Abstract
Background
Immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) have improved advanced renal cell carcinoma (RCC) outcomes, yet median progression-free survival (PFS) remains <2 years.
Patients and methods
This randomised (1 : 1 : 1), open-label, phase II study (NCT05805501) evaluated tobemstomig [bispecific anti–programmed cell death protein 1 (PD-1)/lymphocyte-activation gene 3] plus axitinib (VEGF-TKI) and tobemstomig plus tiragolumab (anti–T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains) plus axitinib versus pembrolizumab (anti–PD-1) plus axitinib (control) in patients with untreated, locally advanced unresectable/metastatic clear-cell RCC with intermediate/poor International Metastatic Renal Cell Carcinoma Database Consortium risk. Following a protocol-specified interim futility analysis that led to study termination, the primary endpoint was amended from PFS and incidence/severity of adverse events (AEs) to the latter only. Efficacy was evaluated descriptively.
Results
In the safety population (198 patients: tobemstomig-axitinib, n = 66; tobemstomig-tiragolumab-axitinib, n = 65; control, n = 67), grade 3-4 AEs occurred in 62.1%, 67.7% and 56.7% of patients in the respective arms and treatment-related serious AEs occurred in 22.7%, 29.2% and 13.4%. Confirmed overall response rates were 51.5%, 53.8% and 51.5%; median PFS was 12.4 [95% confidence interval (CI) 8.4-16.3], 12.5 (95% CI 7.3-17.2) and 12.5 months (95% CI 9.5 to not estimable).
Conclusions
Tobemstomig-containing regimens were associated with increased toxicity and did not demonstrate meaningful efficacy improvement relative to control.
Key words: immune checkpoint inhibitor, LAG3, renal cell carcinoma, TIGIT, tobemstomig, tyrosine kinase inhibitor
Highlights
-
•
Advanced RCC treated with first-line VEGF-TKI/anti-PD-1 combinations typically progresses within 2 years.
-
•
Tobemstomig combinations showed no superior benefit to pembrolizumab-axitinib in intermediate/poor IMDC-risk RCC.
-
•
There were more grade 3-4 AEs with tobemstomig combinations, particularly with tobemstomig-tiragolumab-axitinib.
-
•
The findings did not support further development of tobemstomig-based regimens in advanced RCC.
Introduction
The treatment landscape for advanced renal cell carcinoma (RCC) has evolved substantially with the introduction of immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs), particularly in combination.1 For example, pembrolizumab [an anti–programmed cell death protein 1 (PD-1) antibody] plus axitinib (a VEGF receptor TKI) has demonstrated significantly improved overall survival (OS) and objective response rate (ORR) over sunitinib (a multitargeted TKI) in the first-line setting for advanced RCC.2
Despite these advances, median progression-free survival (PFS) with first-line ICI/TKI regimens is generally <2 years,3,4 underscoring the need for novel therapeutic strategies to enhance response durability and broaden clinical benefit.
Inhibition of novel immune checkpoints such as lymphocyte-activation gene 3 (LAG3) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) demonstrated promising early results in RCC.5,6 LAG3 and TIGIT contribute to T-cell exhaustion and resistance to PD-1 blockade.7,8 In RCC, high LAG3 and TIGIT expression correlates with immunosuppressive tumour microenvironments and poorer prognosis.5,9 The clinical relevance of these pathways is further supported by the U.S. Food and Drug Administration approval of nivolumab plus relatlimab (anti-LAG3) in advanced melanoma (based on the RELATIVITY-047 trial).10
This randomised phase II study (BO43936; NCT05805501) evaluated tobemstomig (bispecific anti-PD-1 and LAG3) and tiragolumab (an anti-TIGIT antibody), both combined with axitinib, versus the standard-of-care combination of pembrolizumab and axitinib in patients with previously untreated, advanced clear-cell RCC (ccRCC). Following a protocol-specified futility analysis, additional enrolment of patients into the study was discontinued. Here, we present safety and efficacy findings from the final descriptive analysis.
