Tislelizumab—Current Status and Future Directions: A Review Article

Abstract

Tislelizumab is a humanized IgG4 monoclonal antibody targeting programmed death-1 (PD-1), uniquely engineered to minimize Fcγ-receptor (FcγR) binding on macrophages, thereby reducing macrophage-mediated clearance of PD-1-expressing effector T cells. This design sustains antitumor immune responses and distinguishes it mechanistically from earlier PD-1 inhibitors. Clinical evidence from the phase III RATIONALE trials demonstrates broad efficacy across multiple solid tumors, including esophageal squamous cell carcinoma (ESCC), gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC). In ESCC, tislelizumab significantly improved overall survival in both second-line (RATIONALE-302) and first-line (RATIONALE-306) settings, while in G/GEJ adenocarcinoma (RATIONALE-305), dual primary endpoints of overall survival were achieved in both PD-L1-positive and intention-to-treat populations. The RATIONALE-301 trial in HCC showed noninferiority to sorafenib with improved tolerability. In NSCLC (RATIONALE-304 and 307), combination therapy with platinum-based chemotherapy prolonged progression-free survival and response rates, while RATIONALE-312 extended benefits to extensive-stage SCLC with survival improvement and manageable toxicity. Across studies, adverse events were consistent with the PD-1 inhibitor class and generally less frequent or severe than chemotherapy backbones. Collectively, tislelizumab delivers broad antitumor activity, durable responses, and a favorable safety profile. Ongoing investigations are exploring its role in perioperative, combinatorial, and biomarker-driven strategies, supporting its emergence as a versatile PD-1 inhibitor with potential to reshape contemporary oncology practice.

Keywords

medical oncology - tislelizumab - PD-1 inhibitor - immunotherapy - RATIONALE trials

Introduction

Immune checkpoint inhibition against the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has transformed the treatment landscape across many solid tumors. While several PD-1/PD-L1 antibodies are now standard of care, tislelizumab is differentiated by intentional Fc engineering to diminish Fcγ-receptor (FcγR) engagement and mitigate macrophage-mediated clearance of PD-1+ effector T cells, a mechanism proposed to underlie primary or acquired resistance to anti-PD-1 therapy.[1] [2] Since its first approvals, an expanding program of randomized trials has established activity in esophageal squamous cell carcinoma (ESCC), gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), with additional perioperative and biomarker-directed efforts underway.[3] [4] [5] [6] [7] [8] Regulatory approval of tislelizumab varies by indication and jurisdiction. It is approved in China for multiple malignancies including ESCC, G/GEJ adenocarcinoma, NSCLC, SCLC, and HCC, while approvals in other regions remain limited or under regulatory review. At the same time, maturing population pharmacokinetic (PK) models and exposure–response analyses support practical, flat-dose regimens and inform dose scheduling.[9]

This article reviews the biologic rationale for tislelizumab's engineering, summarizes pivotal evidence across tumor types, and outlines evolving frontiers such as multimodality sequencing, combinatorial strategies, and precision selection. Interpretation of efficacy across studies should be approached with caution due to inherent limitations of cross-trial comparisons, including heterogeneity in patient populations, geographic enrollment, disease burden, PD-L1 assays and scoring systems (tumor area positivity [TAP] vs. combined positivity score [CPS] vs. immune cell score [IC]), chemotherapy backbones, duration of follow-up, and access to postprogression therapies. Regional differences in supportive care and immunotherapy availability may further influence survival outcomes.

Methodology

A structured literature search was conducted in PubMed, Embase, and major oncology congress proceedings (American Society of Clinical Oncology, European Society for Medical Oncology, and World Conference on Lung Cancer) up to March 2025 using the terms “tislelizumab,” “PD-1 inhibitor,” and individual tumor types, prioritizing peer-reviewed phase II/III trials, regulatory submissions, and major conference updates.

