Abstract
Introduction
Patients with limited-stage SCLC (LS-SCLC) have a substantial unmet clinical need for new treatments that delay disease progression and prolong survival.
Methods
In this phase 2, multicenter, randomized, multiarm, open-label trial, patients with untreated LS-SCLC received ociperlimab and tislelizumab plus concurrent chemoradiotherapy (cCRT) (arm A), tislelizumab plus cCRT (arm B), or cCRT (arm C). The primary objective was to compare progression-free survival (PFS) per investigator for arms A and B versus C (NCT04952597). The contribution of ociperlimab was explored by comparison of arms A versus B. Statistical analyses were descriptive, with no formal hypothesis testing.
Results
A total of 126 patients were randomized to arms A (N = 41), B (N = 42), and C (N = 43). The median PFS [95% confidence interval] exhibited a trend for improvement in arms A (12.6 [8.7–not estimable] months) and B (13.2 [8.5–not estimable]) compared with C (9.5 [8.3–14.4]); the PFS benefit was comparable between Arms A and B.
The objective response rate, complete response rate, and median duration of response were numerically higher in arms A and B than in C. The median overall survival was not reached in all three arms, and the median distant metastasis–free survival revealed no trend for improvement for arms A and B compared with C. All patients experienced at least one treatment-related treatment-emergent adverse event.
Conclusions
Ociperlimab and tislelizumab plus cCRT and tislelizumab plus cCRT exhibited a trend for improvement in PFS and numerically higher objective response rate compared with cCRT, with no new safety signals beyond the known profiles of immune checkpoint inhibitors and cCRT. Adding ociperlimab to tislelizumab plus cCRT was not associated with additional improvement in efficacy.
Keywords: Limited-stage small-cell lung cancer (LS-SCLC), Concurrent chemoradiotherapy (cCRT), TIGIT, PD-L1
Introduction
SCLC is an aggressive form of lung cancer that accounts for approximately 15% of lung cancers.1 Limited-stage SCLC (LS-SCLC) is a type of SCLC confined to the hemithorax, mediastinum, or the supraclavicular lymph nodes, and accounts for approximately 30% of patients with SCLC.2
The current standard of care for most patients with LS-SCLC is concurrent chemoradiotherapy (cCRT), typically with etoposide plus a platinum-based regimen and thoracic radiation therapy.3 Although most patients are sensitive to initial cCRT, most have a rapid occurrence of tumor relapse or metastasis approximately a year after completing initial therapy.4,5 The prognosis for patients with LS-SCLC is poor, with a median overall survival (OS) of 19 to 30 months and 2-year OS rates of 35% to 56%.4, 5, 6 There is a substantial unmet clinical need to delay disease progression and prolong survival benefit. Current clinical studies investigating novel treatments for LS-SCLC include the phase 3 ADRIATRIC study, in which an interim analysis reported that consolidation therapy with durvalumab (a programmed cell death-ligand 1 [PD-L1] inhibitor) after cCRT extended survival compared with placebo.7 In addition, atezolizumab and durvalumab, both PD-L1 inhibitors, and tislelizumab, a programmed cell death protein 1 (PD-1) inhibitor, have exhibited improvements in survival when added to standard of care in patients with extensive-stage SCLC (ES-SCLC) in the IMpower133, CASPIAN, and RATIONALE-312 trials, respectively.8, 9, 10 These studies provided the rationale for combining new agents with novel mechanisms of action and nonoverlapping toxicity, such as immune checkpoint inhibitors, with established treatments.
As SCLC is considered a “cold” lung cancer subtype that lacks an effective immune response because of insufficient cytotoxic T-lymphocyte infiltration,11 a key step in treatment may be transforming the tumor into a “hot” subtype to enhance the antitumor effects of immune checkpoint inhibition. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune checkpoint receptor expressed on immune cells, including cytotoxic T cells, regulatory T cells, and natural killer (NK) cells,12,13 and its expression may suppress immune responses, including inhibition of NK cell degranulation, cytokine production, and NK cell-mediated cytotoxicity.14 TIGIT is co-expressed with PD-1, including on CD8+ T cells,15 and synergizes to regulate CD226, a co-stimulatory receptor that plays a role in antitumor CD8+ T-cell responses.16 Preclinical studies of solid tumors suggest that blockade of TIGIT and PD-1 synergizes to produce an enhanced antitumor response.17 Therefore, treatment with an anti-TIGIT may help activate or enhance the tumor microenvironment and improve the antitumor effects of anti–PD-1 therapy. Adapting radiotherapy to immunotherapy may also have the potential to improve the efficacy of radiotherapy in LS-SCLC.18
Ociperlimab is a humanized Fc intact immunoglobulin G1 monoclonal antibody designed to target TIGIT with high specificity and affinity, and tislelizumab is an anti–PD-1 monoclonal antibody that blocks the PD-1/PD-L1 immune checkpoint, resulting in T-cell activation.
This article reports efficacy and safety results from AdvanTIG-204, a phase 2, multicenter, randomized, multiarm, open-label study of ociperlimab and tislelizumab plus cCRT in LS-SCLC.
