatin-containing pembrolizumab regimens have a category 2A recommendation for a PD-L1 CPS of 10 or greater. Both platinum-based pembrolizumab regimens have a category 2B recommendation for a PD-L1 CPS of less than 10.⁴

Nivolumab Immunotherapy

Nivolumab (Opdivo; Bristol Myers Squibb) is a PD-1–blocking monoclonal antibody that was initially approved on June 10, 2020, as subsequent monotherapy for patients with unresectable locally advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine-based and platinum-based chemotherapy.⁹ Nivolumab monotherapy is a category 1, preferred subsequent therapy for patients with unresectable locally advanced, recurrent, or metastatic ESCC (when local therapy is not indicated) in the NCCN Guidelines.⁴

More recently, nivolumab has shown efficacy as first-line therapy both in combination with chemotherapy and in combination with CTLA-4–targeting monoclonal antibody ipilimumab (Yervoy; Bristol Myers Squibb). On May 27, 2022, nivolumab in combination with fluoropyrimidine-based and platinum-based chemotherapy and nivolumab in combination with ipilimumab received FDA approval as first-line therapies for patients with advanced or metastatic ESCC.¹⁰ These approvals were based on the open-label, randomized, phase 3 CheckMate 648 trial (NCT03143153), in which 970 patients with previously untreated or recurrent (but who had not received previous systemic therapy for advanced disease), unresectable locally advanced, or metastatic ESCC were randomly assigned 1:1:1 to receive nivolumab plus chemotherapy (5-fluorouracil and cisplatin), nivolumab plus ipilimumab (referred to as dual immunotherapy), or chemotherapy alone for up to 2 years. Among the trial participants, 49% had PD-L1 expression of 1% or greater (n = 473), approximately 7% had locoregional recurrent disease (n = 71), and 21% had distant recurrent disease (n = 205).¹¹

The coprimary end point of OS in the patient subpopulation of PD-L1 expression of 1% or greater and in the overall study population was met in both the nivolumab-plus-chemotherapy and the dual immunotherapy treatment arms. Patients with PD-L1 expression of 1% or greater in the nivolumab-plus-chemotherapy arm demonstrated an improved median OS vs chemotherapy alone (15.4 months vs 9.1 months; HR, 0.54; 99.5% CI, 0.37-0.80; P < .001). There was statistically significant improvement with nivolumab plus chemotherapy in the overall study population (13.2 months vs 10.7 months; HR, 0.74; 99.1% CI, 0.58-0.96; P = .002). Patients with PD-L1 expression of 1% or greater in the dual immunotherapy arm demonstrated an improved median OS vs chemotherapy alone (13.7 months vs 9.1 months; HR, 0.64; 98.6% CI, 0.46-0.90, P = .001). In the overall study population, dual immunotherapy improved median OS as well (12.7 months vs 10.7 months; HR, 0.78; 98.2% CI, 0.62-0.98; P = .01).¹¹

The coprimary end point of PFS in the patient subpopulation with PD-L1 expression of 1% or greater was met only in the nivolumab-plus-chemotherapy arm (6.9 months vs 4.4 months; HR, 0.65; 98.5% CI, 0.46-0.92; P = .002). However, there was not a significant difference in median PFS in the overall study population with nivolumab plus chemotherapy (5.8 months vs 5.6 months; HR, 0.81; 98.5% CI, 0.64-1.04; P = .04). Dual immunotherapy did not result in a significant difference in median PFS in patients with PD-L1 expression of 1% or greater (4.0 months vs 4.4 months; HR, 1.02; 98.5%, 0.73- 1.43; P=.90). Because of the lack of statistical significance in the subpopulation of PD-L1 expression of 1% or greater, PFS analysis was not conducted in the overall study population for the dual immunotherapy arm.¹¹

Based on the results of the CheckMate 648 study, nivolumab in combination with a fluoropyrimidine (5-fluorouracil or capecitabine) and a platinum-based agent (cisplatin or oxaliplatin) is a category 2A, preferred first-line therapy for HER2 overexpression–negative patients with unresectable locally advanced, recurrent, or metastatic ESCC (when local therapy is not indicated) in the NCCN Guidelines. Nivolumab in combination with ipilimumab is additionally recommended as a category 2A, preferred first-line therapy in this patient population.⁴

Conclusion

Immunotherapy has been a widely explored treatment option in numerous solid tumor disease states, and recently it has been shown to have clinical benefit in unresectable locally advanced or metastatic ESCC as first-line therapy. Pembrolizumab plus chemotherapy demonstrated clinical superiority vs chemotherapy alone in median OS and median PFS in all major prespecified subgroups and in the overall study population in the KEYNOTE-590 trial.⁸ Both nivolumab-based regimens resulted in statistically significant improvements in median OS in the subgroup of PD-L1 expression of 1% or greater and in the overall study population.¹¹ However, it should be noted that there were mixed results for nivolumab-based regimens in the PFS analyses across multiple subgroups and in the overall study population. These PFS interpretations should be analyzed in the context of differing statistical methods in the nivolumab study (98.5% CI compared with medical standard of 95% CI).¹¹ Additional immunotherapy research through large randomized clinical trials is needed to further improve survival outcomes in unresectable locally advanced or metastatic ESCC.

About The Author

Kevin Pang, PharmD, is an associate oncology scientist and medical writer at the National Comprehensive Cancer Network.

References

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