Molecular Design and Mechanism of Action

Fc Engineering to Minimize FcγR Binding

Tislelizumab retains the PD-1-blocking function of the IgG4 class but is engineered to minimize FcγRI (CD64) and broader FcγR interactions on macrophages.[1] [2] Preclinical work comparing parental constructs demonstrated that FcγRI cross-linking can paradoxically switch an anti-PD-1 antibody from inhibitory to agonistic signaling and promote antibody-dependent cellular phagocytosis of PD-1+ T cells by macrophages, with diminished antitumor activity in vivo; conversely, the low-FcγR-binding construct preserved T cell function and tumor control.[1] These findings provide a mechanistic rationale unique among clinically deployed PD-1 antibodies and remain a cornerstone of tislelizumab's design.

Target Binding and Immunobiology

Tislelizumab exhibits high-affinity PD-1 binding and blocks interaction with PD-L1/PD-L2 to restore effector T cell function in the tumor microenvironment, similar to the PD-1 class.[1] [2] [3] The engineered Fc behavior is not intended to augment direct effector functions (e.g., antibody-dependent cellular cytotoxicity) but rather to avoid deleterious macrophage interactions, potentially sustaining a more durable effector T cell pool in PD-1-rich niches.[1] [2] [10] [11]

Clinical Pharmacology

Pharmacokinetics and Exposure–Response

A large population PK analysis (14,473 concentrations from 2,596 patients across 12 studies) showed approximately linear PK for tislelizumab over 0.5 to 10 mg/kg every 2 to 3 weeks and with a flat 200 mg Q3W dose; common covariates (body weight, albumin, tumor size, tumor type, antidrug antibodies) had limited clinical impact on exposure.[9] Exposure–response modeling supports flat dosing and aligns with class expectations for half-life and receptor occupancy.[9] [10] Clinically meaningful immunogenicity has been low, without evident exposure penalties across subgroups in the pooled analyses to date.[9] [10]

Esophageal Squamous Cell Carcinoma

Second-Line Setting—RATIONALE-302

In RATIONALE-302, 512 patients with previously treated advanced or metastatic ESCC were randomized 1:1 to tislelizumab 200 mg every 3 weeks versus investigator's-choice chemotherapy (paclitaxel, docetaxel, or irinotecan).[3]

• After a median follow-up of 10.3 months, the median overall survival (OS) was 8.6 months with tislelizumab versus 6.3 months with chemotherapy (hazard ratio [HR] 0.70; 95% confidence interval [CI] 0.57–0.85; p = 0.0001). The 12-month OS rate reached 37.4% compared with 23.7% in the control arm, indicating a sustained late-tail separation typical of durable immune responses.

• Progression-free survival (PFS) was comparable (median 1.6 vs. 2.1 months), reflecting the immunotherapy response-kinetics pattern, yet the objective response rate (ORR) doubled (20.3% vs. 9.8%). Duration of response (DoR) was also prolonged (median 7.1 vs. 4.0 months).

• Safety favored tislelizumab, with grade ≥ 3 treatment-related adverse events (TRAEs) occurring in 46% versus 68% of chemotherapy recipients. Immune-related AEs (irAEs) such as hypothyroidism (8%), rash (6%), and pneumonitis (2%) were manageable with standard algorithms.

• Subgroup analyses demonstrated consistent OS benefit across PD-L1 TAP < 10% and ≥ 10%, geographic regions, and prior taxane exposure.

• Importantly, quality-of-life (QoL) data showed significant preservation of global health status and functional scores compared with deterioration under chemotherapy.[12] [13]

First-Line Setting—RATIONALE-306

The phase III RATIONALE-306 trial enrolled 997 patients with previously untreated, unresectable, or metastatic ESCC. Patients received tislelizumab + platinum/fluoropyrimidine chemotherapy versus placebo + chemotherapy.[4]

• With a median follow-up of 15 months, median OS improved from 11.5 months (placebo arm) to 17.2 months with tislelizumab (HR 0.70; 95% CI 0.60–0.81; p < 0.0001). The 12-month OS rate was 66% versus 50%, and PFS increased to 7.3 versus 5.6 months (HR 0.65). ORR rose to 63% compared with 47%, and median DoR = 7.1 versus 4.5 months.

• PD-L1 TAP subgroup analyses showed pronounced benefit in TAP ≥ 10% (HR 0.58) but a maintained trend even in TAP-low cohorts (HR 0.83). Tislelizumab's toxicity profile aligned with class expectations; grade ≥ 3 TRAEs occurred in 58% versus 64%, and discontinuations due to AEs were 7% versus 10%.

