Abstract CT039: Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC

Abstract

Results From RATIONALE 303: A Global Phase 3 Study of Tislelizumab (TIS) vs Docetaxel (TAX) as Second- or Third-Line Therapy for Patients With Locally Advanced or Metastatic NSCLC Background: Anti-PD-1/L1 therapies have improved OS by 2-4 mo vs TAX in patients (pts) with advanced NSCLC who progressed after platinum regimens. TIS is an anti-PD-1 antibody engineered to minimize FcγR binding on macrophages, a mechanism of T-cell clearance and potential anti-PD-1 resistance. Methods: RATIONALE 303 (BGB-A317-303; NCT03358875) compared efficacy and safety of TIS vs TAX as 2 or 3L therapy for pts with advanced NSCLC. Patients without oncogenic driver mutation who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive TIS 200 mg IV Q3W (Arm A) or TAX 75 mg/m2 IV Q3W (Arm B). Dual primary endpoints were OS in the ITT analysis set and OS in the PD-L1 high (≥25% TC) analysis set. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76% of planned events); in the IA, formal OS superiority testing was conducted only in the ITT. The IA results are presented. Results: Overall, 805 pts were randomized (n=535, TIS; n=270, TAX); demographics were generally balanced between arms. With a 19-mo median follow-up (441 OS events), median OSITT was significantly longer in Arm A vs B (17.2 vs 11.9 mo; HR=0.64 [95% CI: 0.53, 0.78]; P<.0001). OS benefit was also observed in the PD-L1 high analysis set (19.1 vs 11.9 mo; HR=0.52 [95% CI: 0.38, 0.71]) and across most subgroups including histology. In the ITT analysis set, PFS, ORR, and DoR were also improved in Arm A vs B (Table). Anemia (TIS) and alopecia (TAX) were the most commonly reported AEs (Table); pneumonia (TIS) and neutropenia (TAX) were the most common grade ≥3 AEs. AEs leading to death were 6.0% (TIS) and 4.3% (TAX); treatment-related AEs leading to death were 1.5% (TIS) and 1.6% (TAX). Conclusions: RATIONALE 303 demonstrated that, as 2 or 3L therapy in pts with advanced NSCLC, TIS was tolerable and prolonged OS by 5-7 mo with improved PFS and ORR vs TAX regardless of histology or PD-L1 expression. ITT Analysis Set (N=805)Arm A Tislelizumab (n=535)Arm B Docetaxel (n=270)EfficacyMedian OS, mo17.211.9OS difference, mo5.3HR (95% CI)a0.64 (0.53, 0.78)P-valuea,b<0.0001Median PFS, mo4.12.6PFS difference, mo1.5HR (95% CI)a0.64 (0.53, 0.76)P-valuea,b<0.0001cORR, n (%)117 (21.9)19 (7.0)ORR difference, %14.9OR (95% CI)3.71 (2.24, 6.14)P-valued<0.0001cMedian DoR, mo (95% CI)13.5 (8.5, 21.8)6.2 (2.1, 7.2)Adverse event profileAEs occurring in ≥15% of patients in either arm, n (%)All gradeGrade ≥3All gradeGrade ≥3Anemia152 (28.5)18 (3.4)112 (43.4)16 (6.2)Alanine aminotransferase increased106 (19.9)4 (0.7)38 (14.7)0Cough104 (19.5)5 (0.9)40 (15.5)1 (0.4)Aspartate aminotransferase increased101 (18.9)5 (0.9)31 (12.0)1 (0.4)Appetite decreased82 (15.4)5 (0.9)59 (22.9)3 (1.2)Weight decreased81 (15.2)4 (0.7)26 (10.1)0Alopecia5 (0.9)0122 (47.3)2 (0.8)Neutrophil count decreased15 (2.8)3 (0.6)95 (36.8)71 (27.5)Neutropenia9 (1.7)3 (0.6)81 (31.4)72 (27.9)White blood cell count decreased20 (3.7)1 (0.2)74 (28.7)47 (18.2)Leukopenia15 (2.8)1 (0.2)69 (26.7)41 (15.9)Asthenia67 (12.5)6 (1.1)56 (21.7)14 (5.4)Constipation65 (12.2)042 (16.3)0Hypoalbuminemia70 (13.1)041 (15.9)1 (0.4)Nausea59 (11.0)041 (15.9)1 (0.4)Abbreviations: AE, adverse event; DoR, duration of response; HR, hazard ratio; ITT, intent-to-treat; mo, months; NA, not available; OR, odds ratio; ORR, objective response rate; PFS, progression-free survival.aStratified.bOne-sided log-rank test.cDescriptive P-value.dCochran-Mantel-Haenszel. Citation Format: Caicun Zhou, Dingzhi Huang, Xinmin Yu, Yunpeng Liu, Yun Fan, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Mikhail Dvorkin, Elena Poddubskaya, Umut Disel, Andrey Akopov, Yiyuan Ma, Yan Wang, Zhenyu Pan, Cunjing Yu, Gareth Rivalland. Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT039.

