First-Line Tislelizumab Plus Chemotherapy vs Chemotherapy Alone in Advanced Squamous NSCLC

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In the Chinese phase III RATIONALE 307 trial reported in JAMA Oncology, Wang et al found that tislelizumab plus chemotherapy significantly prolonged progression-free survival vs chemotherapy alone in the first-line treatment of patients with advanced squamous non–small cell lung cancer (NSCLC).

As stated by the investigators, “Tislelizumab, a monoclonal antibody with high binding affinity to the [PD-1] receptor, was specifically engineered to minimize Fcγ receptor binding on macrophages, thereby abrogating antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti–PD-1 therapy.”

Study Details

In the multicenter open-label trial, 360 patients with stage IIIB/IV disease were randomly assigned 1:1:1 between July 2018 and June 2019 to receive tislelizumab plus paclitaxel/carboplatin (n = 120), tislelizumab plus nab-paclitaxel (n = 119), or paclitaxel/carboplatin. Tislelizumab was given on day 1 of 21-day cycles until lack of clinical benefit or intolerable toxicity. Chemotherapy consisted of four to six 21-day cycles of paclitaxel at 175 mg/m2 on day 1; carboplatin at AUC 5 on day 1; and nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15.

Patients in the chemotherapy-alone group could cross over to receive tislelizumab monotherapy if they developed progressive disease. The primary endpoint was progression-free survival, as assessed by an independent review committee (IRC).

Progression-Free Survival

Median follow-up was 8.6 months (95% confidence interval [CI] = 8.1–9.0 months) at data cutoff in December 2019. Median progression-free survival on IRC assessment was 7.6 months (95% CI = 6.0–9.8 months) in the tislelizumab plus paclitaxel/carboplatin group (stratified hazard ratio [HR] = 0.524, 95% CI = 0.370–0.742, P < .001, vs chemotherapy alone), 7.6 months (95% CI = 5.8–11.0 months) in the tislelizumab plus nab-paclitaxel group (stratified HR = 0.478, 95% CI = 0.336–0.679, P < .001, vs chemotherapy alone), and 5.5 months (95% CI = 4.2–5.7 months) in the chemotherapy group. Progression-free survival rates at 9 months were 41.7%, 47.2%, and 17.5%, respectively.


  • Both tislelizumab plus paclitaxel/carboplatin and tislelizumab plus nab-paclitaxel improved progression-free survival vs paclitaxel/carboplatin.
  • Median progression-free survival was 7.6 months and 7.6 months vs 5.5 months.

An objective response on IRC assessment was observed in 73% (complete response in 4%), 75% (complete response in 3%), and 50% (complete response in < 1%) of patients, respectively; median durations of response were 8.2 months (95% CI = 5.0 months–not estimable), 8.6 months (95% CI = 6.3 months–not estimable), and 4.2 months (95% CI = 2.8–4.9 months), respectively. Overall survival data were not mature at the time of analysis.

As related by the investigators, no associations between PD-L1 expression and progression-free survival or objective response were observed. Hazard ratios for progression-free survival were 0.64 (95% CI = 0.37–1.10) among 97 patients with expression of < 1% and 0.45 (95% CI = 0.29–0.70) among 144 with expression ≥ 1% for the tislelizumab plus paclitaxel/carboplatin vs chemotherapy group. Hazard ratios for progression-free survival were 0.69 (95% CI = 0.41–1.18) among 96 patients with expression of < 1% and 0.37 (95% CI = 0.23–0.59) among 144 patients with expression ≥ 1%, respectively, for the tislelizumab plus nab-paclitaxel vs chemotherapy group.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 85.8% of the tislelizumab plus paclitaxel/carboplatin group, 83.9% of the tislelizumab plus nab-paclitaxel group, and 80.3% of the chemotherapy group, with the majority being hematologic adverse events consistent with chemotherapy. Serious treatment-related adverse events occurring in ≥ 2% of patients in any group included decreased neutrophil levels (3.3%, 3.4%, and 1.7%, respectively), febrile neutropenia (1.7%, 2.5%, and 0.9%, respectively), thrombocytopenia (0.8%, 0.8%, and 2.6%, respectively), and pneumonitis (2.5%, 1.7%, and 0%, respectively).

Adverse events of any cause resulted in discontinuation of any treatment component in 12.5% (tislelizumab in 10.0%), 29.7% (tislelizumab in 10.2%), and 15.4% of patients, respectively.  Adverse events of any cause led to death in 3.3%, 4.2%, and 4.3% of patients, and were considered related to treatment in one patient, two patients, and three patients, respectively, with no deaths considered solely attributable to tislelizumab.

Hyperglycemia, hypothyroidism, and pneumonia were the most common potential immune-mediated adverse events in patients receiving tislelizumab, with most being grade 1 to 2 and none leading to discontinuation of treatment.

The investigators concluded, “In this phase III randomized clinical trial, adding tislelizumab to chemotherapy was associated with significantly prolonged IRC-assessed progression-free survival, higher IRC-assessed objective response rates, and a manageable safety/tolerability profile in patients with advanced squamous NSCLC, regardless of PD-L1 expression.”

Jie Wang, MD, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by BeiGene, Ltd. For full disclosures of the study authors, visit

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