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
Authors: Zhou Caicun , Huang Dingzhi , Yu Xinmin , Liu Yunpeng , Fan Yun , Shu Yongqian , Ma Zhiyong , Wang Ziping , Cheng Ying , Wang Jie , Hu Sheng , Liu Zhihua , Dvorkin Mikhail , Poddubskaya Elena , Disel Umut , Akopov Andrey , Ma Yiyuan , Wang Yan , Pan Zhenyu , Yu Cunjing , Rivalland Gareth 
Published: July 2021

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&lt;.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&lt;0.0001Median PFS, mo4.12.6PFS difference, mo1.5HR (95% CI)a0.64 (0.53, 0.76)P-valuea,b&lt;0.0001cORR, n (%)117 (21.9)19 (7.0)ORR difference, %14.9OR (95% CI)3.71 (2.24, 6.14)P-valued&lt;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.