Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC)

ABSTRACT

Introduction

Non-small cell lung cancer (NSCLC) accounts for most lung cancers worldwide and has a poor prognosis at later stages; programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have provided promising new treatment approaches for these patients. Tislelizumab, an anti-PD-1 monoclonal antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Tislelizumab has demonstrated clinical activity and is approved in China for treatment of previously treated classical Hodgkin lymphoma and previously treated metastatic PD-L1–high urothelial carcinoma.

Areas covered

This review summarizes the clinical efficacy, safety, and tolerability of tislelizumab in patients with NSCLC and examines the mechanism of action, pharmacokinetic, and pharmacodynamic profiles of tislelizumab.

Expert opinion

Tislelizumab has higher affinity to PD-1 than pembrolizumab and nivolumab, potentially due to its differential PD‑1 binding orientation. Tislelizumab demonstrated encouraging efficacy results, long duration of response, and a manageable safety profile across multiple clinical trials in advanced NSCLC. Ongoing trials of drug combinations (e.g. tislelizumab plus angiogenesis inhibitors, immune checkpoint inhibitors, or immune agonists) and examining efficacy across the severity of disease will provide opportunities to understand and feature tislelizumab in clinical practice.

KEYWORDS:

• Tislelizumab
• programmed cell death protein-1 (PD-1)
• immunotherapy
• Fc gamma receptor (FcγRs)
• immune checkpoint inhibitor
• non-small cell lung cancer

1. Introduction

With approximately 2.1 million new cases and 1.8 million deaths each year, lung cancer is the leading cause of cancer-related death worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancers and has a poor prognosis at later stages [2,3]. The immune system plays an integral role in tumorigenesis and escape from immune surveillance is a recognized feature of cancer[4]. Many new therapeutic strategies have focused on agents that block inhibitory T-cell immune checkpoints, including antibodies toward cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1) [5,6,7]. Despite limitations to access for some patients, PD-1/PD-L1 inhibitors continue to evolve to address the high mortality rate and are becoming part of the standard-of-care for many patients with NSCLC [8].

2. Overview of the market

2.1. Checkpoint inhibitor monotherapy for previously treated NSCLC

Findings from key trials of patients with previously treated NSCLC receiving checkpoint inhibitor monotherapy are described below and included in Table 1. The global phase 2/3 KEYNOTE-010 study investigated different doses of pembrolizumab for patients with pretreated PD-L1–positive advanced NSCLC and showed improvements in median overall survival at both doses tested (pembrolizumab 2 mg/kg or 10 mg/kg) versus patients receiving docetaxel[9]. Similarly, two global phase 2 trials (BIRCH and FIR) demonstrated that atezolizumab monotherapy had antitumor activity regardless of the line of therapy [10,11]. The potential benefits of nivolumab monotherapy for patients with pretreated advanced nonsquamous and squamous NSCLC was investigated in two large phase 3 trials (CheckMate 017 and CheckMate 057); both trials showed improved overall survival for patients receiving nivolumab versus those receiving docetaxel [12,13]. Additionally, durvalumab treatment resulted in longer overall survival than placebo in patients with stage III, unresectable NSCLC who did not have disease progression after concurrent radiotherapy in the PACIFIC trial [14].

Table 1. Key immune checkpoint inhibitor monotherapy trials in patients with previously treated advanced NSCLC

Drug	Phase	Comparator	Trial	N	Population	ORR, %	Median OS, mo	Median PFS, mo
Atezolizumab^a	2	None	BIRCH [10]	667	1 L, 2 L, 3 L+ advanced NSCLC	1 L: 22 2 L: 19 3 L+: 18	1 L: 20.1 2 L: 15.5 3 L+: 13.2	1 L: 5.4 2 L: 2.8 3 L+: 2.8
Atezolizumab	2	None	FIR [11]	138	NSCLC; PD-L1 ≥ 5% TC/IC	1 L: 32 2 L+: 21 2 L + w/brain met: 23	1 L: 14.4 2 L+: 9.3 2 L + w/brain met: 6.8	1 L: 5.5 2 L+: 3.7 2 L + w/brain met: 4.3
Durvalumab	3	Placebo	PACIFIC [14]	709	Stage III unresectable NSCLC, prior concurrent chemoradiotherapy	30 vs 18	NR vs 28.7	17.2 vs 5.6
Nivolumab	3	Docetaxel	CheckMate 017 [12]	272	Advanced SQ NSCLC after progression on plat	20 vs 9	9.2 vs 6.0	3.5 vs 2.8
Nivolumab	3	Docetaxel	CheckMate 057 [13]	582	Advanced NSQ NSCLC after progression on plat	19 vs 12	12.2 vs 9.4	2.3 vs 4.2
Pembrolizumab	2/3	Docetaxel	KEYNOTE-010 [9]	1,034	Advanced NSCLC after progression on ≥1 L, including plat; PD-L1 ≥ 1%	18 (2 mg/kg) and 18 (10 mg/kg) vs 9	10.4 (2 mg/kg) and 12.7 (10 mg/kg) vs 8.5	3.9 (2 mg/kg) and 4.0 (10 mg/kg) vs 4.0