Materials and Methods
Patients
For inclusion in the study, patients had to meet the following criteria: (1) were at least aged 18 years and older with histologically or cytologically proven diagnosis of LS-SCLC (stage Tx, T1–T4, N0–3 per American Joint Committee on Cancer staging criteria) that could be safely treated with definitive radiation doses; (2) not received any previous treatment for LS-SCLC; (3) had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; (4) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) less than or equal to 2 assessed within 7 days before the first administration of study intervention; (5) a life expectancy of at least 12 weeks; (6) adequate organ function as indicated by absolute neutrophil count not less than 1.5 × 109/L, platelets greater than or equal to 100 × 109/L, hemoglobin of at least 90 g/L, international normalized ratio or prothrombin time less than or equal to 1.5 times the upper limit of normal (ULN), activated partial thromboplastin time less than or equal to 1.5 times the ULN, serum total bilirubin less than or equal to 1.5 times the ULN, aspartate aminotransferase, alanine aminotransferase, or both less than or equal to 2.5 times the ULN, and calculated creatinine clearance of at least 45 mL/min; and (7) females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study.
Exclusion criteria included (1) patients who had mixed SCLC; (2) had received surgical resection for LS-SCLC; (3) had a tumor that was considered resectable by surgery and stereotactic body radiation therapy, stereotactic ablative radiotherapy, or both; (4) were expected to require any other form of antineoplastic therapy while in the study; (5) had previous therapy with an anti–PD-1, anti–PD-L2, anti-TIGIT, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways; (6) had received interleukin, interferon, thymosin, or any investigational therapies within 14 days or five half-lives before randomization; and (7) patients with radiation treatment plans likely to encompass a volume of whole lung receiving at least 20 Gy in total (V20) of more than 38% of lung volume.
Trial Design and Interventions
This was a phase 2, multicenter, randomized, open-label trial in patients with previously untreated LS-SCLC (ClinicalTrials.gov identifier: NCT04952597) conducted in the People's Republic of China, South Korea, and the United States. Patients were randomly allocated 1:1:1 to receive ociperlimab and tislelizumab plus cCRT, followed by ociperlimab and tislelizumab (arm A), tislelizumab plus cCRT followed by tislelizumab (arm B), or cCRT alone (arm C) (Supplementary Fig. 1). Patients were randomized by permuted block stratified randomization with a stratification factor for disease stage (stage I/II versus stage III) by site personnel using an interactive response technology system.
Treatment was ociperlimab 900 mg intravenously (IV) every 3 weeks plus tislelizumab 200 mg IV every 3 weeks and cCRT for four cycles, followed by ociperlimab 900 mg IV every 3 weeks and tislelizumab 200 mg IV every 3 weeks; tislelizumab 200 mg IV every 3 weeks and cCRT for four cycles, followed by tislelizumab 200 mg IV every 3 weeks; or cCRT for four cycles. Ociperlimab and tislelizumab were started on cycle 1 day 1 before chemotherapy and administered for a duration of 12 months (up to 17 cycles of treatment) or until disease progression according to RECIST version 1.1, unacceptable toxicity, death, or other discontinuation criteria. Chemotherapy administered as part of cCRT consisted of cisplatin 75 mg/m2 on day 1 of each cycle and etoposide 100 mg/m2 on days 1, 2, and 3 for four cycles; however, if cisplatin on day 1 was not tolerated, cisplatin 25 mg/m2 on days 1, 2, and 3 was allowed. If cisplatin was contraindicated or not tolerated after completing one or more cycles of cisplatin treatment, carboplatin at a dose of area under the plasma or serum concentration curve 5 was administered as an IV infusion every 3 weeks on day 1 of each cycle for four cycles. Radiation therapy was started early in cycle 1 or 2, with a total dose of 60 to 70 Gy, given in once-daily fractions over 6 to 7 weeks. Prophylactic cranial irradiation was permitted at the investigator’s discretion, with a preferred total dose for the whole brain of 25 Gy in 10 daily fractions.
Assessments
Tumor imaging was performed at 28 days or earlier before randomization. During the trial, tumor imaging was performed at approximately 12 weeks (±7 days) from the date of randomization, then every 6 weeks (±7 days) for the next 54 weeks, and subsequently every 12 weeks (±7 days) on the basis of RECIST version 1.1.
Safety was assessed by monitoring and recording all adverse events (AEs) graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). Laboratory values, vital signs, electrocardiograms, and physical examinations were used to assess safety. Treatment-emergent AEs (TEAEs) were any AE that had an onset date or a worsening in severity from baseline (pretreatment) on or after the first dose of study drug and up to 30 days after study treatment discontinuation or initiation of new anticancer therapy, whichever occurred first.
Assessed biomarkers included PD-L1 tumor area positivity, which was assessed by the Ventana PD-L1 (SP263) assay (Roche Diagnostics, Basel, Switzerland), and TIGIT immune cell scoring, which was assessed by a formulation locked assay with the Roche SP410 antibody.
Outcomes
The primary objective was to compare progression-free survival (PFS), as defined from the date of randomization to the date of the first documented disease progression as determined by the investigator using RECIST version 1.1 or death from any cause, for arm A versus arm C and arm B versus arm C.
