O-drug Approved as First-line Immunotherapy for Gastric Cancer and What Other Domestic Counterparts to Expect

Recently (April 16), FDA approved PD-1 nivolumab (opdivo) of BMS, Bristol-Myers Squibb Co.) for patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma in combination with first-line chemotherapy, which caused a great sensation in the tumor circle. This approval makes nivolumab the first approved immunotherapy for first-line treatment of gastric cancer. 

It is based on a study called CheckMate-649, a randomized, multicenter, open-label phase III clinical study, serving to assess the efficacy of combined chemotherapy with nivolumab in the treatment of advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma compared to chemotherapy alone. The study only included patients with negative HER2 expression and no previous treatment. 

The primary endpoint of such study was the overall survival (OS) and progression free survival (PFS) assessed by BICR of patients with positive PD-L1 expression (CPS≥5) treated with nivolumab (opdivo) combined with chemotherapy compared with chemotherapy alone. 

The study involved a total of 2,032 patients, including 208 in the Chinese subgroup. Research findings show that in terms of OS, the median OS of patients with PD-L1 CPS≥5 was 15.5 months in the combined treatment group and 9.6 in the chemotherapy alone group (Fig. a). In patients with PD-L1 CPS≥1, the median OS was 14.3 months in the combined treatment group and 9.9 in the chemotherapy alone group (Fig. b). Among all randomized populations, the OS was 14.3 months in the combined treatment group and 10.3 in the chemotherapy alone group (Fig. c). Among all randomized populations, the combined treatment group proved a clinically significant overall survival benefit. 

For progression free survival (PFS) of patients with PD-L1 CPS≥5, the median PFS was 8.5 months in the combined treatment group and 4.3 in the chemotherapy alone group (Fig. a). In patients with PD-L1 CPS≥1, the median PFS was 8.3 months in the combined treatment group and 4.9 in the chemotherapy alone group (Fig. b). Among all randomized populations, the median PFS was 8.3 months in the combined treatment group and 5.6 in the chemotherapy alone group (Fig. c). Among all randomized populations, the combined treatment group proved clinically significant progression PFS benefits. 

Nivolumab combined with the first-line chemotherapy treatment of unresectable advanced or metastatic gastric cancer and gastroesophageal junction cancer has garnered clinically significant OS and PFS benefits in the Chinese population, compared with chemotherapy alone. The OS and PFS benefits were observed in patients with positive PD-L1 expression and combined positive score (CPS) ≥5, CPS≥1, and all other randomized populations. 

While imported PD-1 McAb opdivo shows impressive curative effect in gastric cancer, domestic PD-1 McAb is also heading its way ahead. Pharmasource, a vertical e-commerce online marketplace serving the pharmaceutical industry, could offer you not only PD-1 McAb but also pharmaceutical laboratory equipments. Please contact us if you are interested in various types of active pharmaceutical ingredients, too. Next, let's take a glance at what combinations can we foresee. 

1. Camrelizumab plus Capecitabine and CAPOX and sequential therapy of combined Camrelizumab and Apatinib 

The Clinical Cancer Research virtually published the results of first-line treatment of HER2 negative advanced gastric/gastroesophageal junction adenocarcinoma with Camrelizumab plus Capecitabine and CAPOX and sequential therapy of combined Camrelizumab and Apatinib on March 25. This was a national multi-center Phase II clinical trial led by Professor Shen Lin from Beijing Cancer Hospital. It was revealed in the results that the objective response rate (ORR) of the protocol was 58.3% among the 48 patients subject efficacy and safety analysis. The disease control rate (DCR) was 93.8%, and the median overall survival (mOS) 14.9 and the median progression-free survival (mPFS) were 14.9 and 6.8 months respectively (95% CI 5.6-9.5). 

The OS of the whole population in this study extended to 14.9 months, which repeatedly verified the potential of combined immunotherapy. 

2. Sintilimab plus chemotherapy as the first-line treatment of adenocarcinoma of the gastroesophageal junction

The study, open-label, multi-center and in its Phase Ib, enrolled 20 patients with unresectable advanced or metastatic adenocarcinoma of the gastroesophageal junction. The patient accepted an intravenous injection of 200mg Sintilimab plus CapeOx once every 21 days for 6 cycles; and after the combined treatment, the patient continued to accepted Sintilimab (200 mg) as maintenance therapy once every 3 weeks. Efficacy endpoints consist of ORR, DCR, PFS and OS. 