^a1 December 2015 data cutoff.

Abbreviations: 1 L, first-line; 2 L, second-line; 3 L+, third-line or higher; IC, immune cell; met, metastases; NR, not reached; NSCLC, non-small cell lung cancer; NSQ, nonsquamous; ORR, objective response rate; OS, overall survival, PD-L1, programmed death-ligand 1; PFS, progression-free survival; plat, platinum-based chemotherapy; SQ, squamous; TC, tumor cell.

2.2. Checkpoint inhibitors alone or in combination as first-line treatment of advanced NSCLC

Early indications that anti-PD-(L)1 therapy could provide clinical benefits as first-line treatment for patients with advanced NSCLC came from the phase 1 CheckMate 012 trial, in which 52 patients treated with first-line nivolumab monotherapy for advanced NSCLC had a median overall survival of 19.4 months after a median follow-up of 14.3 months [15]. Because platinum-doublet chemotherapy is the historical first-line therapy for patients with advanced NSCLC without a targetable driver oncogene (e.g. EGFR, ALK, ROS1) [16], many clinical studies combined PD-(L)1 inhibitors with chemotherapy as first-line treatment for advanced lung cancer and demonstrated improved survival [17,18,19]; key clinical trials are included in Table 2. In KEYNOTE-024, pembrolizumab monotherapy showed longer overall survival in patients with tumor proportion score (TPS) ≥50%. In KEYNOTE-042, patients with TPS ≥1% treated with pembrolizumab monotherapy also demonstrated an improved overall survival at the end of the study across all PD-L1 expression subgroups [20,21]. Despite the statistically positive results at the end of KEYNOTE-042, chemotherapy initially out performed single-agent pembrolizumab across all TPS PD-L1 expression subgroups (≥50%, ≥20%; ≥1%). The overall positive result may have been driven by the survival of patients in the TPS PD-L1 ≥50% subgroup, which comprised nearly half of the study population. As such, it has been proposed that pembrolizumab monotherapy may not represent the best treatment strategy for patients with TPS PD-L1 scores of 1% to 49% [22]. Furthermore, CheckMate 026 did not demonstrate a significant overall survival benefit for patients receiving first-line nivolumab versus those receiving chemotherapy (HR: 1.02; 95% CI: 0.80, 1.30) [23].

Table 2. Key trials of first-line immune checkpoint inhibitors, as monotherapy and with chemotherapy, in patients with advanced NSCLC