Secondary objectives included the comparison of arm A versus arm C and arm B versus arm C for complete response (CR) rate, defined as the proportion of patients who had CR; objective response rate (ORR), defined as the proportion of patients who had CR or partial response (PR); duration of response (DoR), defined as the time from the date of the first occurrence of a documented objective response to the date of documented disease progression; distant metastases-free survival (DMFS), defined as the time from the date of randomization to the date of the first documented distant metastasis, or death from any cause, whichever occurs first; OS, defined as the time from the date of randomization to the date of death because of any cause; and the incidence and severity of TEAEs.
Statistical Analysis
This trial was a proof-of-concept study to obtain preliminary efficacy and safety data; approximately 120 patients were planned to be enrolled in a 1:1:1 ratio across three arms. With a sample size of approximately 40 patients in each arm, the binomial probabilities of detecting one or more TEAEs with a frequency of 5% and 1% were approximately 0.87 and 0.33, respectively. No formal interim analysis was conducted.
The intention-to-treat (ITT) analysis set, which consisted of all randomized patients, was the primary analysis set for all efficacy analyses. The safety analysis set, which included all patients who received at least one dose of any component of the study drugs, was the analysis set for the safety analyses.
The efficacy end points, including PFS, CR rate, ORR, DoR, and OS, were summarized by arm in the ITT analysis set. The efficacy end points were compared in arm A versus arm C and arm B versus arm C. The contribution of tislelizumab to the efficacy results is exhibited by descriptive analysis of PFS, ORR, and DoR in the comparison of arm B versus arm C; the contribution of adding ociperlimab plus tislelizumab will be exhibited by a similarly descriptive analysis in the comparison of arm A versus arm C (p value provided for descriptive purposes only). Subgroup analysis of PFS was conducted using the prespecified demographic and baseline disease characteristics.
As an exploratory analysis, the contribution of adding ociperlimab was exhibited by a similarly descriptive analysis in the comparison of arm A versus arm B.
Results
Baseline Characteristics
Between July 15, 2021, and July 26, 2023, a total of 126 patients were randomized to arm A (N = 41), arm B (N = 42), or arm C (N = 43) (Fig. 1). As of the data cutoff date of July 26, 2023, the median study follow-up time (range) in the ITT analysis set was 18.5 months (2.7–24.4) for arm A, 18.2 months (0.4–24.2) for arm B, and 18.3 months (3.5–24.2) for arm C.
Figure 1.
CONSORT diagram. AE, adverse event.
Baseline characteristics were generally balanced across the three arms, except for smoking history, with the percentage of patients who were never smokers reported as 14.6% (6/41) in arm A, 4.8% (2/42) in arm B, and 7.0% (3/43) in arm C, and ECOG PS, with the percentage of patients reported with an ECOG PS of 0 as 41.5% (17/41) in arm A, 33.3% (14/42) in arm B, and 18.6% (8/43) in arm C (Table 1).
Table 1.
Demographics and Baseline Characteristics (ITT Analysis Set)
| Characteristic | Arm A Ociperlimab + tislelizumab + cCRT (n = 41) |
Arm B Tislelizumab + cCRT (n = 42) |
Arm C cCRT (n = 43) |
Total (N = 126) |
|---|---|---|---|---|
| Age, median (range), y | 64.0 (29–73) | 59.0 (47–74) | 64.0 (34–76) | 61.5 (29–76) |
| Male, n (%) | 31 (75.6) | 33 (78.6) | 35 (81.4) | 99 (78.6) |
| Race, n (%) | ||||
| Asian | 41 (100.0) | 42 (100.0) | 42 (97.7) | 125 (99.2) |
| White | 0 (0.0) | 0 (0.0) | 1 (2.3) | 1 (0.8) |
| Country, n (%) | ||||
| People's Republic of China | 39 (95.1) | 40 (95.2) | 41 (95.3) | 120 (95.2) |
| South Korea | 2 (4.9) | 2 (4.8) | 1 (2.3) | 5 (4.0) |
| United States | 0 (0.0) | 0 (0.0) | 1 (2.3) | 1 (0.8) |
| Time since diagnosis, median (range), d | 13.0 (1–356) | 12.5 (1–35) | 14.0 (1–55) | 13.5 (1–356) |
| Disease stage, n (%) | ||||
| I | 1 (2.4) | 0 (0.0) | 1 (2.3) | 2 (1.6) |
| II | 3 (7.3) | 2 (4.8) | 1 (2.3) | 6 (4.8) |
| III | 37 (90.2) | 40 (95.2) | 41 (95.3) | 118 (93.7) |
| Location of local metastases at initial diagnosis, n (%) | ||||
| Lung | 36 (87.8) | 38 (90.5) | 35 (81.4) | 109 (86.5) |
| Lymph nodes | 33 (80.5) | 36 (85.7) | 36 (83.7) | 105 (83.3) |
| Other | 3 (7.3) | 0 (0.0) | 2 (4.7) | 5 (4.0) |
| Histology, n (%) | ||||
| SCLC | 41 (100.0) | 42 (100.0) | 42 (97.7) | 125 (99.2) |
| Mixed SCLC with neuroendocrine carcinoma origin | 0 (0.0) | 0 (0.0) | 1 (2.3) | 1 (0.8) |
| Smoking history, n (%) | ||||
| Never | 6 (14.6) | 2 (4.8) | 3 (7.0) | 11 (8.7) |
| Current | 5 (12.2) | 1 (2.4) | 7 (16.3) | 13 (10.3) |
| Former | 23 (56.1) | 29 (69.0) | 23 (53.5) | 75 (59.5) |
| Missing | 7 (17.1) | 10 (23.8) | 10 (23.3) | 27 (21.4) |
| ECOG PS, n (%) | ||||
| 0 | 17 (41.5) | 14 (33.3) | 8 (18.6) | 39 (31.0) |
| 1 | 24 (58.5) | 28 (66.7) | 35 (81.4) | 87 (69.0) |
Baseline is defined as the last nonmissing value before or on the first study drug administration date, or the last value on or before the randomization date for any randomized, untreated patients.
