Lung cancer remains the most common cancer and a leading cause of cancer-related mortality, with improved but still suboptimal survival outcomes despite advances in treatment. At a recent symposium chaired by Dr Shi-Feng Nyaw, Specialist in Clinical Oncology, Hong Kong, Professor Tianqing Chu, Consultant at the Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai, China, highlighted how tislelizumab, a novel immunotherapy agent, differs from other anti–programmed death receptor 1 (PD-1) therapies. She presented efficacy and safety data for tislelizumab in both squamous and non-squamous non-small-cell lung cancer (NSCLC) from RATIONALE-307/304 and her routine clinical practice. Additionally, Professor Victor Lee, Clinical Professor at the Department of Clinical Oncology, The University of Hong Kong, shared real-world cases illustrating the clinical benefits of tislelizumab in NSCLC patients.
Tislelizumab: A novel immunotherapy for NSCLC
“Immunotherapy has revolutionized the treatment landscape of NSCLC over the past decade, significantly improving survival outcomes and becoming the mainstay for managing locally advanced and metastatic disease lacking targetable oncogenic drivers,” said Chu.
Building on this progress, tislelizumab, a humanized immunoglobulin G4 monoclonal antibody targeting PD-1, has gained approval from the European Medicines Agency (EMA) and in Hong Kong, and is recommended by the European Society for Medical Oncology (ESMO) guidelines as a first-line immunotherapy option, in combination with chemotherapy, for adult patients with squamous or non-squamous NSCLC. [Cancer 2025;131:e35476; ESMO Living Guideline, v1.2 January 2025; Tevimbra SmPC; Tevimbra Hong Kong Prescribing Information, 2025]
Tislelizumab: An innovative and unique PD-1 inhibitor
“Tislelizumab binds differently from other anti–PD-1 antibodies that primarily target flexible loops of PD-1. Its distinctive molecular structure enables it to engage the front β-sheet of PD-1, mimicking the way PD-L1 binds. This unique binding mode allows tislelizumab to block the PD-1/PD-L1 interaction with higher affinity and a notably slower dissociation rate than other anti–PD-1 antibodies. It also enables prolonged receptor engagement, which may enhance inhibitory effects on PD-1/PD-L1 signalling, potentially leading to improved antitumour immune responses and better clinical outcomes,” pointed out Chu. [Biochem Biophys Res Commun 2020;527:226-231; Cancer Res 2019;79(13 Suppl):2383; Cureus 2025;17:e87664]
“Moreover, tislelizumab was engineered to minimize binding to Fcγ receptors on macrophages, thereby reducing antibody-dependent phagocytosis — a process that can deplete T cells and contribute to anti– PD-1 therapy resistance — and allowing T cells to remain activated and maintain their effector functions,” Chu added. [Expert Opin Investig Drugs 2020;29:1355-1364]
Emerging evidence from translational research suggests that engagement of Fcγ receptors on tumour-associated macrophages may promote tumour progression and hyperprogression, a paradoxical boost in tumour growth observed in some patients treated with immune checkpoint inhibitors (ICIs). An in vitro study confirmed that, unlike other anti–PD-1 antibodies, tislelizumab exhibits no binding to Fcγ receptors. “Thus, tislelizumab is theoretically less likely to induce hyperprogression, a phenomenon observed with other anti–PD-1 antibodies, which is characterized by an early crossing of survival curves — reflecting an initial period of rapid tumour growth and inferior progression-free survival [PFS] and/or overall survival [OS] during the first 3–6 months of treatment — followed by a later overcrossing suggestive of improved long-term outcomes,” said Chu. [Clin Cancer Res 2019;25:989-999; Cancer Immunol Immunother 2018;67:1079-1090; Lancet 2019;393:1819-1830; Clin Cancer Res 2020;26:1846-1855; N Engl J Med 2015;373:1627-1639]
Efficacy of tislelizumab
Tislelizumab has demonstrated improved outcomes in both squamous and non-squamous NSCLC in the phase III RATIONALE-307 and RATIONALE-304 trials, respectively. “The data supported the regulatory approval of tislelizumab and were highly relevant to real-world practice in Hong Kong, as these trials primarily recruited Asian patients with advanced disease,” highlighted Chu. [JAMA Oncol 2021;7:709-717; J Thorac Oncol 2021;16:1512-1522]
The open-label RATIONALE-307 trial included 355 treatment-naïve patients with stage IIIB (34 percent) or IV (66 percent) squamous NSCLC, randomized in a 1:1:1 ratio to receive either tislelizumab plus paclitaxel and carboplatin (PC), tislelizumab plus nab-paclitaxel and carboplatin (nab-PC), or chemotherapy (PC) alone, followed by tislelizumab maintenance. [JAMA Oncol 2021;7:709-717]