These results mirror and, in some subgroups, surpass OS gains seen with pembrolizumab in KEYNOTE-590, consolidating tislelizumab plus chemotherapy as a first-line standard of care for ESCC in regions where regulatory approval has been granted, particularly in China.

Gastric and Gastroesophageal Junction Adenocarcinoma

First-Line G/GEJ—RATIONALE-305

RATIONALE-305 is the largest global phase III trial of tislelizumab in this setting, enrolling 997 patients with previously untreated, locally advanced, or metastatic HER2-negative G/GEJ adenocarcinoma.[5] Participants received tislelizumab 200 mg Q3W + platinum-fluoropyrimidine chemotherapy versus placebo + chemotherapy. Dual primary endpoints were OS in PD-L1 TAP ≥ 5% and in the intention-to-treat (ITT) population.

The trial met both endpoints:

• In PD-L1 TAP ≥ 5%, median OS = 18.1 versus 12.9 months (HR 0.66; 95% CI 0.56–0.78).

• In ITT, median OS = 15.8 versus 12.0 months (HR 0.75; p = 0.002). PFS improved modestly (HR 0.79), while ORR was 61% versus 51%.

Safety results were comparable: grade ≥ 3 TRAEs in 59% versus 61%; immune-related events were mostly thyroid disorders (8%), hepatitis (3%), and rash (2%). Subgroup analyses revealed benefit across geographic regions, histologic subtypes, and CPS strata. Compared with nivolumab + chemotherapy from CheckMate 649 (HR 0.80 in ITT), RATIONALE-305's HR 0.75 suggests at least comparable efficacy, lending weight to tislelizumab's potential class equivalence with possible regional access advantages.

Hepatocellular Carcinoma

First-Line HCC—RATIONALE-301

The RATIONALE-301 study compared tislelizumab monotherapy with sorafenib 400 mg "twice a day as first-line therapy in 674 patients with unresectable HCC.[6]

• Tislelizumab achieved noninferior OS (median 15.9 vs. 14.1 months; HR 0.85; 95% CI 0.71–1.02) and a clinically higher ORR (14.3% vs. 5.4%), reflecting more durable immunologic responses.

• 12-month OS rate: 61.1% versus 53.3%.

• Median DoR = 36.1 versus 13.4 weeks.

• Safety favored tislelizumab: grade ≥ 3 AEs ≈ 48% versus 65%, with far fewer hand-foot reactions and hypertension cases.

• Subgroup outcomes were consistent across hepatitis B virus-dominant Asian populations and nonviral etiologies.

Although not superior to sorafenib in median OS, the late-survival divergence and tolerability mirror those of nivolumab or pembrolizumab monotherapy in similar populations. Ongoing phase II/III trials are evaluating tislelizumab + antiangiogenic combinations (e.g., bevacizumab, surufatinib) and with TACE as bridging therapy—key to challenging the atezolizumab + bevacizumab benchmark.

Non-Small Cell Lung Cancer

Nonsquamous—RATIONALE-304

• In 733 patients with stage IIIB/IV nonsquamous NSCLC without EGFR/ALK (epidermal growth factor receptor/anaplastic lymphoma kinase) alterations, tislelizumab + pemetrexed/platinum significantly prolonged PFS (9.7 vs. 7.6 months; HR 0.65; p = 0.004) and showed a positive OS trend.[7] [14]

• Updated analysis (2024): median OS = 22.9 versus 18.7 months (HR 0.81), ORR = 57% versus 37%, DoR = 8.6 versus 5.0 months.

• The benefit persisted irrespective of PD-L1 expression, smoking status, or age > 65 years.

• Grade ≥ 3 TRAEs = 53% versus 50%; immune hepatitis and pneumonitis < 3%.

These findings echo KEYNOTE-189 (pembrolizumab + chemo), underscoring tislelizumab's therapeutic equivalence.