cCRT, concurrent chemoradiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention-to-treat.
A total of 87.3% (110/126) of patients completed cCRT; in arms A, B, and C, respectively, 87.8% (36/41), 85.7% (36/42), and 88.4% (38/43) completed all chemotherapy, and 97.6% (40/41), 95.2% (40/42), and 93.0% (40/43) completed radiotherapy. Overall, 41 patients in arm A, 40 patients in arm B, and 40 patients in arm C received radiotherapy. The median cumulative dose of radiotherapy administered (range) was 60.0 (16.0–66.0) in arm A, 60.0 (54.0–60.0) in arm B, and 60.0 (60.0–68.0) in arm C.
The median duration of exposure (range) to ociperlimab and tislelizumab in arm A was 7.8 (0.7–18.2) months, and to tislelizumab in arm B was 9.6 (0.4–14.1) months.
Efficacy
The median PFS (95% confidence interval [CI]) as determined by the investigator exhibited a trend for improvement in arm A (12.6 [8.7–not estimable (NE)] mo) and arm B (13.2 [8.5–NE] mo) compared with arm C (9.5 [8.3–14.4] mo) (Fig. 2A). For arm A versus arm C the hazard ratio (HR) was 0.84 ([95% CI: 0.46–1.52]; nominal p value = 0.2793) and for arm B versus arm C the HR was 0.80 ([95% CI: 0.45–1.44]; nominal p value = 0.2414). Subgroup analysis of PFS by demographics and baseline characteristics revealed a favorable trend for arm A and arm B versus arm C in most subgroups, with some exceptions; however, this should be treated with caution because of the small sample sizes (Supplementary Fig. 2A and B). No meaningful correlation between PD-L1 or TIGIT expression and efficacy was observed. An exploratory comparison revealed a comparable PFS benefit between arm A and arm B (HR: 1.05 [95% CI: 0.59–1.87]).
Figure 2.
Kaplan-Meier curves for PFS (A) and OS (B) (ITT analysis set). CI, confidence interval; ITT, intention-to-treat; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival.
ORR [95% CI] as determined by the investigator was numerically higher in arm A (85.4% [70.8–94.4]) and arm B (88.1% [74.4–96.0]) than arm C (76.7% [61.4–88.2]) (Table 2). The CR rate [95% CI] as determined by the investigator was numerically higher in arm A (7.3% [1.5–19.9]) and arm B (9.5% [2.7–22.6]) than arm C (2.3% [0.1–12.3]) (Table 2). The median DoR [95% CI] was numerically longer in arm A (10.1 [6.0–NE] mo) and arm B (11.5 [6.9–NE] mo) than arm C (8.2 [5.6–NE] mo) (Table 2). The median OS was not reached in any arm, and there was a similar trend for survival across the three arms (Fig. 2B, Table 2); the OS data were not mature as approximately 70% of patients were ongoing without events. The median DMFS revealed no trend for improvement in arms A and B compared with C, with a median DMFS (95% CI) of 17.9 (9.7–NE) months in arm A, 15.3 (9.8–NE) months in arm B, and 20.0 (8.6–NE) months in arm C (Table 2).
Table 2.