Methods
This was a randomised, open-label, phase II study. The three treatment regimens were administered in repeated 21-day cycles until RECIST v1.1 disease progression, unacceptable toxicity or ≤24 months (whichever occurred first): tobemstomig 600 mg intravenously (i.v.) every 3 weeks (Q3W) plus axitinib 5 mg orally (p.o.) biduum two days in arm A, tobemstomig 600 mg i.v. Q3W plus tiragolumab 600 mg i.v. Q3W and axitinib 5 mg p.o. biduum two days in arm B and pembrolizumab 200 mg i.v. Q3W plus axitinib 5 mg p.o. biduum two days in the control arm.
Eligible patients were aged ≥18 years and had histologically confirmed RCC containing a clear-cell component (sarcomatoid features allowed), previously untreated, locally advanced, unresectable or metastatic disease measurable according to RECIST v1.1 and an International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score of intermediate or poor. Key exclusions were active central nervous system metastases, prior systemic therapy for advanced RCC or clinically meaningful autoimmune disease.
The study planned to enrol ∼210 participants, with primary endpoints of investigator-assessed PFS per RECIST v1.1 and incidence and severity of adverse events (AEs). A protocol-specified interim analysis for futility was conducted by an independent monitoring committee after the first 105 randomly allocated participants had ≥3 months of follow-up to stop one or both experimental arms if the ORR data indicated futility. The criterion to terminate an experimental arm was a prespecified difference in the confirmed ORR of >11% favouring the control arm. As a result of the futility findings, enrolment was terminated in all treatment arms after 199 patients had been randomly allocated. Subsequently, the sponsor discontinued the development of tobemstomig and the primary study endpoint was amended to incidence and severity of AEs only (protocol version 6). Ongoing treatment was permitted at the investigator’s discretion for patients deriving clinical benefit. Although the planned formal analysis of efficacy endpoints could not be carried out, a descriptive analysis of efficacy [ORR, PFS, duration of response (DOR) and OS] was completed in the efficacy-assessable population.
The trial was conducted according to Good Clinical Practice guidelines of the International Conference on Harmonisation and the principles of the Declaration of Helsinki. The trial protocol was approved by independent review boards or ethics committees at each of the study sites. All patients provided written informed consent.
Results
The protocol-specified futility analysis (clinical cut-off date: 22 April 2024) was conducted in the first 105 enrolled patients with ≥3 months of follow-up. The tobemstomig plus axitinib arm crossed the futility boundary for ORR, with an observed difference of 11.44% favouring the control arm. As no meaningful efficacy advantage was seen in either of the experimental arm and numerically higher incidences of serious AEs (SAEs), grade 3-4 AEs and immune-mediated AEs were reported, further study enrolment was paused for all three arms.
Patients
Between 21 April 2023 and 11 July 2024, 199 patients were enrolled and randomly allocated. At the data cut-off date for the final descriptive analysis (1 February 2025), the median follow-up was ∼11 months across the treatment arms (Table 1). The safety-assessable population included 198 patients (one randomly allocated patient did not receive any study treatment): 67 patients in the control arm, 66 patients in arm A and 65 patients in arm B. The efficacy-assessable population included 197 patients as two patients were mistakenly randomly allocated but did not meet the eligibility criteria (66, 66 and 65 patients, respectively; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2026.108587). Approximately half of these patients remained on treatment at data cut-off; the most common reasons for treatment discontinuation were progressive disease (PD) in the control arm and arm A and AEs and PD in arm B.
Table 1.
Efficacy in the efficacy-assessable population
| Outcome | Arm A: tobemstomig + axitinib (n = 66) | Arm B: tobemstomig + tiragolumab + axitinib (n = 65) | Control: pembrolizumab + axitinib (n = 66) |
|---|---|---|---|
| Follow-up (months), median (range) | 11.3 (1-20) | 11.1 (2-21) | 11.7 (1-21) |
| Confirmed ORR, n (%) | 34 (51.5) | 35 (53.8) | 34 (51.5) |
| Complete response | 0 | 2 (3.1) | 0 |
| Partial response | 34 (51.5) | 33 (50.8) | 34 (51.5) |
| Stable disease | 23 (34.8) | 24 (36.9) | 27 (40.9) |
| Progressive disease | 4 (6.1) | 4 (6.2) | 3 (4.5) |
| NE | 1 (1.5) | 1 (1.5) | 0 |
| Missing | 4 (6.1) | 1 (1.5) | 2 (3.0) |
| Unconfirmed ORR, n (%) | 36 (54.5) | 41 (63.1) | 40 (60.6) |
| Responders, n | 34 | 35 | 34 |
| Responders with subsequent event, n (%) | 11 (32.4) | 12 (34.3) | 10 (29.4) |
| Death, n | 0 | 1 | 2 |
| Disease progression, n | 11 | 11 | 8 |
| Duration of response (months), median (95% CI) | 12.4 (8.5-NE) | 14.7 (9.5-NE) | NE (9.6-NE) |
| PFS (months), median (95% CI) | 12.4 (8.4-16.3) | 12.5 (7.3-17.2) | 12.5 (9.5-NE) |
No missing data were imputed. Patients without postbaseline tumour assessments were considered nonresponders for ORR. Statistical analyses were carried out using SAS 9.4.