Drug	Comparator	Clinical trial	Primary endpoint(s)	Patient population	ORR, %	Median OS, mo	Median PFS, mo
Monotherapy
Atezolizumab	Plat	IMpower110 [24] (N = 572)	OS	1 L stage IV NSQ or SQ NSCLC; PD-L1 ≥ 1%	TC ≥50% or IC ≥10%: 38 vs 29 TC/IC ≥5%: 31 vs 32 TC/IC ≥1%: 29 vs 32	TC ≥50% or IC ≥10%: 20.2 vs 13.1 TC/IC ≥5%: 18.2 vs 14.9 TC/IC ≥1%: 17.5 vs 14.1	TC ≥50% or IC ≥10%: 8.1 vs 5.0 TC/IC ≥5%: 7.2 vs 5.5 TC/IC ≥1%: 5.7 vs 5.5
Nivolumab	None	CheckMate 012 [15] (N = 52)	Safety/ tolerability	1 L advanced NSCLC	28	19.4	3.6
Nivolumab	Plat	CheckMate 026 [23] (N = 423)	PFS	1 L stage IV or recurrent NSCLC; PD-L1 ≥5%	26 vs 33	14.4 vs 13.2	4.2 vs 5.9
Pembrolizumab	Plat	KEYNOTE-024 [20] (N = 305)	PFS	1 L advanced NSCLC; PD-L1 ≥50%	45 vs 28	Not reached in either group	10.3 vs 6.0
Pembrolizumab	Plat	KEYNOTE-042 [21] (N = 1,274)	OS	1 L advanced or metastatic NSCLC; PD-L1 ≥1%	PD-L1 ≥50%: 39 vs 32 PD-L1 ≥20%: 33 vs 29 PD-L1 ≥1%: 27 vs 27	PD-L1 ≥50%: 20.0 vs 12.2 PD-L1 ≥20%: 17.7 vs 13.0 PD-L1 ≥1%: 16.7 vs 12.1	PD-L1 ≥50%: 7.1 vs 6.4 PD-L1 ≥20%: 6.2 vs 6.6 PD-L1 ≥1%: 5.4 vs 6.5
Combination therapy
Atezolizumab + plat	Plat	IMpower130 [29] (N = 723)	PFS, OS	1 L stage IV NSQ NSCLC	49 vs 32	18.6 vs 13.9	7.0 vs 5.5
Atezolizumab + plat	Plat	IMpower131 [30] (N = 1,021)	PFS, OS	1 L stage IV SQ NSCLC	50 vs 41	14.2 vs 13.5	6.3 vs 5.6
Atezolizumab + plat	Plat	IMpower150 [28] (N = 1,202)	PFS, OS	1 L stage IV or recurrent metastatic NSQ NSCLC	64 vs 48	19.2 vs 14.7	8.3 vs 6.8
Durvalumab ± tremelimumab	Plat	MYSTIC [25] (N = 1,118)	PFS, OS	1 L metastatic NSCLC; PD-L1 TC ≥25%	Durvalumab only: 36 Durvalumab combo: 34 Plat: 38	Durvalumab only: 16.3 Durvalumab combo: 11.9 Plat: 12.9	Durvalumab only: 4.7 Durvalumab combo: 3.9 Plat: 5.4
Nivolumab + ipilimumab	Plat	CheckMate 227 [46] (Part 1: N = 299)	PFS, OS	1 L advanced NSCLC with high TMB	45 vs 27	Not reported	4.9 vs 5.5
Nivolumab + ipilimumab + plat	Plat	CheckMate 9LA [26] (Interim: N ≈ 322)	OS	1 L advanced NSCLC with no known EGFR/ALK alterations	Not reported	15.6 vs 10.9	Not reported
Pembrolizumab + pemetrexed/plat	Plat/ pemetrexed	KEYNOTE-189 [27] (N = 616)	PFS, OS	1 L metastatic NSQ NSCLC	48 vs 19	22.0 vs 10.7	9.0 vs 4.9
Pembrolizumab + plat	Plat	KEYNOTE-407 [18] (N = 559)	PFS, OS	1 L metastatic SQ NSCLC	58 vs 38	15.9 vs 11.3	6.4 vs 4.8

Abbreviations: 1 L, first-line; IC, immune cell; NSCLC, non-small cell lung cancer; NSQ, nonsquamous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; plat, platinum-based chemotherapy; SQ, squamous; TC, tumor cell; TMB, tumor mutational burden.

2.3. Checkpoint inhibitors for first-line treatment of advanced squamous and nonsquamous NSCLC

Treatment regimens utilizing checkpoint inhibitors have also been investigated as therapy for nonsquamous and squamous NSCLC (Table 2). KEYNOTE-189 found that first-line pembrolizumab plus pemetrexed-platinum resulted in longer median overall survival versus the placebo plus chemotherapy combination group in patients with nonsquamous NSCLC[27]. Atezolizumab plus chemotherapy also demonstrated longer median progression-free and overall survival compared with chemotherapy alone in patients with nonsquamous NSCLC in the IMpower150 and IMpower130 studies [28,29]. While patients with squamous NSCLC receiving pembrolizumab plus chemotherapy in KEYNOTE-407 also saw survival benefits compared with the placebo-chemotherapy group[18], the results in patients with squamous NSCLC receiving atezolizumab plus chemotherapy were less straightforward. In IMpower131, overall survival benefits were not statistically significant with atezolizumab plus chemotherapy compared with chemotherapy alone, despite improved progression-free survival[30].