Secondary Efficacy End Points (ITT Analysis Set)
| Characteristic | Arm A Ociperlimab + tislelizumab + cCRT (n = 41) |
Arm B Tislelizumab + cCRT (n = 42) |
Arm C cCRT (n = 43) |
|---|---|---|---|
| CR rate, n (%) | 3 (7.3) | 4 (9.5) | 1 (2.3) |
| 95% CIa | 1.5–19.9 | 2.7–22.6 | 0.1–12.3 |
| OR (95% CI)b | 3.26 (0.32–32.79) | 4.40 (0.50–39.13) | – |
| Risk difference, % (95% CI)c | 4.9 (−4.2 to 14.0) | 7.4 (−2.7 to 17.5) | – |
| ORR, n (%) | 35 (85.4) | 37 (88.1) | 33 (76.7) |
| 95% CIa | 70.8–94.4 | 74.4–96.0 | 61.4–88.2 |
| OR (95% CI)b | 1.78 (0.58–5.47) | 2.26 (0.70–7.33) | – |
| Risk difference, % (95% CI)c | 8.7 (−7.9 to 25.4) | 11.4 (−4.5 to 27.4) | – |
| Best overall response, n (%) | |||
| CR | 3 (7.3) | 4 (9.5) | 1 (2.3) |
| PR | 32 (78.0) | 33 (78.6) | 32 (74.4) |
| Stable disease | 4 (9.8) | 2 (4.8) | 7 (16.3) |
| PD | 0 (0.0) | 1 (2.4) | 1 (2.3) |
| Not evaluable | 2 (4.9) | 2 (4.8) | 2 (4.7) |
| Median OS (95% CI), mod | NR (NE–NE) | NR (19.8–NE) | NR (20.0–NE) |
| HR (95% CI)e | 0.85 (0.39–1.85) | 0.92 (0.43–1.98) | – |
| Median DoR (95% CI), mod | 10.1 (6.0–NE) | 11.5 (6.9–NE) | 8.2 (5.6–NE) |
| Median DMFS (95% CI), mod | 17.9 (9.7–NE) | 15.3 (9.8–NE) | 20.0 (8.6–NE) |
| HR (95% CI)e | 0.95 (0.47–1.92) | 0.92 (0.46–1.84) | – |
cCRT, concurrent chemoradiotherapy; CI, confidence interval; CR, complete response; DMFS, distant metastasis-free survival; DoR, duration of response; HR, hazard ratio; NE, not estimable; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PR, partial response.
The 95% CI was estimated using the Clopper–Pearson method.
Mantel–Haenszel common OR was estimated along with its 95% CI constructed by a normal approximation of log OR and the Robins, Breslow, and Greenland variance estimate stratified by disease stage.
Mantel–Haenszel common risk difference was estimated along with its 95% CIs constructed by a normal approximation and Sato's variance estimator stratified by disease stage.
Medians and other quartiles were estimated using the Kaplan-Meier method with 95% CIs estimated using the Brookmeyer and Crowley method with log-log transformation.
HR and 95% CIs were estimated using a Cox regression model stratified by disease stage.
Safety
All patients experienced at least one treatment-related TEAE (Table 3). The three most common treatment-related TEAEs were anemia, nausea, and alopecia (Fig. 3). These treatment-related TEAEs were consistent with the known safety profile of ociperlimab, tislelizumab, and cCRT. Grade 3 or higher treatment-related TEAEs occurred in a higher percentage of patients in arm A (73.2% [30/41]) and arm B (78.6% [33/42]) than arm C (65.1% [28/43]) (Table 3); grade 3 or higher TEAEs related to ociperlimab or tislelizumab or both occurred in 22.0% (9/41) and 19.0% (8/42) of patients in arms A and B, respectively.
Table 3.
Overview of AEs (Safety Analysis Set)
| AEs | Arm A Ociperlimab + tislelizumab + cCRT (n = 41) |
Arm B Tislelizumab + cCRT (n = 42) |
Arm C cCRT (n = 43) |
|---|---|---|---|
| Patients with any TEAE, n (%) | 41 (100.0) | 42 (100.0) | 43 (100.0) |
| Grade ≥3 | 32 (78.0) | 34 (81.0) | 33 (76.7) |
| Serious | 25 (61.0) | 20 (47.6) | 12 (27.9) |
| Leading to deatha | 1 (2.4) | 1 (2.4) | 1 (2.3) |
| Leading to treatment discontinuation | 11 (26.8) | 10 (23.8) | 3 (7.0) |
| Patients with any treatment-related TEAE, n (%) | 41 (100.0) | 42 (100.0) | 43 (100.0) |
| Grade ≥3 | 30 (73.2) | 33 (78.6) | 28 (65.1) |
| Serious | 21 (51.2) | 14 (33.3) | 10 (23.3) |
| Leading to deatha | 1 (2.4) | 1 (2.4) | 1 (2.3) |
| Leading to treatment discontinuation | 11 (26.8) | 9 (21.4) | 2 (4.7) |
| Patients with any treatment-related TEAE related to ociperlimab or tislelizumab or both, n (%) | 38 (92.7) | 36 (85.7) | – |
| Grade ≥3 | 9 (22.0) | 8 (19.0) | – |
| Serious | 13 (31.7) | 6 (14.3) | – |
| Leading to deatha | 1 (2.4) | 0 (0.0) | – |
| Patients with any treatment-related TEAE related to chemotherapy, n (%) | 41 (100.0) | 42 (100.0) | 43 (100.0) |
| Grade ≥3 | 26 (63.4) | 33 (78.6) | 27 (62.8) |
| Serious | 13 (31.7) | 7 (16.7) | 6 (14.0) |
| Leading to deatha | 1 (2.4) | 1 (2.4) | 0 (0) |
| Patients with any treatment-related TEAE related to radiotherapy, n (%) | 39 (95.1) | 40 (95.2) | 35 (81.4) |
| Grade ≥3 | 15 (36.6) | 26 (61.9) | 20 (46.5) |
| Serious | 11 (26.8) | 9 (21.4) | 8 (18.6) |
| Leading to deatha | 1 (2.4) | 0 (0) | 1 (2.3) |
| Patients with any immune-mediated AE, n (%) | 28 (68.3) | 25 (59.5) | 2 (4.7) |
| Patients with IRRs, n (%) | 0 (0) | 0 (0) | 0 (0) |
AEs were graded for severity using CTCAE v5.0. Treatment-related TEAEs include those events considered by the investigator to be related or with missing assessment of the causal relationship. Immune-mediated AEs were identified from all AEs that had an onset date or a worsening in severity from baseline on or after the first dose of study drug and up to 90 days from the last dose of study drug, regardless of whether the patient starts a new anticancer therapy.