Squamous—RATIONALE-307

• This trial enrolled 360 patients with stage IV squamous NSCLC.[15] Tislelizumab + platinum/taxane improved PFS (7.6 vs. 5.5 months; HR 0.48; p < 0.001) and increased ORR (72% vs. 50%) and DoR (8.3 vs. 4.2 months).

• OS at 24 months = 44% versus 31%.

• Final analysis (2024) confirmed OS HR ≈ 0.73 (95% CI 0.59–0.90).

• Toxicities were manageable; hematologic AEs dominated (neutropenia 33%, anemia 23%), with grade ≥ 3 irAEs < 5%.

• Health-related QoL analyses showed sustained symptom control and slower functional decline compared with chemotherapy alone.

Collectively, RATIONALE-304/307 position tislelizumab as a first-line standard PD-1 option across NSCLC histologies.

Small Cell Lung Cancer

First-Line Extensive-Stage SCLC—RATIONALE-312

In the pivotal phase III RATIONALE-312 trial, 462 patients with previously untreated extensive-stage SCLC (ES-SCLC) were randomized 1:1 to receive tislelizumab 200 mg every 3 weeks in combination with platinum (carboplatin or cisplatin) and etoposide, or placebo plus the same chemotherapy backbone.[8] [16]

• The study met its primary endpoint of PFS improvement and showed a favorable OS trend.

• At final analysis, median PFS was 5.6 months with tislelizumab versus 4.5 months for placebo (HR 0.70; 95% CI 0.56–0.88; p = 0.002).

• Median OS was 15.5 versus 13.3 months (HR 0.76; 95% CI 0.62–0.92), with 12-month OS rates of 59 and 48%, respectively.

• The ORR was 70% versus 60%, and median DoR reached 6.9 versus 4.3 months.

• Subgroup analyses revealed consistent OS benefit across age, sex, Eastern Cooperative Oncology Group status, and PD-L1 subgroups. Patients with liver metastases and extensive disease burden also benefited, suggesting broad activity.

• Grade ≥ 3 TRAEs occurred in approximately 66% of both groups, primarily hematologic; irAEs were manageable, with hypothyroidism (6%), rash (4%), and pneumonitis (2%) most frequent. No new safety signals were detected.

Compared with class benchmarks, these outcomes are comparable to atezolizumab (IMpower133, HR 0.70) and durvalumab (CASPIAN, HR 0.73). The Fc-engineered structure of tislelizumab may theoretically enhance sustained T cell engagement while limiting macrophage-mediated immune exhaustion, though head-to-head comparisons are lacking.

Exploratory patient-reported outcome analyses confirmed preserved QoL with slower decline in physical and global health scores compared with chemotherapy alone.[16] Together, RATIONALE-312 establishes tislelizumab plus platinum-etoposide as a safe and effective first-line standard for ES-SCLC, further expanding its therapeutic reach across thoracic malignancies.

Safety and Tolerability

Class-Consistent irAEs; Fewer High-Grade TRAEs versus Chemotherapy in ESCC 2L

Across tumor types, tislelizumab's irAEs mirror those of the PD-1 class—thyroid dysfunction, rash, hepatitis, colitis, and pneumonitis being the most frequent and clinically relevant.[3] [12] [14] [15] [16] In RATIONALE-302, grade ≥ 3 TRAEs were substantially lower with tislelizumab than with chemotherapy, an observation replicated qualitatively in other settings.[3]

Pooled and Supportive Analyses

Pooled analyses and systematic reviews (NSCLC and gastrointestinal [GI] cohorts) indicate no new safety signals and reinforce overall tolerability in monotherapy and combination backbones.[14] [15] [17] [18] As real-world data sets accrue, late immune toxicities and survivorship issues merit ongoing pharmacovigilance and standardized management pathways.

