Tislelizumab trumps docetaxel in pre-treated NSCLC

The anti-PD-1 antibody tislelizumab may help improve patient outcomes vs docetaxel as second- or third-line treatment for advanced or metastatic non–small-cell lung cancer (NSCLC) regardless of histology or PD-L1 expression, interim findings from the phase III RATIONALE 303 study have shown.

“Tislelizumab improved survival and response rates … it was also associated with a notably lower incidence of grade 3 or higher adverse events,” reported study investigator Dr Caicun Zhou from Shanghai Pulmonary Hospital in China at the AACR 2021 virtual meeting.

After a median follow-up of 19 months, the risk for death was 36 percent lower with tislelizumab than with docetaxel. [AACR 2021, abstract CT039]

Median overall survival (OS) in the intent-to-treat population (ITT) was significantly longer in the tislelizumab arm than in the docetaxel arm  (17.2 vs 11.9 months; hazard ratio [HR], 0.64; p<0.0001). The 12- and 24-month survival rates were 61.9 percent and 39.4 percent for tislelizumab vs 49.8 percent and 25.0 percent for docetaxel.

Among patients with high PD-L1 expression (≥25 percent tumour cell staining; 42–43 percent of the cohort), the risk for death was 48 percent lower with tislelizumab than with docetaxel, with OS of 19.1 and 11.9 months, respectively (HR, 0.52; p<0.0001).

“OS benefits were similar across most subgroups studied, including squamous vs nonsquamous histology and different PD-L1 expression levels,” said Zhou.

In addition, median progression-free survival (4.1 vs 2.6 months), objective response rate (21.9 vs 7.1 percent), and median duration of response (approximately 13.5 vs 6.2 months) were significantly better with tislelizumab than with docetaxel.

Checkpoint inhibition in pre-treated NSCLC

RATIONALE 303 enrolled 805 patients with locally advanced or metastatic NSCLC who had no known  EGFR mutations or ALK fusions but failed at least 1 prior systemic therapy including a platinum regimen. They were randomly assigned to receive intravenous tislelizumab 200 mg (n=535) or docetaxel 75 mg/m² every 3 weeks (n=270).  

Patients' median age was 61 years, 77 percent were male, 80 percent were Asian, and about 70 percent were current or former smokers. Roughly 46 percent had squamous histology, and about 43 percent had PD-L1 expression of ≥25 percent.

Dual primary endpoints were OS in the ITT and PD-L1 ≥25 percent populations. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76 percent of planned events).

Patients were still on treatment at data cut-off: 20.2 percent and 4.4 percent in the tislelizumab and docetaxel groups, respectively.

In terms of safety, 14.4 percent of those who received tislelizumab experienced a grade 3 or higher treatment-related adverse event (TRAE) during a mean 10.5 cycles of treatment, compared with 66.3 percent of those who received docetaxel for a mean 9.4 cycles.

Serious TRAEs occurred in 12.5 percent of patients on tislelizumab and 22.9 percent of those on docetaxel. Treatment-related deaths were  1.5 percent (n=8) and 1.6 percent (n=4), respectively.

Anaemia was the most commonly reported AE of any grade with tislelizumab, occurring in 28.5 percent of patients. This rate was lower than that seen with docetaxel at 43.4 percent. The most common AE with docetaxel was alopecia (reported by 47.3 percent of patients vs  0.9 percent for tislelizumab).

“Tislelizumab showed a tolerable and manageable safety profile … it prolonged OS by about 5  months, with improved PFS and ORR vs docetaxel regardless of histology or PD-L1 expression,” Zhou summarized. “Overall, tislelizumab produced meaningful clinical benefits.”

Why results matter

Anti-PD-1/L1 therapies have improved OS vs docetaxel in patients with advanced NSCLC who progressed after platinum regimens.

Tislelizumab may be a new treatment option, engineered to minimize Fc-gamma receptor binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential anti-PD-1 resistance, said Zhou.