Similarly, RATIONALE-304 enrolled 332 treatment-naïve patients with stage IIIB (18 percent) or IV (82 percent) non-squamous NSCLC, randomized 2:1 to receive tislelizumab plus platinum chemotherapy and pemetrexed followed by maintenance tislelizumab plus pemetrexed, or chemotherapy alone followed by maintenance pemetrexed. [J Thorac Oncol 2021;16:1512-1522]
Prolonged PFS in both squamous and non-squamous NSCLC
In both RATIONALE-307 and RATIONALE-304, median PFS was significantly extended with tislelizumab plus chemotherapy vs chemotherapy alone, after a median follow-up of 16.7 and 12 months, respectively. [ESMO Open 2024;9:103727; J Thorac Oncol 2021;16:1512-1522]
Notably, in RATIONALE-304, patients with PD-L1 expression ≥50 percent experienced the greatest benefit, with a median PFS of 14.6 vs 4.6 months (hazard ratio [HR], 0.31; 95 percent confidence interval [CI], 0.18–0.55), after a median follow-up of 16.5 months. (Figure 1) [Oncol Ther 2025;doi:10.1007/s40487-025-00378-8]
Higher response rate and durable response
Compared with chemotherapy alone, tislelizumab plus chemotherapy resulted in higher and more durable overall response rates (ORRs) in both trials. “In RATIONALE-307, substantially higher ORR and longer duration of response [DoR] were observed in patients with squamous NSCLC receiving tislelizumab plus PC [72.5 percent; 8.2 months] or nab-PC [74.8 percent; 8.6 months] vs chemotherapy alone [49.6 percent; 4.2 months],” noted Chu. (Figure 2) “The increase in ORR with tislelizumab plus chemotherapy was observed regardless of PD-L1 expression levels.” [Wang J, et al. Presentation at CSCO 2020]
In RATIONALE-304, ORR was also substantially higher with tislelizumab plus chemotherapy (57.4 percent; median DoR, 8.5 months) vs chemotherapy alone (36.9 percent; median DoR, 6.0 months). [J Thorac Oncol 2021;16:1512-1522]
Long-term survival benefits
Long-term follow-up (median, 50.3 months) of RATIONALE-307 demonstrated meaningful OS benefits with tislelizumab plus PC or nab-PC vs chemotherapy alone (cross-over adjusted median OS, 26.1 [HR, 0.53; 95 percent CI, 0.34–0.84] and 23.3 months [HR, 0.65; 95 percent CI, 0.39–1.07], respectively, vs 16.0 months). The 4-year OS rates were 32.2 and 26.0 percent, respectively, vs 19.2 percent. PFS benefits were also sustained in both tislelizumab groups (HRs, 0.45; 95 percent CI, 0.33–0.62), indicating consistent long-term disease control with these regimens. [Wang Z, et al, ESMO 2024, FPN 1323P]
“More importantly, 17.6 percent of patients in RATIONALE-307 received ≥35 cycles of tislelizumab, with a median of 58 treatment cycles. The ORR was 100 percent, and the 4-year OS rate was 97.5 percent. This clearly reflects how effective and tolerable tislelizumab is in this patient population,” Chu remarked.
Similarly, long-term data from RATIONALE-304 demonstrated a 4-year OS rate of 32.8 percent with tislelizumab plus chemotherapy (adjusted HR, 0.67; 95 percent CI, 0.48–0.95), with PFS benefits also maintained (HR, 0.61; 95 percent CI, 0.46–0.82). [Ann Oncol 2024;35:S1637]
Safety profile of tislelizumab
First-line treatment with tislelizumab plus chemotherapy was generally well tolerated. Adverse events (AEs) were manageable and comparable to those observed with other PD-1 or PD-L1 inhibitors combined with chemotherapy. Most reported AEs were mild to moderate, consistent with typical chemotherapy-related toxicity. Most potential immune-mediated AEs were of grade 1 or 2, and seldom resulted in treatment discontinuation. [JAMA Oncol 2021;7:709-717; J Thorac Oncol 2021;16:1512-1522]
Real-world experience with tislelizumab
“In clinical practice, young and fit patients with good performance status may benefit more from tislelizumab plus chemotherapy than from tislelizumab monotherapy. Among nearly 400 patients treated at our hospital, combination therapy was associated with high ORR, long DoR, and potentially long-term survival, making it the preferred approach,” noted Chu, in response to Nyaw’s question on treatment selection.
Chu and Lee shared patient cases who had impressive outcomes with tislelizumab treatment (cases 1–3). Importantly, no new safety signals were observed in these cases. The outcomes were consistent with published data and further support routine use of tislelizumab in clinical practice.
The use of tislelizumab in the clinical cases reflects
the clinical judgment of the treating physicians. For detailed information on
locally approved usage and indications, please refer
to the Hong Kong package insert.