Biomarkers and Patient Selection

PD-L1 Testing and the TAP Score

Many tislelizumab trials adopted the VENTANA SP263 assay with TAP scoring, which quantifies the percentage of tumor area with PD-L1-expressing tumor and immune cells.[3] [4] [5] RATIONALE-305 applied TAP cut-points (e.g., ≥ 5%) for coprimary endpoints, and RATIONALE-302/306 incorporated TAP in stratified analyses.[3] [4] [5] As with the PD-1 class, benefit tends to increase with PD-L1 expression, but ITT-level improvements (e.g., RATIONALE-305) argue for broad applicability, particularly in combination regimens.[5]

Beyond PD-L1: Microenvironmental Context and FcγR Biology

The mechanistic premise for tislelizumab suggests that tumor macrophage density and FcγRI expression might modulate response via T cell clearance dynamics.[1] [2] [11] Emerging preclinical and translational work continues to explore how FcγR biology and myeloid ecosystems interface with PD-1 blockade, raising the possibility that immunophenotypic or spatial signatures could refine patient selection and guide combinations (e.g., antiangiogenics to normalize myeloid compartments).[11] [17] [18]

Emerging Biomarkers Beyond PDL1

Beyond PD-L1 expression, additional biomarkers such as tumor mutational burden, interferon-γ–related gene expression signatures, and circulating tumor deoxyribonucleic acid (ctDNA) dynamics are under investigation for predicting response to PD-1 blockade. While exploratory data suggest potential complementary value, none have yet demonstrated sufficient prospective validation to guide routine patient selection for tislelizumab. PD-L1 testing itself is limited by spatial and temporal heterogeneity, assay variability, and dynamic modulation under therapy.

Perioperative and Neoadjuvant Strategies

Evidence supporting perioperative and neoadjuvant use of tislelizumab is currently derived from phase II trials and real-world observational cohorts. These data should be considered hypothesis-generating until confirmed by randomized phase III studies with long-term event-free (EFS) and OS outcomes.

Ongoing randomized studies are evaluating perioperative and combination strategies, including neoadjuvant tislelizumab plus chemotherapy in ESCC (NCT04973303), dual immunotherapy approaches such as anti-TIGIT BGB-A1217 combined with tislelizumab (NCT04746924), and biomarker-driven expansion cohorts across thoracic and GI malignancies.

Early-phase experiences across ESCC and G/GEJ suggest that neoadjuvant chemoimmunotherapy with tislelizumab can achieve high major pathologic response (MPR) and pathologic complete response (pCR) rates with acceptable safety, warranting randomized confirmation and longer-term EFS/OS readouts. While phase II reports in the public domain vary in regimen and inclusion criteria, the signals are congruent with the class experience of PD-1 blockade in resectable upper GI tumors and portend organ-preservation strategies in ESCC once durability and long-term morbidity are established.[5] [14] [17] [18] Integration with radiotherapy (including low-dose priming concepts) is mechanistically attractive but requires rigorous, controlled evaluation.

Positioning within the PD-(L)1 Class

Comparative Performance and Differentiators

Across ESCC and G/GEJ, tislelizumab's phase III outcomes (OS superiority in RATIONALE-302/306/305) compare favorably with contemporary PD-1 regimens, with numerical differences generally within the class range when controlling for population, assay, and backbone differences.[3] [4] [5] [14] [15] In NSCLC and SCLC, the results are likewise concordant with class expectations for chemoimmunotherapy.[7] [8] [15] [16] The distinctive feature remains the low-FcγR-binding Fc design, a theoretically beneficial attribute that could prove clinically meaningful in macrophage-rich microenvironments; however, head-to-head trials would be required to demonstrate outcome differences attributable to Fc engineering per se[1] [2] [11] [17] [18] ([Table 1]).