Cost-Effectiveness of Tislelizumab Versus Docetaxel for Previously Treated Advanced Non-Small-Cell Lung Cancer in China

“…A partitioned survival model was developed based on the RATIONALE 303 clinical trial (NCT03358875) to measure the clinical and economic outcomes of two second- or third-line treatment strategies for patients with advanced NSCLC: 1) tislelizumab 200 mg every three weeks (Q3W) and 2) docetaxel 75 mg/m 2 every three weeks (Q3W) ( Zhou et al, 2021 ). A hypothetical cohort with locally advanced or metastatic squamous or non-squamous NSCLC patients previously treated by one–two prior therapies including at least the platinum-doublet chemotherapy, with negative EGFR mutation or ALK translocation established to compare these two treatments.…”

“…K-M survival data for PFS and OS were available from the phase III RATIONALE 303 trial ( Zhou et al, 2021 ). The PFS and OS probabilities were extracted from the PFS and OS K-M curves of each treatment group using GetData Graph Digitizer (version 2.24, http://www.getdata-graph-digitizer.com/download.php ).…”

“…Costs were estimated from the perspective of the Chinese healthcare system, which only considered direct medical costs ( Liu et al, 2020 ), including drug acquisition, management of grade 3/4 AEs, routine follow-up in the PFS state, subsequent systemic therapy after progression, and BSC and terminal phase treatment ( Table 1 ). In accordance with the RATIONALE 303 trial, 200 mg tislelizumab and 75 mg/m 2 docetaxel were administered intravenously on the first day of every 3 weeks in two treatment arms, respectively ( Zhou et al, 2021 ). The unit cost of tislelizumab referred to the China’s National Reimbursement Drug List (NRDL) 2020 ( NHSA, 2020 ).…”

“…Excitingly, tislelizumab has shown great antineoplastic activity both in hematological cancers and advanced solid tumors ( Lee and Keam, 2020 ). The efficacy and safety of tislelizumab in treating advanced NSCLC have been demonstrated in several clinical studies ( Lu et al, 2021 ; Zhou et al, 2021 ). Tislelizumab significantly prolongs progression-free survival (PFS) and overall survival (OS) as well as improves the response rate compared with docetaxel in patients with locally advanced or metastatic NSCLC with disease progression after initial platinum-based chemotherapy ( Zhou et al, 2021 ).…”

“…The efficacy and safety of tislelizumab in treating advanced NSCLC have been demonstrated in several clinical studies ( Lu et al, 2021 ; Zhou et al, 2021 ). Tislelizumab significantly prolongs progression-free survival (PFS) and overall survival (OS) as well as improves the response rate compared with docetaxel in patients with locally advanced or metastatic NSCLC with disease progression after initial platinum-based chemotherapy ( Zhou et al, 2021 ). Currently, due to the exorbitant price of PD-1/PD-L1 antibodies, neither pembrolizumab nor nivolumab present to be cost-effective as second-line treatment for patients with NSCLC in China ( Liu et al, 2019 ; Zhou et al, 2019 ; Shi et al, 2021 ).…”