CI, confidence interval; NE, not estimable; ORR, objective response rate; PFS, progression-free survival.
Baseline demographics and disease characteristics were generally balanced (Table 2). Most patients had IMDC intermediate risk (81.7%; 161 of 197), stage IV disease at diagnosis (52.8%; 104 of 197), metastatic disease at enrolment (88.3%; 174 of 197) and ≥1% PD-L1 expression (63.6%; 110 of 173 of assessable patients).
Table 2.
Baseline demographics and disease characteristics in the efficacy-assessable population
| Characteristic | Arm A: tobemstomig + axitinib (n = 66) | Arm B: tobemstomig + tiragolumab + axitinib (n = 65) | Control: pembrolizumab + axitinib (n = 66) | All patients (N = 197) |
|---|---|---|---|---|
| Age (years), median (range) | 61.0 (40-86) | 62.0 (41-78) | 61.5 (34-82) | 61.0 (34-86) |
| Age, n (%) | ||||
| <65 years | 38 (57.6) | 38 (58.5) | 40 (60.6) | 116 (58.9) |
| ≥65 years | 28 (42.4) | 27 (41.5) | 26 (39.4) | 81 (41.1) |
| Sex, n (%) | ||||
| Male | 51 (77.3) | 52 (80.0) | 55 (83.3) | 158 (80.2) |
| Female | 15 (22.7) | 13 (20.0) | 11 (16.7) | 39 (19.8) |
| Race, n (%) | ||||
| Asian | 29 (43.9) | 25 (38.5) | 23 (34.8) | 77 (39.1) |
| Black/African American | 0 | 0 | 1 (1.5) | 1 (0.5) |
| White | 27 (40.9) | 34 (52.3) | 35 (53) | 96 (48.7) |
| Unknown | 1 (1.5) | 0 | 1 (1.5) | 2 (1.0) |
| Not reported | 9 (13.6) | 6 (9.2) | 6 (9.1) | 21 (10.7) |
| ECOG performance status, n (%) | ||||
| 0 | 26 (39.4) | 29 (44.6) | 32 (48.5) | 87 (44.2) |
| 1 | 40 (60.6) | 36 (55.4) | 34 (51.5) | 110 (55.8) |
| Karnofsky performance status score, n | 66 | 63 | 65 | 194 |
| 70-80, n (%) | 30 (45.5) | 31 (49.2) | 18 (27.7) | 79 (40.7) |
| 90-100, n (%) | 36 (54.5) | 32 (50.8) | 47 (72.3) | 115 (59.3) |
| IMDC risk (IxRS), n (%) | ||||
| Intermediate | 54 (81.8) | 53 (81.5) | 54 (81.8) | 161 (81.7) |
| Poor | 12 (18.2) | 12 (18.5) | 12 (18.2) | 36 (18.3) |
| Smoking status, n (%) | ||||
| Current/former | 25 (37.9) | 30 (46.2) | 34 (51.5) | 89 (45.2) |
| Never | 41 (62.1) | 35 (53.8) | 32 (48.5) | 108 (54.8) |
| Initial diagnosis staging, n (%) | ||||
| Stage I | 6 (9.1) | 12 (18.5) | 8 (12.1) | 26 (13.2) |
| Stage II | 13 (19.7) | 5 (7.7) | 4 (6.1) | 22 (11.2) |
| Stage III | 13 (19.7) | 14 (21.5) | 18 (27.3) | 45 (22.8) |
| Stage IV | 34 (51.5) | 34 (52.3) | 36 (54.5) | 104 (52.8) |
| Disease status at enrolment, n (%) | ||||
| Metastatic | 57 (86.4) | 60 (92.3) | 57 (86.4) | 174 (88.3) |
| Locally advanced | 9 (13.6) | 5 (7.7) | 9 (13.6) | 23 (11.7) |
| Prior cancer radiotherapy, n | 66 | 65 | 66 | 197 |
| Yes, n (%) | 8 (12.1) | 5 (7.7) | 10 (15.2) | 23 (11.7) |
| No, n (%) | 58 (87.9) | 60 (92.3) | 56 (84.8) | 174 (88.3) |
| Prior nephrectomy, n (%) | ||||
| Yes | 31 (47.0) | 33 (50.8) | 29 (43.9) | 93 (47.2) |
| No | 35 (53.0) | 32 (49.2) | 37 (56.1) | 104 (52.8) |
| PD-L1 status by SP263 (TAP score), n | 57 | 57 | 59 | 173 |
