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Esophageal cancer is the sixth most common cause of cancer-related death in the world, and about 90% of esophageal cancers in China, with a high incidence of esophageal cancer, are esophageal squamous cell carcinomas.
From April 26th to 27th, the 2024 Chinese Society of Oncology (CSCO) Guidelines Meeting was held in Jinan, Shandong. Professor Zhang Bo from the Cancer Hospital of the Chinese Academy of Medical Sciences explained the key points of the update of the CSCO Guidelines for the Diagnosis and Treatment of Esophageal Cancer 2024 Edition (hereinafter referred to as the Guidelines).
Distant metastatic squamous cell carcinoma: first-line treatment
- In the level I recommendation for distant metastatic squamous cell carcinoma, "sugemalimab + cisplatin + 5-FU (class 1A)" was added
- First-line standard therapy options are abundant, and the treatment regimens in the original level II and level III recommendations have no indications and are removed.
Table 1 Distant metastatic disease: first-line treatment for squamous cell carcinoma
The adjustment is based on data reported in the multicenter, randomized, double-blind, Phase III GEMSTONE-304 study[1], which compared the efficacy and safety of a PD-L1 inhibitor with placebo in combination with chemotherapy as a first-line treatment for unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma. The primary endpoints of the trial were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints included investigator-assessed PFS, BICR, and investigator-assessed objective response rate (ORR), duration of response (DoR), and safety.
The results showed that compared with placebo plus chemotherapy, PD-L1 inhibitor combined with chemotherapy was more effective in improving PFS and OS in patients with locally advanced, recurrent or metastatic esophageal squamous cell carcinoma, and the 6-month and 12-month PFS rates in the PD-L1 inhibitor + chemotherapy group were higher than those in the placebo + chemotherapy group, and the OS was also significantly prolonged and the safety profile was also significantly prolonged (Figure 1). Therefore, data from the GEMSTONE-304 trial support PD-L1 inhibitor in combination with chemotherapy as a new first-line immunotherapy option for esophageal squamous cell carcinoma.
Fig.1 PFS(a) and OS(b) in the PD-L1 inhibitor + chemotherapy group and placebo + chemotherapy group[1]
Distant metastatic adenocarcinoma: first-line treatment
01
HER-2 positive
- "PD-L1 expression CPS ≥1" was added after the regimen of "trastuzumab + pembrolizumab + cisplatin/oxaliplatin + fluorouracil"
- At the same time, the important reference value of PD-L1 expression level for protocol selection was emphasized.
Table 2 First-line treatment of HER-2-positive adenocarcinoma
This adjustment is based on the results of the randomized, double-blind, phase III KEYNOTE-811 study[2]. The study evaluates the efficacy and safety of pembrolizumab in combination with trastuzumab and chemotherapy in advanced HER-2-positive gastric cancer or gastroesophageal junction adenocarcinoma. After a median follow-up of 28.4 months, pembrolizumab plus trastuzumab + chemotherapy showed a statistically significant improvement in PFS in the advanced HER-2-positive gastric/gastroesophageal junction adenocarcinoma intention-to-treat (ITT) population, reducing the risk of disease progression or death by 29% compared with trastuzumab plus chemotherapy alone. Pembrolizumab regimens have also been shown to reduce the risk of disease progression or death by 30% compared with trastuzumab treatment and chemotherapy alone in the PD-L1 CPS≥1 population (Figure 2).
Fig.2 PFS results of KEYNOTE-811 study[2]
02
For HER-2 negative, the regimens of "pembrolizumab + oxaliplatin + fluorouracil" and "sugemalimab + oxaliplatin + capecitabine (PD-L1 CPS≥5)" were added, both of which were level I recommendations.
Table 3 First-line treatment of HER-2-negative adenocarcinoma
This adjustment is based on the results of the KEYNOTE-859 study [3] and the GEMSTONE-303 study [4], respectively. The KEYNOTE-859 study is a randomized, controlled, double-blind, Phase III study comparing the safety and efficacy of pembrolizumab in combination with FP/CAPOX and placebo in combination with FP/CAPOX in the first-line treatment of GC/GEJC, with a primary endpoint of OS. The study achieved a positive result on the primary endpoint, that is, the intention-to-treat (ITT) population, which was HR=0.78, which was comparable to the HR results of other studies of the same kind, and the P value was much less than 0.0001, and the curves between the two groups slowly separated with the extension of follow-up time, and the difference in OS rate between the two groups reached about 10% at 2-year follow-up, which further reflected the characteristics of long-term survival achieved by immunotherapy.