The results showed that ORR was 85%, all of which were subject to PR; and DCR was 100%. The median PFS was 7.5 months, and the 6-month incidence of PFS was 88%. The median OS was not realized, and the 6-month and 12-month OS rates were 100.0% and 68.0%, respectively. The median TTR was 2.1 months, and the median DOR 5.9 months; and the total number of lesions declined somehow in all patients. With regard to safety, the incidence and severity of TRAEs, after treatment with Sintilimab and CapeOx, are substantially the same as the known side effects of conventional chemotherapy. No treatment-related deaths were reported in this study. 

3. Toripalimab plus chemotherapy as the first-line treatment of advanced gastric cancer

This is an open-label, multicenter, phase Ib/II trial and classifies patients with advanced gastric cancer into 2 cohorts. In Cohort 1, Toripalimab (3 mg/kg d1, Q2W) monotherapy was administered to 58 patients with chemotherapy-refractory advanced gastric cancer. In Cohort 2, first-line treatment of Toripalimab (360mg d1, Q3W) plus XELOX (CAPOX 130mg/m2qd, d1; Capecitabine 1000mg/m2BID, d1-d14; Q3W) was administered to 18 chemotherapy-naive patients with advanced gastric cancer. 

Efficacy results in Cohort 1 displayed that the ORR and DCR of patients (refractory advanced gastric cancer) were 12.1% and 39.7% respectively, and the median DOR, median PFS and median OS were 9.4, 1.9 and 4.8 months respectively. The ORR and DCR of Cohort 2 patients were 66.7% and 88.9% respectively, the median PFS was 5.8 months, and the median OS was not achieved. 

4. Tislelizumab plus chemotherapy as first-line treatment under research

Tislelizumab, a PD-1 humanized monoclonal antibody independently developed by BeiGene, was approved by the NMPA in December 2019 for treating relapsed/refractory classic Hodgkin's lymphoma (r/r cHL). In April 2020, it claimed the domestically original PD-1/PD-L1 monoclonal antibody approved for urothelial cancer indications. 

In September 2020, the results of the RATIONALE-205 study of Tislelizumab combined with chemotherapy in the first-line treatment of esophageal squamous cell carcinoma and gastric/gastroesophageal junction cancer were duly presented in Clinical Cancer Research. A total of 15 patients were admitted to the gastric/gastroesophageal junction cancer cohort of this study. The ORR and DCR were 46.7% and 80%, respectively. The combined Tislelizumab and chemotherapy showed a long-lasting effect and the median DoR was not mature. As to safety, the most common adverse events (AE) fall into anemia, decreased appetite, nausea, and fatigue. In reference to this, a globally randomized, double-blind, multi-center Phase III study, regarding Tislelizumab combined with chemotherapy and placebo combined with chemotherapy for the first-line treatment of advanced gastric/gastroesophageal junction cancer, is in progress. 

It is known from the foregoing that the domestic PD-1 monoclonal antibody has presented ideal results in the treatment of gastric cancer and reaped breakthrough data. We look forward to its launch as soon as possible to allow for more options for cancer patients. 

References:

1.https://www.onclive.com/view/fda-approves-nivolumab-for-frontline-gastric-cancer；

2.Lin Shen et al.First-line nivolumab plus chemotherapy versus chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer/ esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis. 2021 AACR；

3.Camrelizumab combined with chemotherapy followed by camrelizumab plus apatinib as first-line therapy for advanced gastric or gastroesophageal junction adenocarcinoma.

4.Clin Cancer Res. 2020 Sep1;26(17):4542-4550. 

About  the Author:    

Yefenghong

Ye  Fenghong, a medical editor specializing in oncology at a healthcare internet  company, has conducted in-depth research on the pathogenesis and clinical  treatment of lung cancer and breast cancer. She has previously been involved  in the design and synthesis of anti-tumor drugs and has some experience in  computer-aided drug design. She is currently devoted to introducing  cutting-edge cancer treatment drugs to a wide range of readers, aiming to  help more people avoid cancer pain and embrace good health.