| Negative (<1%), n (%) | 15 (26.3) | 23 (40.4) | 25 (42.4) | 63 (36.4) |
| Positive (≥1%), n (%) | 22 (38.6) | 21 (36.8) | 21 (35.6) | 64 (37.0) |
ECOG, Eastern Cooperative Oncology Group; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IxRS, interactive voice and web response system; PD-L1, programmed death-ligand 1; SP263, Ventana PD-L1 (SP263) assay (Ventana Medical Systems, Tucson, AZ); TAP, tumour area positivity.
Safety overview
Treatment exposure is summarised in Supplementary Table S1 (available at https://doi.org/10.1016/j.esmoop.2026.108587). Grade 3-4 AEs occurred in 56.7% (38 of 67) of patients in the control arm, 62.1% (41 of 66) of patients in arm A, and 67.7% (44 of 65) of patients in arm B (Table 3). Grade 5 AEs were reported in 3.5% (7 of 198) of patients overall (Table 3). AEs were sepsis (control arm); atrioventricular block, gastrointestinal obstruction and haemoptysis (arm A) and stroke, unexplained death and suicide (arm B); none were considered treatment-related. SAEs were reported in 31.3% (21 of 67), 42.4% (28 of 66) and 61.5% (40 of 65) of patients in the control arm, arm A and arm B, respectively (Table 3). Treatment-related SAEs were observed in 13.4% (control 9 of 67), 22.7% (arm A 15 of 66) and 29.2% (arm B 19 of 65) of patients (Table 3; Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2026.108587). Treatment-related AEs leading to discontinuation of any study treatment were observed in 11.9% (control 8 of 67), 12.1% (arm A 8 of 66) and 29.2% (arm B 19 of 65) of patients (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2026.108587).
Table 3.
Safety summary in the safety-assessable population
| AE | Arm A: tobemstomig + axitinib (n = 66) | Arm B: tobemstomig + tiragolumab + axitinib (n = 65) | Control: pembrolizumab + axitinib (n = 67) | All patients (N = 198) |
|---|---|---|---|---|
| Total number of patients (%) with ≥1 AE | 65 (98.5) | 64 (98.5) | 66 (98.5) | 195 (98.5) |
| Total number of AEs, n | 777 | 784 | 784 | 2345 |
| Grade 3-4 AE, n (%) | 41 (62.1) | 44 (67.7) | 38 (56.7) | 123 (62.1) |
| SAE, n (%) | 28 (42.4) | 40 (61.5) | 21 (31.3) | 89 (44.9) |
| Treatment-related SAE, n (%) | 15 (22.7) | 19 (29.2) | 9 (13.4) | 43 (21.7) |
| Grade 5 AE, n (%)a | 3 (4.5)b | 3 (4.6)c | 1 (1.5)d | 7 (3.5) |
| Immune-mediated AE, n (%) | 50 (75.8) | 52 (80.0) | 47 (70.1) | 149 (75.3) |
| AE leading to withdrawal from any study treatment, n (%) | 8 (12.1) | 19 (29.2) | 10 (14.9) | 37 (18.7) |
| AE leading to withdrawal of: | ||||
| Pembrolizumab, n (%) | 0 | 0 | 6 (9.0) | 6 (3.0) |
| Tiragolumab, n (%) | 0 | 17 (26.2) | 0 | 17 (8.6) |
| Tobemstomig, n (%) | 8 (12.1) | 18 (27.7) | 0 | 26 (13.1) |
| Axitinib, n (%) | 2 (3.0) | 6 (9.2) | 7 (10.4) | 15 (7.6) |
AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 in the safety-assessable population (all randomised patients who received at least one dose of any study treatment).