Table 1 Pivotal rationale trials of tislelizumab

Trial [Ref], indication	Key eligibility	n	Regimen	Key efficacy outcomes
RATIONALE-302[1] ESCC, 2L	Advanced/metastatic ESCC; ≥ 1 prior systemic therapy	512	Tislelizumab vs. chemotherapy	OS HR 0.70 mOS 8.6 vs. 6.3 mo ORR 20.3% vs. 9.8%
RATIONALE-306[2] [4] ESCC, 1L	Unresectable/metastatic ESCC; no prior systemic therapy	997	Tislelizumab + chemo vs. placebo + chemo	OS HR 0.70 mOS 17.2 vs. 11.5 mo PFS HR 0.65
RATIONALE-305[6] G/GEJ, 1L	HER2-negative advanced/metastatic G/GEJ	997	Tislelizumab + chemo vs. placebo + chemo	OS HR 0.66 (TAP ≥ 5%) HR 0.75 (ITT)
RATIONALE-301[7] HCC, 1L	Unresectable HCC; Child–Pugh A	674	Tislelizumab vs. sorafenib	OS HR 0.85 (noninferiority) ORR 14.3% vs. 5.4%
RATIONALE-304[8] NSCLC non-sq, 1L	Stage IIIB/IV; EGFR/ALK wild-type	733	Tislelizumab + pemetrexed/platinum vs. chemo	PFS HR 0.65 OS HR 0.81
RATIONALE-307[9] [10] NSCLC sq, 1L	Stage IV squamous NSCLC	360	Tislelizumab + platinum/taxane vs. chemo	PFS HR 0.48 OS HR ≈ 0.73
RATIONALE-312[11] ES-SCLC, 1L	Previously untreated ES-SCLC	462	Tislelizumab + platinum/etoposide vs. placebo + chemo	PFS HR 0.70 OS HR 0.76

Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ESCC, esophageal squamous cell carcinoma; ES-SCLC, extensive-stage small cell lung cancer; G/GEJ, gastric and gastroesophageal junction; HCC, hepatocellular carcinoma; HR, hazard ratio; ITT, intention-to-treat; mOS, median overall survival; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TAP, tumor area positivity.

Note: Where efficacy or survival data are derived from conference presentations or abstracts without full peer-reviewed publication, findings should be regarded as preliminary and subject to change with longer follow-up.

Practical Considerations: Dosing, Schedules, and Supportive Care

PK-PD modeling supports flat dosing (e.g., 200 mg Q3W), with limited covariate impact on exposure and no compelling need for individualized adjustments beyond standard clinical judgment.[9] [10] irAE recognition and standardized algorithms (steroid-based management, selective immunosuppression for refractory events) parallel class practice, with institutional pathways facilitating safe, timely treatment.

Unanswered Questions and Future Directions

1. Perioperative ESCC and G/GEJ: Randomized trials should test whether high neoadjuvant MPR/pCR rates with tislelizumab-chemo convert to EFS/OS gains, define optimal chemotherapy backbones, and clarify the role of chemoradiation versus chemoimmunotherapy alone. Organ preservation and functional outcomes merit explicit endpoints.

2. Biomarker refinement: Beyond PD-L1 TAP, myeloid signatures, spatial immune contexture, and integrative multiomic predictors could enrich responders and identify patients likely to derive fast, durable benefit versus those who need intensified combinations.[1] [2] [11] Standardization across assays and jurisdictions (TAP vs. CPS vs. IC scores) remains a practical priority.

3. Rational combinations: Mechanism-based partners include antiangiogenics (vascular normalization; myeloid reprogramming), radiotherapy (antigen release/priming), and coinhibitory/costimulatory targets (e.g., TIGIT, LAG-3, OX40). Early human data (e.g., anti-TIGIT BGB-A1217 with tislelizumab) indicate robust biologic synergy requiring phase III validation.[19]

4. Liver-predominant disease and HCC: In HCC, monotherapy noninferiority to sorafenib with improved tolerability suggests a niche for patients unfit for anti-vascular endothelial growth factor regimens; combinations with antiangiogenics or locoregional therapy should be prioritized to emulate or exceed class-leading doublets.[6] [20]

5. Long-term safety: Multiyear survivors call for structured irAE survivorship frameworks and registries to delineate late toxicities, endocrine sequelae, and rare neurologic/cardiac events. Expanded pooled analyses and real-world studies will be essential.[14] [15] [17] [18]

Conclusion

Tislelizumab is a mature PD-1 inhibitor distinguished by Fc engineering to minimize FcγR binding, underpinned by robust phase III efficacy in ESCC (second- and first-line) and G/GEJ, supportive results across NSCLC and SCLC, and noninferior OS in HCC with favorable tolerability. As perioperative programs, biomarker-driven strategies, and rational combinations advance, tislelizumab's role is likely to broaden. Key priorities include assay harmonization, prospective biomarker validation, and comparative/combination trials to optimize value across global practice settings.

Conflict of Interest

None declared.

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Publication History

Article published online:
05 February 2026