2.4. Potential role of PD-L1 expression in the treatment of NSCLC

Several clinical trials have turned toward selecting patient populations using PD-L1 expression; however, to date, there is no universally accepted definition or standard assay for PD-L1–positivity. Tumor proportion score, PD-L1 tumor cell expression, and composite positive score, which includes tumor-infiltrating immune cells, have all been used to describe PD-L1 expression. This lack of a consistent definition has resulted in difficulties determining if PD-L1 is a universal predictive biomarker of response. Furthermore, the predictive value of PD-L1 expression is not always consistent within a single therapeutic agent. CheckMate 012 did not require PD-L1 expression for enrollment and indicated that first-line nivolumab monotherapy elicited durable responses in patients with advanced NSCLC[15], but CheckMate 026, which only enrolled NSCLC patients with tumor cell PD-L1 expression ≥5%, did not demonstrate a significant survival benefit in patients receiving first-line nivolumab versus chemotherapy[23]. Patients with PD-L1–positive NSCLC enrolled in KEYNOTE-024 and −042 studies were more consistent, as longer median overall survival was observed in both trials for patients receiving pembrolizumab monotherapy versus those receiving chemotherapy, including all PD-L1 expression levels examined in KEYNOTE-042 (TPS ≥50%, ≥20%, and ≥1%) [20,21].

PD-L1 expression may be more predictive of response to first-line checkpoint inhibitors in squamous versus nonsquamous NSCLC. In patients with squamous NSCLC receiving atezolizumab plus carboplatin and nab-paclitaxel during the IMpower131 trial, median progression-free and overall survival was longer in patients with high PD-L1 expression (PD-L1 expression on ≥50% of tumor cells or ≥10% of immune cells) versus those with lower levels of PD-L1 expression[30]. However, patients with nonsquamous NSCLC receiving atezolizumab plus chemotherapy as part of the IMpower130 trial demonstrated clinical benefit versus chemotherapy regardless of PD-L1 expression[29].

3. Introduction to tislelizumab

Tislelizumab (BGB-A317) is an anti-PD-1 monoclonal antibody that was engineered with a nullified Fc portion of the antibody to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy (Box 1) [31,32]. Specifically, anti-PD-1 antibodies that bind FcγRs may mediate crosslinking between PD-1–positive T cells and FcγR-positive macrophages, which could induce macrophages to phagocytose active PD-1–positive T cells and possibly diminish cytolytic destruction of tumor cells [31,32]. As an antagonist to PD-L1/PD-L2–mediated cell signaling, tislelizumab leads to increased cytokine production and restoration of T-cell activation, resulting in immune-mediated tumor cell death[31].

Box 1. Drug Summary

Drug name (generic)	Tislelizumab
Phase	3
Indication	Non-small cell lung cancer
Pharmacology description/mechanism of action	Tislelizumab is a humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death protein-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy
Route of administration	Intravenous
Pivotal trial(s)	NCT03358875; NCT03663205; NCT03594747
Chemical structure	Not available

4. Chemistry

Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against the immune checkpoint-inhibitory receptor, PD-1 [31].

5. Pharmacodynamics

Tislelizumab has a different binding orientation to PD‑1 versus pembrolizumab and nivolumab; the binding surface on PD‑1 for tislelizumab partially overlaps with that for pembrolizumab but differs significantly from that for nivolumab [33]. With a disassociation constant (K_D) of 0.15 nmol/L, tislelizumab binds to Gln75, Thr76, Asp77, and Arg86 of human PD-1 with high specificity and affinity [33,34]. Nivolumab and pembrolizumab do not require these epitopes to bind and have faster dissociation rates than tislelizumab. Tislelizumab has shown an approximately 50-fold and 100-fold slower dissociation rate compared with nivolumab and pembrolizumab, respectively [33]. Studies with pembrolizumab and nivolumab have demonstrated that maximal receptor occupancy on circulating CD3 + T cells occurs at concentrations that are much lower than the clinical dose for nivolumab and pembrolizumab [35,36]. When the target-binding activity of tislelizumab was examined by fluorescence-activated cell sorting using a PD-1–expressing HuT78 cell line, the effective concentration for 50% of maximal activity was estimated to be 86 ng/mL.

6. Pharmacokinetics and metabolism

Tislelizumab is available as a sterile, injectable concentrate solution in a 100 mg per vial dosage form [37]. After a single intravenous dose, tislelizumab demonstrated linear pharmacokinetics over a dose range of 0.5–10 mg/kg, including the recommended clinical dose of 200 mg every 3 weeks (Q3W) [38]. After multiple-dose administration, steady-state concentration was achieved after 12 weeks with 200 mg Q3W. As the steady-state trough levels were greater than 30 μg/mL, tislelizumab is expected to reach maximal binding to PD-1.