AE, adverse event; SAE, serious adverse event.
None of these grade 5 AEs were related to the study treatment.
Atrioventricular block, gastrointestinal obstruction and haemoptysis.
Stroke, unexplained death and suicide.
Sepsis.
Overall, higher incidences of grade 3-4 AEs, SAEs, immune-mediated AEs and AEs leading to treatment withdrawal were observed in arm B, followed by arm A and the control arm (Table 3). The most common clinically relevant grade 3-5 AEs, treatment-related SAEs and immune-mediated AEs are summarised in the Supplementary Results (available at https://doi.org/10.1016/j.esmoop.2026.108587).
Efficacy
Confirmed ORRs were observed in 51.5% of patients (34 of 66) in the control arm, 51.5% of patients (34 of 66) in arm A and 53.8% of patients (35 of 65) in arm B (Table 1). Notably, arm B included two patients with complete responses (CRs), whereas all other responses across arms were partial responses. The median DOR was not estimable [NE; 95% confidence interval (CI) 9.6-NE] in the control arm, 12.4 months (95% CI 8.5-NE) in arm A and 14.7 months (95% CI 9.45-NE) in arm B (Figure 1B).
Figure 1.
(A) PFS, (B) DOR and (C) OS (efficacy-assessable population). No missing data were imputed. Patients without postbaseline tumour assessments were considered nonresponders for ORR. Statistical analyses were carried out using SAS 9.4.
axi, axitinib; CI, confidence interval; DOR, duration of response; NE, not estimable; ORR, objective response rate; OS, overall survival; pembro, pembrolizumab; PFS, progression-free survival; tira, tiragolumab; tobe, tobemstomig.
Median PFS was 12.5 months (95% CI 9.5-NE) in the control arm, 12.4 months (95% CI 8.4-16.3) in arm A and 12.5 months (95% CI 7.3-17.2) in arm B (Table 1, Figure 1A).
Median OS was not reached in any arm; the hazard ratio versus the control arm was 1.8 (95% CI 0.6-4.9) for arm A and 2.1 (95% CI 0.8-5.6) for arm B (Figure 1C). Six-month landmark event-free survival rates were 96.9% (95% CI 92.6-100.0) in the control arm, 93.8% (95% CI 87.9-99.7) in arm A and 90.6% (95% CI 83.5-97.8) in arm B, reflecting slightly lower rates in the experimental arms than in the control arm. Additional analyses of ORR and PFS stratified by IMDC risk factors are presented in Supplementary Figure S2 (available at https://doi.org/10.1016/j.esmoop.2026.108587).
Discussion
Novel approaches are needed to build upon the benefits of immune-based combinations in metastatic RCC. Approaches targeting LAG3 and TIGIT represent viable candidates in RCC given the underlying immune-responsive biology and effect observed in other solid tumours. In this randomised phase II study in patients with untreated, advanced ccRCC, although the overall incidence of AEs was similar among all three arms, the tobemstomig-containing regimens led to numerically higher incidences of clinically relevant AEs. The triplet regimen was associated with higher rates of grade 3-4 AEs, SAEs and AE-related treatment discontinuations compared with the doublet. The grade 5 AEs in arm B were unrelated to treatment and did not prompt additional safety monitoring or protocol amendments before enrolment was halted. These findings highlight the challenges of intensifying established PD-1/VEGF-based regimens with additional immune checkpoint agents, in which increased toxicity may limit the potential for clinical benefit in unselected patient populations. The tobemstomig combinations did not demonstrate a clinical benefit over control, with no meaningful PFS or ORR improvements. Tobemstomig, as a monotherapy and combination therapy, has been assessed in other phase Ib/II studies, including non-small-cell lung cancer (NCT05775289)11 and melanoma (NCT05116202),12 with no improved clinical outcomes compared with ICI-based regimens. Therefore, the development of tobemstomig was discontinued.