AE, adverse event; cCRT, concurrent chemoradiotherapy; CTCAE v5.0, Common Terminology Criteria for Adverse Events version 5.0; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.
The summary of TEAEs leading to death only includes TEAEs leading to death excluding death because of disease under study.
Figure 3.
Treatment-related TEAEs in at least 30% of patients in any arm (safety analysis set). Treatment-related TEAEs include those events considered by the investigator to be related or with missing assessment of the causal relationship. AEs were classified on the basis of MedDRA version 26.0. AE grades were evaluated on the basis of NCI-CTCAE version 5.0. Patients with multiple events for a given preferred term and system organ class were counted only once for each preferred term and system organ class, respectively. AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE v5.0, National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0; TEAE, treatment-emergent adverse event.
Treatment-related serious TEAEs occurred in a higher percentage of patients in arm A (51.2% [21/41]) and arm B (33.3% [14/42]) than in arm C (23.3% [10/43]). The three most common treatment-related serious TEAEs were decreased platelet count, decreased neutrophil count, and decreased white blood cell count, consistent with the known safety profiles of ociperlimab, tislelizumab, and cCRT (Supplementary Table 1). Treatment-related TEAEs that led to treatment discontinuation also occurred in a higher percentage of patients in arm A (26.8% [11/41]) and arm B (21.4% [9/42]) than in arm C (4.7% [2/43]). The most common treatment-related TEAEs leading to treatment discontinuation were radiation pneumonitis, decreased neutrophil count, pneumonitis, and decreased platelet count (Supplementary Table 2). A single patient in each arm experienced a treatment-related TEAE that led to death and included septic shock in arm A (assessed by the sponsor as related to chemotherapy), pneumonia in arm B (assessed as related to chemotherapy), and radiation pneumonitis in arm C (assessed as related to radiotherapy).
Immune-mediated AEs occurred in a higher percentage of patients in arm A (68.3% [28/41]) than arm B (59.5% [25/42]), which could be a consequence of the combination of two immunotherapy compounds. The three most common immune-mediated AEs with a higher incidence in arm A were rash (13.6% [15/41] in arm A, 4.8% [2/42] in arm B, and 0% [0/43] in arm C), eczema (9.8% [4/41] in arm A, 2.4% [1/42] in arm B, and 0% [0/43] in arm C), and pneumonitis (24.4% [10/41] in arm A, 14.3% [6/42] in arm B, and 2.3% [1/43] in arm C), which were consistent with observations in other studies of ociperlimab. Most immune-mediated AEs were of grade 1 to 2 in intensity. No infusion-related reactions were reported.
Discussion
Despite the high sensitivity of patients with LS-SCLC to initial cCRT, there is an unmet need for new combination therapy strategies to delay disease progression and prolong survival benefit. Recent studies regarding TIGIT, an immune checkpoint receptor, were designed to assess whether dual inhibition of TIGIT and PD-1 could enhance the antitumor activity of anti–PD-1 therapy. To our knowledge, ociperlimab is one of the first TIGIT inhibitors to be investigated for LS-SCLC.
In AdvanTIG-204, there was a trend of improvement in PFS in patients treated with ociperlimab and tislelizumab plus cCRT or tislelizumab plus cCRT compared with cCRT alone, whereas PFS benefit was comparable between patients treated with ociperlimab and tislelizumab plus cCRT versus tislelizumab plus cCRT. In terms of the secondary objectives, the ORR, CR rate, and DoR were numerically higher in patients treated with ociperlimab and tislelizumab plus cCRT or tislelizumab plus cCRT than in those treated with cCRT alone, whereas the median OS was not reached in all three arms, and there was no trend of improvement in median DMFS for patients treated with ociperlimab and tislelizumab plus cCRT and tislelizumab plus cCRT versus cCRT.
Overall, ociperlimab and tislelizumab plus cCRT and tislelizumab plus cCRT were tolerable, with no new safety signals identified beyond the known safety profiles of ociperlimab, tislelizumab, and cCRT. The incidence of treatment-related pneumonitis and radiation pneumonitis was less than 30% in any arm. Grade 3 or higher treatment-related TEAEs and immune-mediated AEs occurred in a higher proportion of patients treated with ociperlimab and tislelizumab plus cCRT or tislelizumab plus cCRT compared with cCRT alone, which is in line with the known safety profiles and a consequence of combining two immunotherapy compounds. Treatment-related TEAEs leading to treatment discontinuation also occurred in a higher proportion of patients treated with ociperlimab and tislelizumab plus cCRT or tislelizumab plus cCRT compared with cCRT, which may be attributable to the duration of exposure to ociperlimab or tislelizumab or both. The tolerability of ociperlimab and tislelizumab plus cCRT provides a foundation for future development of similar treatments.
