As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.
The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).
Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.
Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.
In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.
The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
Study Details
RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.
The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.
Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).
Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m2 every 3 weeks (n = 270) until unacceptable toxicity or disease progression.
The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
Survival and Safety
In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.
The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).
In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.
The OS benefit with tislelizumab was observed across nearly all subgroups, Zhou noted.
In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).
The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.
The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
“Very Important Trial”
“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Zhou concluded.
Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”
Citing the range of immunotherapies available for NSCLC, Garassino said, “We have a very crowded space in the treatment of NSCLC. … It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”
RATIONALE 303 was funded by BeiGene. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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