The response rates observed in this study were broadly consistent with previously reported outcomes for anti-PD-1–VEGF-TKI combinations.2,13 Although the interim futility analysis showed a numerically lower ORR for tobemstomig plus axitinib compared with control, the final analysis showed similar confirmed ORRs (51.5% versus 51.5%). This apparent difference likely reflects the impact of a smaller patient sample size and a shorter follow-up period used in the futility analysis. Nevertheless, the final analysis did not demonstrate a meaningful efficacy advantage for either of the tobemstomig-containing regimen. The observed ORRs were similar across arms [51.5% (arm A and the control) and 53.8% (arm B)] and the low CR rates across the experimental arms indicate that tobemstomig with or without tiragolumab did not confer greater antitumour activity compared with established anti-PD-1–VEGF-TKI combinations such as pembrolizumab plus axitinib. The relatively modest activity, particularly the low CR rate and similar progression patterns across arms, may reflect the inherent limitations of PD-1 pathway inhibition, whether alone or in combination with additional checkpoint inhibitors, in this treatment setting.
Our findings echo broader challenges seen in achieving added benefit through triplet regimens in renal cancer. In STELLAR-002, the triplet combination of zanzalintinib (selective VEGF receptor TKI) plus nivolumab (anti-PD-1) and relatlimab (LAG-3 inhibitor) demonstrated a lower ORR (33%) compared with the zanzalintinib plus nivolumab doublet (63%) in the first-line treatment of ccRCC, with similar disease control rates and higher discontinuation due to toxicity, suggesting no added benefit from the triplet strategy in unselected patients.14 In COSMIC-313, cabozantinib plus nivolumab and ipilimumab improved PFS compared with nivolumab plus ipilimumab but did not demonstrate an OS benefit and was associated with increased toxicity and reduced treatment exposure.15 These findings reinforce the notion that triplet regimens, particularly those incorporating TIGIT- or LAG-3-directed agents, may not yield incremental clinical benefit over established ICI and VEGF-targeted combinations in unselected patients.
The observed response data and primary disease progression rates, although broadly consistent with prior studies,2,15,16 may reflect differences in patient selection, particularly with respect to risk stratification and baseline tumour characteristics. All patients in the current study were classified as IMDC intermediate or poor risk, unlike many phase III trials that enrolled patients across all IMDC risk groups, including favourable-risk populations known to have better outcomes and longer survival. These nuances highlight the need for deeper biomarker-driven understanding of response and resistance mechanisms in ccRCC. High levels of CD8+ T-cell infiltration in ccRCC are associated with an unfavourable prognosis,17,18 in contrast with melanoma, suggesting that these T cells are profoundly dysfunctional or ‘fixed’ in an exhausted state, and not readily reversible by single or dual checkpoint blockade. Deciphering this state will require spatial multi-omic profiling to isolate the specific pathways driving this resistance. Future strategies should prioritise novel mechanisms of action beyond current PD-1/VEGF backbones, including the addition of hypoxia-inducible factor-2 alpha inhibitors, metabolic or myeloid modulators, antibody–drug conjugates and engineered T-cell platforms.19,20
In conclusion, the addition of tobemstomig to axitinib demonstrated no added benefit compared with standard of care in patients with previously untreated, advanced ccRCC. The triplet combination of tobemstomig, tiragolumab and axitinib was associated with increased toxicity without meaningful improvement in efficacy. These findings, alongside results from other triplet studies and the plateauing benefit of current PD-1/VEGF-based regimens, highlight the need to reconsider development strategies and prioritise innovative, biology-guided approaches in renal cancer.
Acknowledgements
The authors thank the patients and their families, participating study investigators and 64 hospital or university hospital sites across nine countries (Australia, China, France, Germany, the Republic of Korea, Poland, Spain, the UK, and the United States). The authors acknowledge Pfizer for the provision of axitinib used in this study. Research support in the form of third-party writing assistance for this manuscript, furnished by Thevani Pillay, MSc, of Nucleus Global, an Inizio Company, was provided by F. Hoffmann-La Roche Ltd.
Data availability
Qualified researchers may request access to individual patient-level data through the clinical study data request platform: https://vivli.org/. Further details on Roche’s criteria for eligible studies are available here: https://vivli.org/members/ourmembers/. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.
Funding
This work was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland (no grant number). The funder of the study had a role in study design, provision of study drugs, protocol development, regulatory and ethics approvals, safety monitoring, data collection, data analysis, data interpretation and writing of the report, in collaboration with the study authors.