The population pharmacokinetics of tislelizumab (0.5, 2.0, 5.0, or 10 mg/kg Q2W; 2.0 or 5.0 mg/kg Q3W; or 200 mg Q3W) were analyzed from 798 patients with advanced solid tumors or hematologic malignancies from two phase 1 and one phase 2 studies [39]. Time-varying clearance was not observed; clearance and volume of distribution of the central compartment were estimated as 0.164 L/day and 2.92 L, respectively [39]. The estimated terminal half-life of tislelizumab 200 mg Q3W was 16.8 ± 5.5 days [40]. Covariate analysis of population pharmacokinetics indicated that dose adjustments were not needed based on age, sex, race, body weight, tumor size, serum albumin level, or immunogenicity status [39]. The effect of renal or hepatic impairment on tislelizumab pharmacokinetics has not been directly evaluated, but population pharmacokinetics suggest that neither mild/moderate renal impairment nor mild hepatic impairment would require dose adjustments [37].

No drug–drug interaction (DDI) studies have been conducted for tislelizumab thus far. Since no DDIs have been reported for other anti-PD-1/PD-L1 antibodies, the DDI potential of tislelizumab is expected to be low. Additionally, as the primary elimination pathways are protein catabolism via the reticuloendothelial system or target-mediated disposition, tislelizumab is not expected to induce or inhibit the major drug-metabolizing CYP pathways.

7. Clinical efficacy

Initial antitumor activity of single-agent tislelizumab was assessed in previously treated patients with advanced solid tumors in two early phase clinical studies (Table 3). In a global, phase 1A/1B first-in-human study (BGB-A317-001; NCT02407990), tislelizumab treatment in all patients (n = 451) resulted in a median overall survival of 10.3 months (95% CI: 8.5, 11.6) with a median duration of study follow-up of 8.6 months (range: 0.1, 40.8) [40]. Of the 49 evaluable patients with NSCLC treated with tislelizumab 200 mg Q3W in the phase 1B dose-expansion phase, an objective response rate of 12.2% (95% CI: 4.6, 24.8) was observed, despite a high proportion of patients having received prior systemic drug therapy (n = 44, 90%) [40,41]. Clinical benefit was observed in both Asian and non-Asian patients [40], as well in patients with PD-L1–positive (≥25% of tumor cells exhibiting PD-L1 membrane) staining and PD-L1–negative (<25% PD-L1 tumor cell expression) tumors [41]. Across all patients from an open-label phase 1/2 study conducted in China (BGB-A317-102; NCT04068519), treatment with tislelizumab resulted in a median overall survival of 11.5 months (95% CI: 9.1, 15.0) with a median follow-up of 12.2 months [42]. Among previously treated patients with NSCLC (n = 56), the objective response rate was 18% (95% CI: 8.9, 30.4), with 31 patients achieving confirmed partial response (n = 10; 18%) or stable disease (n = 21; 38%) [42]. Median progression-free survival for patients with NSCLC was 4.0 months (95% CI: 2.1, 8.1) and at the time of data cutoff, median overall survival had not been reached [42]. Consistent with the first-in-human study, responses were observed in patients with NSCLC regardless of PD-L1 status[42].

Table 3. Key tislelizumab trials enrolling patients with lung cancer^a

Drug	Phase	Comparator	Trial	N	Indication	ORR, %	Median OS, mo	Median PFS, mo
Tislelizumab	1A/1B	None	BGB-A317-001[41]	49	Advanced or metastatic NSCLC	13	11.5	4.2
Tislelizumab	1/2	None	BGB-A317-102[42]	56	Advanced NSCLC	18	NR	4.0
Tislelizumab + plat	2	None	BGB-A317-206 [43]	Total: 54 NSQ: 16 SQ-A: 15 SQ-B: 6 SCLC: 17	1 L advanced lung cancer	NSQ: 44 SQ-A: 80 SQ-B: 67 SCLC: 77	NSQ: NR SQ-A: NR SQ-B: NR SCLC: 15.6	NSQ: 9.0 SQ-A: 7.0 SQ-B: NR SCLC: 6.9
Tislelizumab	3	Docetaxel	BGB-A317-303 (RATIONALE 303)	≈640	2/3 L NSCLC	No data (ongoing)	No data (ongoing)	No data (ongoing)
Tislelizumab + plat	3	Plat	BGB-A317-304 (RATIONALE 304)	334	1 L NSQ NSCLC	57 vs 37	No data (ongoing)	9.7 vs 7.6
Tislelizumab + paclitaxel and plat or nab-paclitaxel and plat	3	Plat	BGB-A317-307 (RATIONALE 307) [44]	360	1 L SQ NSCLC	73 or 75 vs 50	No data (ongoing)	7.6 (for both combination treatments) vs 5.5
Tislelizumab + plat	3	Plat	BGB-A317-315 (RATIONALE 315)	≈380	Neoadjuvant and adjuvant NSCLC	No data (ongoing)	No data (ongoing)	No data (ongoing)