Recently, studies have reported the potency of immunotherapy in both LS-SCLC and ES-SCLC. For example, the phase 3 ADRIATIC trial that assessed consolidation therapy with durvalumab versus placebo after cCRT in LS-SCLC7 and the phase 3 RATIONALE-312 trial that assessed tislelizumab plus chemotherapy versus placebo plus chemotherapy in ES-SCLC both reported an improvement in PFS and OS in the experimental arms.10 AdvanTIG-204 explored the safety and efficacy of adding immunotherapy with cCRT in patients with LS-SCLC. Specifically, we observed a trend for improvement in both PFS and ORR in the two experimental arms versus the control arm. The median PFS was prolonged by 3.7 months in the tislelizumab plus cCRT arm compared with the cCRT arm, and despite the limited sample size, the trend for improved clinical benefit in the experimental arms may indicate the activity of immunotherapy in LS-SCLC.
However, the addition of ociperlimab to tislelizumab plus cCRT did not reveal a synergistic effect, which is consistent with other trials assessing anti–PD-L1 and anti-TIGIT combination therapy, such as the SKYSCRAPER-02 study that evaluated tiragolumab plus atezolizumab and chemotherapy in ES-SCLC.19 Whether dual inhibition of PD-1 and TIGIT is a good strategy for patients with SCLC remains unknown. In addition, the phase 3 NRG-LU005 trial in patients with LS-SCLC found no improvement in survival for patients who received atezolizumab plus cCRT compared with cCRT.20 A recent review of numerous clinical studies investigating radioimmunotherapy combinations indicates that the treatment schedule (relative timing and sequencing) may be a major determinant of effect.18 It should be noted that AdvanTIG-204 was a proof-of-concept study, and caution is required in data interpretation because of the limited sample size. Unlike the ADRIATIC trial, which assessed the sequential use of durvalumab after cCRT,7 AdvanTIG-204 assessed the concurrent combination of ociperlimab with tislelizumab plus cCRT. Although the development of ociperlimab has been discontinued as a potential treatment for lung cancer, future studies adapting radiotherapy to immunotherapy by using sequential therapy18 with formal hypothesis testing and larger sample sizes could better address whether dual inhibition of PD-1 and TIGIT or other targets can produce a synergistic effect.
In the phase 2 AdvanTIG-204 trial, ociperlimab and tislelizumab plus cCRT and tislelizumab plus cCRT yielded a trend of improvement in PFS and numerically higher ORR versus cCRT alone, with no new safety signals identified beyond the known profiles of immune checkpoint inhibitors and cCRT, whereas the contribution of ociperlimab has not yet been proven.
CRediT Authorship Contribution Statement
Youling Gong: Resources, formal analysis, writing - review & editing.
Qingsong Pang: Resources, writing - review & editing.
Rong Yu: Resources, writing - review & editing.
Zhengfei Zhu: Resources, writing - review & editing.
Jiangqiong Huang: Resources, writing - review & editing.
Yufeng Cheng: Resources, writing - review & editing.
Diansheng Zhong: Resources, writing - review & editing.
Hongbo Wu: Resources, writing - review & editing.
Seung Soo Yoo: Resources, writing - review & editing.
Tracy Dobbs: Resources, writing - review & editing.
Zinan Bao: Formal analysis, writing - original draft, writing - review & editing.
Yunxia Zuo: Conceptualization, formal analysis, writing - original draft, writing - review & editing.
Yujuan Gao: Data curation, Formal analysis, writing - original draft, writing - review & editing.
Pu Sun: Data curation, formal analysis, writing - original draft, writing - review & editing.
You Lu: Conceptualization, resources, formal analysis, writing - review & editing.
Data Sharing
BeOne Medicines voluntarily shares anonymous data on completed studies responsibly and provides qualified scientific and medical researchers access to anonymous data and supporting clinical trial documentation for clinical trials in dossiers for medicines and indications after submission and approval in the United States, People's Republic of China, and Europe. Clinical trials supporting subsequent local approvals, new indications, or combination products are eligible for sharing once corresponding regulatory approvals are achieved. BeOne Medicines shares data only when permitted by applicable data privacy and security laws and regulations. In addition, data can only be shared when it is feasible to do so without compromising the privacy of study participants. Qualified researchers may submit data requests/research proposals for BeOne Medicines review and consideration through BeOne Medicines’ Clinical Trial Webpage at https://www.beonemedicines.com/science/clinical-trials/.
Ethics Committee Approval and Informed Consent
This trial was approved by institutional review boards or independent ethics committees and conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was obtained from each patient before any trial-specific procedures or treatment. The authors attest to the accuracy and completeness of the data and the fidelity of the trial to the protocol.
Disclosure
Dr. Zhu reports receiving research funding from BeiGene. Dr. Zuo is an employee of BeOne Medicines and reports stock or other ownership with BeOne Medicines and a consulting or advisory role with BeOne Medicines. Drs. Bao, Gao, and Sun are employees of BeOne Medicines. Dr. Lu reports having speaker/project lead/principal investigator roles with Roche, AstraZeneca, BeiGene, and Hengrui; and received honoraria from Pfizer, Merck Sharp & Dohme, and Bristol-Myers Squibb. The remaining authors declare no conflicts of interest.
