Tislelizumab Approved in China for Second-Line Esophageal Squamous Cell Carcinoma

The China National Medical Products Administration (NMPA) has approved tislelizumab (BGB-A317) for use in patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who have disease progression or who are intolerant to frontline standard chemotherapy.¹

The regulatory decision was supported by data from the phase 3 RATIONALE 302 trial (NCT03430843), which showed that tislelizumab (n = 256) resulted in a median overall survival (OS) of 8.6 months (95% CI, 7.5-10.4) vs 6.3 months (95% CI, 5.3-7.0) with chemotherapy (n = 256) in the intent-to-treat population (HR, 0.70; 95% CI, 0.57-0.85; P = .0001).² The 6-month OS rates in the investigative and control arms were 62.3% and 51.8%, respectively; the 12-month OS rates were 37.4% and 23.7%, respectively.

“As a second-line treatment for patients with ESCC, this differentiated checkpoint inhibitor demonstrated significant improvements in OS and was generally well tolerated in our phase 3 trial of tislelizumab,” Mark Lanasa, MD, PhD, senior vice president and chief medical officer of Solid Tumors, at BeiGene, Ltd., stated in a press release. “Tislelizumab regulatory submissions in this indication submitted by Novartis are under review by the US FDA and the European Medicines Agency, highlighting our commitment to advancing its progress on behalf of the many patients around the world with ESCC and other forms of cancer.”

The phase 3 study enrolled patients with advanced or metastatic ESCC who experienced disease progression during or following frontline systemic treatment and an ECOG performance status of 0 or 1.

A total of 512 participants were randomized 1:1 to receive intravenous (IV) tislelizumab at 200 mg every 3 weeks (n = 256) or investigator’s choice of chemotherapy (n = 256), which could have been IV paclitaxel at 135 mg/m² to 175 mg/m² every 3 weeks or 80 mg/m² to 100 mg/m² weekly, IV docetaxel at 75 mg/m² every 3 weeks, or irinotecan at 125 mg/m² on days 1 and 8, given every 3 weeks.

Stratification factors for randomization included region (Asia excluding Japan vs Europe/North America), performance status (0 vs 1), and chemotherapy option (paclitaxel vs docetaxel vs irinotecan).

The primary end point of the trial was OS in all-randomized patients and the key secondary end point was OS in those with a PD-L1 combined positive score (CPS) of 10% or higher. Other secondary end points comprised progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety.

The median age of those who received tislelizumab was 62.0 years (range, 40-86) vs 63.0 years (range, 35-81) with chemotherapy. Most patients were male and had metastatic disease at baseline. Regarding performance status, 74.2% of those in the investigative arm had a score of 1 vs 76.6% of those in the control arm. In the tislelizumab arm, 34.8% of patients had a PD-L1 CPS of 10% or higher, 45.3% had a CPS of less than 10%, and in 19.9%, this information was unknown; in the chemotherapy arm, these rates were 26.6%, 54.7%, and 18.8%, respectively.

Moreover, in the investigative arm, 36.7% of patients previously underwent surgery, 66.0% had prior radiotherapy, and 97.3% received prior platinum-based chemotherapy. In the control arm, 38.7% of patients had prior surgery, 63.7% had previous radiotherapy, and 98.4% had prior platinum-based chemotherapy.

Additional data presented during the 2021 ASCO Annual Meeting indicated that among the population of patients with a PD-L1 CPS of 10% or higher, the median OS with tislelizumab (n = 89) was 10.3 months (95% CI, 8.5-16.1) vs 6.8 months (95% CI, 4.1-8.3) with chemotherapy (n = 68; HR, 0.54; 95% CI, 0.36-0.79; P = .0006). The 6-month OS rates in the investigative and control arms were 67.4% and 50.8%, respectively; the 12-month rates were 44.0% and 27.0%, respectively.

The survival benefit achieved with tislelizumab over chemotherapy was observed across predefined subsets, including PD-L1 expression, race, and region.

The median PFS with tislelizumab was 1.6 months (95% CI, 1.4-2.7) vs 2.1 months (95% CI, 1.5-2.7) with chemotherapy (HR, 0.83; 95% CI, 0.67-1.01). The PFS Kaplan-Meier curves began to separate approximately 3 months following randomization in favor of tislelizumab.

Tislelizumab elicited an ORR of 52% (95% CI, 15.6%-25.8%) vs 25% (95% CI, 6.4%-14.1%) with chemotherapy (odds ratio, 2.4; 95% CI, 1.4-4.0). The median DOR with tislelizumab was 7.1 months (95% CI, 4.1-11.3) vs 4.0 months (95% CI, 2.1-8.2).

Tislelizumab showcased a favorable toxicity profile vs chemotherapy. No new safety signals were observed. Specifically, 73.3% of patients in the investigative arm experienced at least 1 treatment-related adverse effect (TRAE) vs 93.8% of those in the control arm; 18.8% and 55.8% of patients, respectively, experienced a TRAE that was grade 3 or higher in severity.

Serious TRAEs were reported in 14.1% of those in the tislelizumab arm and 13.8% of those in the chemotherapy arm. Two percent of patients who received tislelizumab experienced a TRAE that resulted in death vs 2.9% of those who were given chemotherapy.

The most common TRAEs reported in the investigative and control arms, respectively, were increased aspartate aminotransferase (11.4% vs 3.8%), anemia (11.0% vs 34.6%), hypothyroidism (10.2% vs 0%), fatigue (7.5% vs 13.8%), decreased appetite (6.3% vs 31.3%), diarrhea (5.5% vs 27.5%), asthenia (4.7% vs 11.7%), malaise (3.9% vs 14.6%), weight decreased (3.1% vs 10.4%), and nausea (2.7% vs 27.5%), among others.

“The NMPA’s approval of tislelizumab is welcome news to patients with previously treated ESCC, for whom we are pleased to now be able to provide this new treatment option,” Lin Shen, vice president of clinical oncology at Beijing Cancer Hospital, and the principal investigator of the trial, added in the press release. “The global phase 3 clinical trial of tislelizumab demonstrated positive safety and efficacy outcomes as a second-line treatment for patients with ESCC, 1 of the most common malignant tumors in the digestive tract.”

In September 2021, the FDA accepted for review a biologics license application for tislelizumab as a potential therapeutic option in patients with unresectable recurrent locally advanced or metastatic ESCC following previous systemic therapy. The application was supported by findings from RATIONALE 302.³

References

1. China NMPA approves tislelizumab for patients with second-line esophageal squamous cell carcinoma. News release. BeiGene, Ltd.; April 15, 2022. Accessed April 18, 2022. https://bit.ly/36pRZk9
2. Shen L, Kato K, Kim S-B, et al. RATIONALE 302: randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4012. doi:10.1200/JCO.2021.39.15_suppl.4012
3. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd.; September 13, 2021. Accessed April 18, 2022. https://bit.ly/2YJw17s