^aOnly data for patients with lung cancer are presented.

Abbreviations: 1 L, first-line; 2 L, second-line; 3 L, third-line; NR, not reached; NSCLC, non-small cell lung cancer; NSQ, nonsquamous; ORR, objective response rate; OS, overall survival, PFS, progression-free survival; plat, platinum-based chemotherapy; SCLC, small cell lung cancer; SQ, squamous.

Tislelizumab plus chemotherapy as first-line treatment for NSCLC has been evaluated in three clinical studies. In an open-label phase 2 trial in China (BGB-A317-206; NCT03432598), eligible patients with advanced/metastatic nonsquamous NSCLC, squamous NSCLC, or extensive-stage small cell lung cancer (SCLC) received tislelizumab plus 4–6 cycles of platinum-doublet. The nonsquamous cohort received tislelizumab with pemetrexed plus platinum Q3W for four cycles followed by pemetrexed maintenance. Patients with squamous NSCLC received tislelizumab plus either paclitaxel plus platinum (Cohort A) or gemcitabine plus platinum (Cohort B) Q3W, and patients in the SCLC cohort received tislelizumab plus etoposide plus platinum Q3W[43]. Median progression-free survival estimates were 9.0 months (nonsquamous), 7.0 months (squamous Cohort A), and 6.9 months (SCLC); median progression-free survival was not reached for squamous NSCLC Cohort B. Despite the long survival follow-up times (17.4 months, nonsquamous; 18.3 months, squamous Cohort A; 18.1 months, squamous Cohort B; 15.3 months, SCLC), median overall survival was not reached in all cohorts, except for SCLC (15.6 months). The 1-year overall survival rates were 88% (nonsquamous), 93% (squamous Cohort A), 80% (squamous Cohort B), and 76% (SCLC).

In an open-label, randomized phase 3 trial in China (RATIONALE 307; BGB-A317-307; NCT03594747) examining first-line treatment for advanced squamous NSCLC (n = 360), the addition of tislelizumab to paclitaxel plus carboplatin or nab-paclitaxel plus carboplatin significantly improved progression-free survival when compared with paclitaxel plus carboplatin only (HR: 0.52 and 0.48, respectively) [44]. Median progression-free survival was 7.6 months for both tislelizumab-containing arms; median progression-free survival for chemotherapy alone was 5.5 months. The objective response rate was 72.5% for tislelizumab with paclitaxel plus carboplatin and 74.8% for patients treated with tislelizumab combined with nab-paclitaxel plus carboplatin, respectively; the objective response rate for chemotherapy alone was 49.6%. Median duration of response was 8.2 months for patients receiving tislelizumab combined with paclitaxel plus carboplatin, 8.6 months for tislelizumab combined with nab-paclitaxel plus carboplatin, and 4.2 months for chemotherapy alone. There was no association between PD-L1 expression levels (<1%, 1–49%, and ≥50%) and progression-free survival or clinical response. Together, these data represent the second clinical trial to demonstrate positive clinical outcomes in patients with squamous NSCLC.

In April 2020, it was announced that an interim analysis of an open-label phase 3 trial (RATIONALE 304; BGB-A317-304; NCT03663205) evaluating first-line tislelizumab plus pemetrexed and platinum-based chemotherapy for patients with nonsquamous NSCLC met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival, as assessed by an independent review committee, versus chemotherapy alone [45]. The safety profile of tislelizumab plus pemetrexed and platinum-based chemotherapy was consistent with the known risks of each study treatment component; no new safety signals were identified.