Acknowledgments
This study was sponsored by BeOne Medicines Ltd. (formerly BeiGene, Ltd.). Medical writing support was provided by Lee Blackburn, MSc, of Amiculum, supported by BeOne Medicines. The authors thank the investigators, site support staff, and especially the patients for participating in this study.
Footnotes
Presented in part at the American Association for Cancer (AACR) Annual Meeting, San Diego, CA, April 5–10, 2024.
Cite this article as: Gong Y, Pang Q, Yu R, et al. AdvanTIG-204: a phase 2, randomized, open-label study of ociperlimab plus tislelizumab and concurrent chemoradiotherapy versus tislelizumab and concurrent chemotherapy versus concurrent chemoradiotherapy in first-line limited-stage SCLC. JTO Clin Res Rep. 2025;6:100911.
Note: To access the supplementary material accompanying this article, visit the online version of the JTO Clinical and Research Reports at www.jtocrr.org and at https://doi.org/10.1016/j.jtocrr.2025.100911.
Supplementary Data
References
- 1.American Cancer Society Cancer facts & figures 2023. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
- 2.Farago A.F., Keane F.K. Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res. 2018;7:69–79. doi: 10.21037/tlcr.2018.01.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tjong M.C., Mak D.Y., Shahi J., Li G.J., Chen H., Louie A.V. Current management and progress in radiotherapy for small cell lung cancer. Front Oncol. 2020;10:1146. doi: 10.3389/fonc.2020.01146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Faivre-Finn C., Snee M., Ashcroft L., et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017;18:1116–1125. doi: 10.1016/S1470-2045(17)30318-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Miller A.A., Wang X.F., Bogart J.A., et al. Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002. J Thorac Oncol. 2007;2:645–651. doi: 10.1097/JTO.0b013e318074bbf5. [DOI] [PubMed] [Google Scholar]
- 6.Turrisi A.T., 3rd, Kim K., Blum R., et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999;340:265–271. doi: 10.1056/NEJM199901283400403. [DOI] [PubMed] [Google Scholar]
- 7.Cheng Y., Spigel D.R., Cho B.C., et al. Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 2024;391:1313–1327. doi: 10.1056/NEJMoa2404873. [DOI] [PubMed] [Google Scholar]
- 8.Horn L., Mansfield A.S., Szczęsna A., et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–2229. doi: 10.1056/NEJMoa1809064. [DOI] [PubMed] [Google Scholar]
- 9.Paz-Ares L., Dvorkin M., Chen Y., et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (Caspian): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929–1939. doi: 10.1016/S0140-6736(19)32222-6. [DOI] [PubMed] [Google Scholar]
- 10.Cheng Y., Fan Y., Zhao Y., et al. Tislelizumab plus platinum and etoposide versus placebo plus platinum and etoposide as first-line treatment for extensive-stage SCLC (RATIONALE-312): a multicenter, double-blind, placebo-controlled, randomized, phase 3 clinical trial. J Thorac Oncol. 2024;19:1073–1085. doi: 10.1016/j.jtho.2024.03.008. [DOI] [PubMed] [Google Scholar]
- 11.Chen Y., Li H., Fan Y. Shaping the tumor immune microenvironment of SCLC: mechanisms, and opportunities for immunotherapy. Cancer Treat Rev. 2023;120 doi: 10.1016/j.ctrv.2023.102606. [DOI] [PubMed] [Google Scholar]
- 12.Zhou X.M., Li W.Q., Wu Y.H., et al. Intrinsic expression of immune checkpoint molecule TIGIT could help tumor growth in vivo by suppressing the function of NK and CD8+ T cells. Front Immunol. 2018;9:2821. doi: 10.3389/fimmu.2018.02821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Harjunpää H., Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200:108–119. doi: 10.1111/cei.13407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Chauvin J.M., Zarour H.M. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8 doi: 10.1136/jitc-2020-000957. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Chauvin J.M., Pagliano O., Fourcade J., et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. 2015;125:2046–2058. doi: 10.1172/JCI80445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Banta K.L., Xu X., Chitre A.S., et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8(+) T cell responses. Immunity. 2022;55:512–526.e9. doi: 10.1016/j.immuni.2022.02.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Chu X., Tian W., Wang Z., Zhang J., Zhou R. Co-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: mechanisms and clinical trials. Mol Cancer. 2023;22:93. doi: 10.1186/s12943-023-01800-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Galluzzi L., Aryankalayil M.J., Coleman C.N., Formenti S.C. Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol. 2023;20:543–557. doi: 10.1038/s41571-023-00782-x. [DOI] [PubMed] [Google Scholar]
- 19.Rudin C.M., Liu S.V., Soo R.A., et al. SKYSCRAPER-02: tiragolumab in combination with atezolizumab plus chemotherapy in untreated extensive-stage small-cell lung cancer. J Clin Oncol. 2024;42:324–335. doi: 10.1200/JCO.23.01363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Higgins K., Hu C., Ross H.J., et al. Concurrent chemoradiation ± atezolizumab (atezo) in limited-stage small cell lung cancer (LS-SCLC): results of NRG Oncology/Alliance LU005. Int J Radiat Oncol Biol Phys. 2024;120:S2. doi: 10.1016/j.ijrobp.2024.04.072. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.