Sintilimab Expected to Break the “Iron Triangle” to Become the Fourth Major Immunotherapy for Esophagus Cancer in China

The incidence and mortality of esophageal cancer separately rank 7th and 6th among cancers in the world. China is a country with a high incidence of esophageal cancer, with incidence and mortality accounting for more than half of global incidence and mortality. Unlike the pathological types of esophageal cancer in Europe and North America, which are mostly adenocarcinomas, more than 90% of the pathological types of esophageal cancer in China are squamous cell carcinomas. Current clinical treatments mainly include surgery, chemotherapy, radiation therapy, and targeted therapy. Chemoradiotherapy has become the standard treatment for advanced esophageal cancer as about half of patients have distant metastasis at the time of clinical diagnosis. However, both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma are intrinsically resistant to traditional treatment, with limited treatment response to first-line chemotherapy, and the application of targeted drugs in esophageal cancer treatment is very limited, therefore, new therapeutic methods are urgently needed to improve esophageal cancer prognosis. Immunotherapy has brought revolutionary therapeutic changes to other tumor types, and although esophageal cancer immunotherapy started relatively late, it has made some achievements.

Pembrolizumab, camrelizumab, and nivolumab are recommended in the current CSCO Guidelines as second-line immunotherapies for esophageal cancer and constitute the “iron triangle” of immunotherapy for esophageal cancer. A clinical trial has been conducted to use the Chinese-produced sintilimab as a second-line therapy for advanced ESCC and has achieved positive results. As a result, sintilimab is expected to become the fourth major immunotherapy for esophagus cancer in China. Let’s see the new recommendations for immunotherapy for esophageal cancer below.

Pembrolizumab (squamous cell carcinoma, PD-L1 CPS≥10, Level 1A evidence)

Pembrolizumab, one of the two major anti-PD-1 monoclonal antibodies, has received Level I recommendation (Level 1A evidence) as a second-line therapy for patients with advanced ESCC (CPS ≥ 10). Its approval was based on phase 3 KEYNOTE-181 clinical study. As an international multicenter, randomized, controlled phase 3 clinical study, KEYNOTE-181 enrolled 123 patients with recurrent, locally advanced, or metastatic esophageal cancer in the Chinese subgroup to randomly receive pembrolizumab (62 cases) or chemotherapy (61 cases).

According to the results, the OS benefits of Chinese patients with ESCC who received pembrolizumab were more significant, with death risk reduced by 45%, 3 times the death risk of the overall study population (45% vs 15%, with HR separately of 0.55 and 0.85).

Recommendation level: Squamous cell carcinoma patients with CPS≥10. The Level III recommendation by experts in the old Guidelines has been “promoted” to Level I recommendation, and the level of evidence has been adjusted from 2B to 1A.

Camrelizumab (squamous cell carcinoma, Level 1A evidence)

Camrelizumab is the first Chinese-produced immune drug approved for advanced esophageal cancer in China. The recommendation was mainly based on the results of the randomized, open, chemotherapeutic-controlled, multicenter phase III ESCORT clinical study. ESCORT study, the first study with the largest sample size on immune checkpoint inhibitors conducted in patients with advanced ESCC in China, enrolled a total of 457 patients with advanced or metastatic ESCC who failed first-line chemotherapy (camrelizumab group and chemotherapy group separately having 228 and 220). According to the results, the median OS of the two groups was separately 8.3 months vs 6.2 months, and camrelizumab reduced the death risk by about 30%; the ORR was separately 20.2% vs 6.4%, DOR was separately 7.4 months vs 3.4 months, and patients could benefit from camrelizumab treatment regardless of the PD-L1 expression state; in terms of safety, camrelizumab had good tolerance, and the rate of Grade 3 and above treatment-related adverse events (TRAEs) was half that of the chemotherapy group (19.3% vs 39.5%). Therefore, it has received Level I recommendation (Level 1A evidence) for ESCC. If you want to buy medical supplies online, then Pharmasources would be your best choice for there are many professional medical products companies on Pharmasources who could provide medicine of many different kinds.

Nivolumab (squamous cell carcinoma, Level 2A evidence)

As a multicenter, randomized, global study, ATTRACTION-3 study enrolled patients with advanced ESCC who progressed following or were intolerant to the first-line fluoropyrimidine- and platinum-based therapies to assess the efficacy and safety of nivolumab vs. chemotherapy (docetaxel or paclitaxel), with patients mainly from Asia (about 96%).

Compared to the chemotherapy group, the OS of the nivolumab group was extended by 2.5 months (10.9 months vs 8.4 months, HR 0.77, p = 0.019). The survival benefits of the nivolumab group were observed regardless of the tumor PD-L1 expression level.

The PFS of the two groups had no significant difference (HR = 1.08), however, the median duration of response (DOR) of the nivolumab group was longer (DOR: 6.9 months vs 3.9 months), showing the advantages of immunotherapy. The ORR of the two groups was separately 19% vs 22%.

Recommendation level: As the study did not enroll Chinese patients, the efficacy in Chinese patients needs to be proven by further data. As a result, the drug has received only Level II recommendation (level of evidence: 2A) for squamous cell carcinoma patients.

Sintilimab—Promising future

As a randomized phase 2 study, ORIENT-2 has enrolled 190 patients with advanced ESCC who failed first-line therapy. Patients have been grouped according to 1:1 to receive sintilimab or paclitaxel/irinotecan standard-dose chemotherapy at the investigator’s choice.

The median OS of the two groups was separately 7.2 months vs. 6.2 months (HR 0.70, P = 0.034), with the median OS of patients with low neutrophil-to-lymphocyte ratio (NLR) being longer (HR 0.54，P = 0.019). The ORR of the sintilimab group was higher, being 12.6% vs 6.3% of the chemotherapy group. In the subgroup with PD-L1 (TPS)≥ 1%, the ORR of the two groups was separately 20.2% vs 0, while in the subgroup with PD-L1 ≥ 10%, the ORR of the two groups was separately 35.7% vs 0. The DOR of the two groups was separately 8.3 months vs 6.2 months.

Sintilimab is not recommended in the Guidelines updated recently as its data were just released at the ASCO Annual Meeting, however, according to the study results, sintilimab could significantly prolong the OS (7.2 months) and had good safety in patients with advanced ESCC refractory to first-line chemotherapy compared to chemotherapy.

Considering the above study results, although there are no phase 3 study data of sintilimab, sintilimab offered significant clinical benefits compared to chemotherapy, showing that it has great potential for the treatment of advanced esophageal cancer and is expected to become the fourth major immunotherapy for esophageal cancer in China.

References:

1. Guidelines for the Diagnosis and Treatment of Esophageal Cancer 2020 of the Chinese Society of Clinical Oncology (CSCO);

2. https://www.drugs.com/newdrugs/fda-approves-opdivo-nivolumab-patients-advanced-esophageal-squamous-cell-carcinoma-escc-after-prior-5258.html；

3. Chen J, Luo S, Qin S, et al. Pembrolizumab versus Chemotherapy in Patients with Advanced/Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus as Second-line Therapy: Analysis of the Chinese Sub-group in KEYNOTE-181. 2019 ESMO, abstract 760P.

4. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial [published correction appears in Lancet Oncol. 2019 Nov;20(11):e613]. Lancet Oncol. 2019;20(11):1506–1517. doi:10.1016/S1470-2045(19)30626-6.