8. Safety and tolerability

As monotherapy, the adverse events reported in patients treated with tislelizumab were manageable and generally mild-to-moderate in severity [40,42]. In the first-in-human study, median treatment duration of tislelizumab was 2.8 months (range: 0.13–43.7) and 65 patients (14.4%) received treatment for ≥12 months [40]. Treatment-related adverse events led to discontinuation in 5.3% of patients [40]. In the open-label phase 1/2 study, median treatment duration of patients receiving tislelizumab 200 mg was 18 weeks (range: 0.9, 95.7) [42]. Treatment-emergent adverse events led to discontinuation in 8% of patients and the only treatment-related adverse events that led to discontinuation in more than one patient were autoimmune myocarditis, lung infection, central nervous system metastases, and death (n = 2 each) [42]. In this study, most adverse events considered related to tislelizumab by the investigator were generally of grade ≤2 severity and no new immune-related safety signals were observed [42].

In the phase 2 study of first-line tislelizumab plus chemotherapy in patients with lung cancer (n = 54), six patients (11%) discontinued tislelizumab due to adverse events (pneumonitis [n = 2], dyspnea, increased conjugated bilirubin, decreased platelet count, myocarditis, immune-mediated hepatitis, post-procedural discomfort, and rhabdomyolysis [n = 1 each]) [43].

In the phase 3 study of first-line tislelizumab plus chemotherapy for squamous NSCLC, the most commonly reported grade ≥3 adverse events were hematologic toxicities (e.g. neutropenia), which is consistent with adverse events known to be associated with chemotherapy. Adverse events leading to discontinuation of any treatment were reported in 12.5% of patients receiving tislelizumab plus paclitaxel and carboplatin, and in 15.4% of patients receiving paclitaxel and carboplatin [44]. Tislelizumab had no impact on the tolerability of chemotherapy and did not affect exposure duration, numbers and cycles of administration, or dose intensity of chemotherapy.

9. Regulatory affairs

In December 2019, tislelizumab received conditional approval from China’s National Medical Products Administration (NMPA) for patients with relapsed/refractory classical Hodgkin lymphoma who have received ≥2 prior therapies. In April 2020, the NMPA also approved tislelizumab for patients with previously treated locally advanced or metastatic urothelial carcinoma with PD-L1–high expression [37]. The NMPA accepted for review two supplemental new drug applications for tislelizumab plus chemotherapy as first-line treatment for advanced squamous (April 2020) and nonsquamous (June 2020) NSCLC. In addition to the three previously described studies, tislelizumab efficacy and safety are being assessed as second- and third-line treatments for patients with advanced NSCLC (RATIONALE 303; BGB-A317-303; NCT03358875).

10. Conclusions

Tislelizumab was generally well tolerated with no unexpected safety concerns observed in patients with advanced NSCLC. Promising efficacy was observed regardless of ethnicity and PD-L1 expression in patients receiving tislelizumab as monotherapy in heavily pretreated NSCLC patients and with chemotherapy as first-line treatment for squamous and nonsquamous NSCLC. The results support further investigation of tislelizumab in NSCLC.

11. Expert opinion

Anti-PD-1/PD-L1 antibodies, either alone or with chemotherapy, have significantly improved clinical benefit in patients with squamous and nonsquamous advanced NSCLC, both as first-line treatment and as a later line of therapy. However, a significant proportion of patients remain unresponsive or subsequently progress following initial treatment. Therefore, novel checkpoint inhibitor therapies and new approaches, such as bispecific antibodies (e.g. M7824), which have the potential to simultaneously inhibit the PD-(L)1 pathway with inhibition of other cellular processes, have also been investigated for the treatment of NSCLC. To develop effective treatment regimens, more knowledge of NSCLC disease biology is needed, including a better understanding of de novo/emerging mechanisms of resistance, the biomarkers and phenotypes associated with each, and novel treatment approaches to overcome any resistance that develops.

In the current age of personalized medicine, identification of predictive biomarkers of response may enable better-informed treatment decisions and provide consistency in immune checkpoint inhibitor selection. As clinicians strive to achieve better patient outcomes, additional predictive indicators of response to immunotherapy outside of PD-L1 expression, such as tumor mutational burden (TMB), blood TMB (bTMB), and circulating tumor DNA (ctDNA), are being investigated. High TMB is indicative of genomic instability and has been correlated with responses to immunotherapy and improved efficiency of immune checkpoint inhibitor treatment [46–48]. However, the predictive value on long-term survival in patients with NSCLC requires further evaluation. Because many patients with advanced cancer cannot provide enough tumor tissue for molecular testing[49], noninvasive approaches utilizing advances in DNA sequencing technology are attractive options. As such, bTMB, which represents a rapid blood-based assay that may be less impacted by intratumor heterogeneity than tissue-based TMB, has garnered much interest [49]. Additionally, examination of key tumor-related genes via ctDNA has introduced the possibility of achieving earlier cancer detection and improved therapeutic outcomes by enabling early intervention [50].