Fig.3 Results of KEYNOTE-859 study[3]
The GEMSTONE-303 study is a randomized, double-blind, multicenter Phase III clinical study with a median follow-up of 25 months in patients with previously untreated, unidentified HER-2-positive status, ≥5% PD-L1 expression, unresectable advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma randomized in a 1:1 ratio. PFS data for the primary endpoint showed a significant improvement in median PFS in the Suge+CAPOX group compared to placebo + CAPOX compared with placebo + CAPOX, with a more pronounced PFS benefit in the PD-L1≥10% population. OS data showed that compared with placebo + CAPOX, the median OS was extended by nearly 3 months and the risk of death was reduced by 25% in the Suge + CAPOX group, and in the PD-L1≥10% group, the median OS was extended by 5.27 months and the risk of death was reduced by 36%.
Fig.4 Results of GEMSTONE-303 study[4]
Distant metastatic squamous cell carcinoma: second-line and subsequent treatment
- For the second-line and subsequent treatment of distant metastatic squamous cell carcinoma, the ALTER-E-006 study[5] was added to Note c for retrospective analysis.
The study analyzed multicenter, real-world data from anlotinib in combination with immune checkpoint inhibitors (ICIs) in previously immunotreated advanced esophageal squamous cell carcinoma, and the results were presented at the European Society for Medical Oncology-Gastrointestinal Cancer Congress (ESMO-GI) in June 2023: a total of 96 subjects who had previously failed a PD-1/PD-L1/CTLA-4 agent (monotherapy or combination) were included in the study, and among 71 evaluable subjects, The ORR was 29.6% and the disease control rate (DCR) was 91.5%. The median OS was 10.97 months and the median PFS was 6.31 months in 96 participants. As there is no standard treatment for patients with advanced esophageal squamous cell carcinoma who have previously received ICIs in combination with chemotherapy or monotherapy, anlotinib plus ICIs may be considered for these patients based on these results.
- At the same time, for the second-line treatment of distant metastatic squamous cell carcinoma and beyond, the results of the phase Ib/II clinical study COMPASSION-03 in advanced solid tumors were added to Note D [6].
The study evaluated the results of the Phase Ib/II clinical study of cadonilib monotherapy in patients with advanced solid tumors, the first multicenter clinical study of PD-1/CTLA-4 dual ICIs in advanced solid tumors, and the results showed that all 22 patients in the esophageal squamous cell carcinoma cohort had evaluable antitumor activity, with a median follow-up of 17.9 months, 4 patients achieved partial response (PR), and an ORR of 18.2%, Median PFS was 3.5 months, median OS was 9.4 months, and 13 patients died.
Fig.5 PFS and OS of patients in esophageal squamous cell carcinoma cohort[6]
- First-line treatment of distant metastatic squamous cell carcinoma: new recommendation of "sugemalimab + cisplatin + 5-FU" regimen; Removal of all protocols for unapproved indications;
- First-line treatment of distant metastatic HER-2-positive adenocarcinoma: "PD-L1 expression CPS ≥1" was added after the regimen of "trastuzumab + pembrolizumab + cisplatin/oxaliplatin + fluorouracil";
- First-line treatment of distant metastatic HER-2-negative adenocarcinoma: new recommendations for "pembrolizumab + oxaliplatin + fluorouracil" and "sugemalimab + oxaliplatin + capecitabine (PD-L1 expression CPS ≥5)" were added;
- Second-line and subsequent treatment of distant metastatic squamous cell carcinoma: new note: lack of standard therapy in these patients; Patients who have failed ICIs treatment can be considered for anlotinib in combination with ICIs; Patients who have failed prior therapy may be considered for cadonilimab.
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Bibliography:
[1] Li J, Chen Z, Bai Y, et al. First-line sugemalimab with chemotherapy for advanced esophageal squamous cell carcinoma: a randomized phase 3 study. Nat Med. 2024 Feb 1.
[2] Yelena Y. Janjigian，et al. Pembrolizumab plus Trastuzumab and Chemotherapy for HER-2+ Metastatic Gastric or Gastroesophageal Junction （mG/GEJ） Adenocarcinoma: Survival results from the Phase 3, Randomized, Double-blind, Placebo-controlled KEYNOTE-811 Study.2023 ESMO,Abstract 1511O.
[3] Rha SY, Wyrwicz LS, Yanez Weber PE, et al: Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction cancer: Phase III KEYNOTE-859 study. ESMO Virtual Plenary. Abstract VP1-2023. Presented February 16, 2023.
[4] Xiao-tian Zhang，et al. GEMSTONE-303: Prespecified progression-free survival (PFS) and overall survival (OS) final analyses of a phase III study of sugemalimab plus chemotherapy vs placebo plus chemotherapy in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.2023 ESMO, abstract LBA 79#.
[5] Poster Session p-162. 2023 WCGI.
[6] Gao X, Xu N, Li Z, et al. Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial. Lancet Oncol. 2023 Oct; 24(10):1134-1146.
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