Multiple comparisons of traditional cytotoxic chemotherapy combinations that began decades ago led to the adoption of the platinum plus fluorouracil doublet as the standard of care for treatment of recurrent or metastatic esophageal cancer.1 Other combinations created by the addition and/or substitution of modern agents including taxanes, irinotecan, and epirubicin were also studied.2-4 However, platinum plus fluorouracil remains the standard of care comparison per the U.S. Food and Drug Administration (FDA) for development of new therapies.
Drug development efforts beginning in the 21st century grew out of advances in cancer biology.5 One promising approach added growth factor receptor inhibitors (EGFR/HER1, hepatocyte growth factor receptor [HGFR], HER2, vascular endothelial growth factor receptor [VEGFR]) to chemotherapy.6 Each was investigated vs platinum plus fluorouracil or FOLFOX (leucovorin, fluorouracil, oxaliplatin) in randomized, phase III trials (AVAGAST,7 CALGB 80403,8 ToGa,9 RAINBOW,10 RILOMET-111). Only trastuzumab and regorafenib emerged as successful for adenocarcinomas, after which the field seemed stuck.
Targeted Therapies and Immunotherapy
Thereafter, a collection of much-needed new targets emerged. Successful blockade of newer growth factor receptors such as claudin 18.212 and fibroblast growth factor receptor 2 (FGFR2),13 as well as later-line targeting of HER2 with the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki,14 has led to improved survival in several prospective studies. Based upon these studies, it appeared that targeting esophageal or gastroesophageal junction (GEJ) cancer molecularly through a precision medicine approach was indeed feasible. Unfortunately, these advances led to an unmet need—they did not apply to squamous cell carcinoma.
Even more astonishing is the almost logarithmically advancing development of immunotherapy agents. Blockade of the PD-1/PD-L1 and CTLA-4 checkpoints has been successful across multiple solid and liquid tumors, including esophageal and gastric cancers. Starting with single-agent use in a later-line setting, multiple studies with nivolumab and pembrolizumab in combination with chemotherapy in the front-line setting for metastatic or unresectable disease have been completed.
The hazard ratio of 0.57 for the addition of pembrolizumab to patients with squamous cell carcinoma and a CPS ≥ 10 is unprecedented.— Michael K. Gibson, MD, PhD
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Closer Look at KEYNOTE-590
An advance in the treatment of metastatic or unresectable squamous cell carcinoma of the esophagus was reported in The Lancet by Sun et al, of Samsung Medical Center, Sungkyunkwan University in Seoul,15 and discussed in detail in the December 10, 2021, issue of The ASCO Post. This interim analysis of the phase III KEYNOTE-590 trial showed that the addition of pembrolizumab to platinum/fluorouracil in the first-line setting resulted in improved overall and progression-free survival in patients with advanced esophageal and GEJ carcinomas. This led to the March 2021 approval of pembrolizumab combined with platinum plus fluorouracil–based chemotherapy for patients with metastatic or locally advanced esophageal or GEJ (tumors with an epicenter 1–5 cm above the GEJ [Siewert type 1]) carcinoma who are not candidates for surgical resection or definitive chemoradiation therapy.
In this double-blind, randomized, controlled trial, 749 patients irrespective of PD-L1 status from sites in 26 countries were randomly assigned to receive pembrolizumab at 200 mg (n = 373) or placebo (n = 376) every 3 weeks for up to 35 cycles, both combined with fluorouracil at 800 mg/m2 on days 1 to 5 plus cisplatin at 80 mg/m2 on day 1 every 3 weeks for up to 6 cycles. The primary endpoints were overall survival in patients with squamous cell carcinoma and a PD-L1 combined positive score (CPS) ≥ 10; and overall survival and progression-free survival in all patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS ≥ 10, and all randomly assigned patients (squamous cell carcinoma and Siewert type 1 adenocarcinoma).
At first interim analysis, at a median follow-up of 22.6 months among patients with esophageal squamous cell carcinoma and a PD-L1 CPS of at least 10, median overall survival was 13.9 months (95% confidence interval [CI] = 11.1–17.7 months) among 143 pembrolizumab-treated patients vs 8.8 months (95% CI = 7.8–10.5 months) among 143 control patients (hazard ratio [HR] = 0.57, 95% CI = 0.43–0.75, P < .0001). Rates at 24 months were 31% vs 15%.
Among all patients with squamous cell carcinoma, median overall survival was 12.6 months (95% CI = 10.2–14.3 months) among 274 in the pembrolizumab group vs 9.8 months (95% CI = 8.6–11.1 months) among 274 in the control group (HR = 0.72, 95% CI = 0.60–0.88, P = .0006). Rates at 24 months were 29% vs 17%. Median progression-free survival was 6.3 months (95% CI = 6.2–6.9 months) in the pembrolizumab group vs 5.8 months (95% CI = 5.0–6.1 months) in the control group (HR = 0.65, 95% CI = 0.54–0.78, P < .0001).
Among all randomly assigned patients, median overall survival was 12.4 months (95% CI = 10.5–14.0 months) in the pembrolizumab group vs 9.8 months (95% CI = 8.8–10.8 months) in the control group (HR = 0.73, 95% CI = 0.62–0.86, P < .0001). Rates at 24 months were 28% vs 16%. Median progression-free survival was 6.3 months (95% CI = 6.2–6.9 months) vs 5.8 months (95 CI = 5.0–6.0 months; HR = 0.65, 95% CI = 0.55–0.76, P < .0001). Among patients with adenocarcinoma, including esophageal and Siewert type 1 GEJ adenocarcinoma, median overall survival was 11.6 months (95% CI = 9.7–15.2 months) in the pembrolizumab group vs 9.9 months (95% CI = 7.8–12.3 months) in the control group (HR = 0.74, 95% CI = 0.54–1.02).
The hazard ratio of 0.57 for the addition of pembrolizumab to patients with squamous cell carcinoma and a CPS ≥ 10 is unprecedented; the regimen provides a sorely needed option for these patients who previously had the choice of cytotoxic therapy alone. It should be recognized, however, that just 52% of patients (143 of 274) with squamous cell carcinoma possessed tumors with a PD-L1 CPS ≥ 10. The FDA likely recognized this selection limitation when it approved this combination for all patients (HR = 0.73). Celebration of these data is appropriate, but there is much more work to be done. Ongoing trials are exploring combinations with other targeted therapies and novel immune checkpoints.
Dr. Gibson is Director of Translational Research for Esophago-Gastric and Head and Neck Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville.
Disclosure: Dr. Gibson has held a consultant and/or advisory role with Abbvie, Soligenix, and Flagship Biosciences, and has served on a speakers’ bureau for Bristol-Myers Squibb.
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15. Sun JM, Shen L, Shah MA, et al: Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): A randomised, placebo-controlled, phase 3 study. Lancet 398:759-771, 2021.
As reported in The Lancet by Jong-Mu Sun, MD, of Samsung Medical Center, Sungkyunkwan University, Seoul, and colleagues, an interim analysis in the phase III KEYNOTE-590 trial has shown that the addition of first-line pembrolizumab to chemotherapy resulted in improved overall and progression-free...