RATIONALE 307 was only the second trial of a checkpoint inhibitor to meet its full primary endpoint in patients with advanced/metastatic squamous NSCLC; in KEYNOTE-407, patients with metastatic squamous NSCLC receiving pembrolizumab platinum-containing chemotherapy reported significantly prolonged overall survival and progression-free survival (dual primary endpoints) compared with chemotherapy alone [18]. Tislelizumab is being investigated as a single-agent in second- and third-line settings and with chemotherapy as first-line treatment for advanced NSCLC. Additionally, tislelizumab plus chemotherapy is being examined as neoadjuvant treatment and single-agent tislelizumab is being explored as adjuvant maintenance therapy. Tislelizumab was engineered to minimize binding to FcγR on macrophages and may result in prolonged antitumor effects versus therapies where FcγR is engaged. Tislelizumab has demonstrated encouraging efficacy results, long duration of response, a manageable safety profile across multiple clinical trials in advanced NSCLC, and responses were comparable across both Asian and non-Asian patients [40], as well as being comparable regardless of PD-L1 expression [40,42]. The favorable tolerability profile and durable efficacy of tislelizumab in patients with NSCLC suggests that tislelizumab may be appropriate as a checkpoint inhibitor backbone for combination therapies with chemotherapy or other novel agents. Longer survival follow-up from the current clinical trials should allow for an opportunity to examine the impact of tislelizumab on overall survival.

Within the next 5 years, tislelizumab has the potential to bring clinical benefit to patients with NSCLC in all phases of treatment. The safety profile of tislelizumab suggests that it may be an ideal candidate as the backbone of combination therapy with chemotherapy or targeted treatments, which could help to overcome acquired resistance to immunotherapy. Combining tislelizumab with other anticancer agents is currently being investigated in multiple treatment settings and may further improve the survival benefits already observed with tislelizumab.

Multiple PD-(L)1 therapies are available for the treatment of squamous and nonsquamous NSCLC, so it is important to take a holistic approach and to evaluate each agent based on efficacy, safety and tolerability, ease of administration, quality of life and patient-reported outcomes, and cost-effectiveness. Due to the high prevalence of NSCLC, significant economic burden of this illness, and the associated impact on societal and healthcare costs, real-world evidence, and comparative cost-effectiveness analyses will be needed. The value of immune checkpoint inhibitors in novel combinations for areas of unmet medical need (e.g. patients with brain metastases, those who have progressed after prior EGFR tyrosine kinase inhibitor or an immune checkpoint inhibitor) is also an area of ongoing investigation. With a manageable safety profile and long-lasting responses regardless of PD-L1 expression levels, tislelizumab looks to build upon the transformative clinical outcomes brought about by checkpoint inhibitor therapy.

Article highlight

• Tislelizumab is Tislelizumab is a humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death protein-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy

• When administered as either first-line or as a later line of therapy, anti-PD-1/PD-L1 antibodies havesignificantly improved clinical outcomes in patients with squamous and nonsquamous advanced NSCLC alone and when combined with chemotherapy

• As a single-agent, tislelizumab has demonstrated encouraging efficacy regardless of PD-L1 expression levels with a manageable safety/tolerability profile across multiple clinical trials in advanced NSCLC

• In combination with chemotherapy, tislelizumab has shown prolonged survival and durable clinical responses; the safety/tolerability profile was consistent with the known risks of each study treatment component with no new safety signals

• Ongoing trials examining efficacy across the severity of disease will provide additional opportunities to understand and feature tislelizumab in clinical practice

• With a manageable safety profile and long-lasting responses regardless of PD-L1 expression levels, tislelizumab looks to build upon the transformative clinical outcomes brought about by checkpoint inhibitor therapy

Declaration of interest

Yi-Long Wu has received speaker fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Acknowledgments

Financial support for the development of this manuscript was provided by BeiGene, Ltd. This included medical writing and editorial assistance under the authors’ guidance, and was provided by Stephan Lindsey PhD and Elizabeth Hermans PhD of OPEN Health Medical Communications (Chicago, IL, USA).

Additional information

Funding

This article is funded by BeiGene, Ltd.