Disclosure
All authors received research support in the form of third-party medical writing assistance for this manuscript, provided by F. Hoffmann-La Roche Ltd. BIR receives research funding (to institution) from AVEO, Arcus, Merck, HiberCell, Incyte, Janssen, Adela, AstraZeneca, Tempus, Gilead, POINT Biopharma, Bristol Myers Squibb (BMS), Pfizer, Daiichi Sankyo, Genentech, Exelixis, Surface Oncology, Deciphera and Regeneron and consulting fees from Eisai, BMS, Pfizer, AstraZeneca, AVEO, Merck, Exelixis, Formedics, Xencor and Johnson & Johnson. TP serves as a research/advisory board member (honorarium) for AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD in US), Astellas, Johnson & Johnson, Eisai and Roche; receives grant/funding to institution from AstraZeneca, Roche, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD in the US), Astellas, Johnson & Johnson and Eisai and receives support for attending meetings and/or travel from Roche, Pfizer, MSD, AstraZeneca and Ipsen. JMC serves a scientific consultancy role (speaker and advisory role) for and receives support for attending meetings and/or travel from Ipsen, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, BMS, MSD, Adium, Asofarma, Recordati Rare Diseases and Exelixis; receives support for participation in clinical trials from Roche, BMS, MSD, Pfizer, Novartis, Ipsen, Exelixis, AstraZeneca-Medimmune, Janssen, Lilly, Eisai and Astellas and receives research support from Roche, Pfizer, Ipsen, Janssen, Exelixis and MSD. JLL receives research funding (to institution) from Amgen, Arcus Biosciences, AstraZeneca/MedImmune, Bayer Schering Pharma, Bicycle Therapeutics, BMS, GI Innovation, Janssen, MSD, Novartis, Oscotec, Pfizer, Roche/Genetech and LG Chemica; is a consultant for Amgen, Astellas, AstraZeneca, Daiichi Sankyo, Merck and Novartis; serves as a research/advisory board member (receives honorarium) for AstraZeneca and Novartis; receives support for participation on a data safety monitoring or advisory boards from Pfizer Korea, Astellas Korea, Merck Korea, MSD Korea, AstraZeneca, Amgen and Novartis Korea and holds stock options in Amgen, Johnson and Johnson and MSD. JP reports research grants from Roche, Astellas, Pfizer and Merck; has acted as a speaker and reports consultant and advisory roles for AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Novartis, MSD, Pfizer, Gilead, BMS, Rovi and Merck and received travel support from AstraZeneca, Janssen, Merck, Ipsen and Pfizer. AB reports consulting for Eisai, Arcus, EMD Serono and LG Chem. NM serves a scientific consultancy role (speaker and advisory role) for Astellas, Pfizer, Exelixis, Johnson & Johnson, EMD Serono, Eisai and Merck. JH is employed by F. Hoffmann-La Roche Ltd and holds stock options in F. Hoffmann-La Roche Ltd. LC is employed by F. Hoffmann-La Roche Ltd and holds stock options in F. Hoffmann-La Roche Ltd. HP is employed by Genentech and holds stock options in by F. Hoffmann-La Roche Ltd. LA serves a scientific consultancy role (honoraria; all paid to Institution) for AMGEN, Astellas, BMS, Daiichi, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche, Telix and Xencor and receives support for attending meetings and/or travel from BMS, Ipsen, MSD and Pfizer. The other authors have declared no conflicts of interest.
Supplementary data
References
- 1.Plimack E.R., Powles T., Stus V., et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 KEYNOTE-426 study. Eur Urol. 2023;84(5):449–454. doi: 10.1016/j.eururo.2023.06.006. [DOI] [PubMed] [Google Scholar]
- 2.Rini B.I., Plimack E.R., Stus V., et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–1127. doi: 10.1056/NEJMoa1816714. [DOI] [PubMed] [Google Scholar]
- 3.Yanagisawa T., Mori K., Matsukawa A., et al. Updated systematic review and network meta-analysis of first-line treatments for metastatic renal cell carcinoma with extended follow-up data. Cancer Immunol Immunother. 2024;73(2):38. doi: 10.1007/s00262-023-03621-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Ikoma H., Hamamoto S., Tasaki Y., et al. Real-world outcomes of immune checkpoint inhibitor-based combination therapy in older adult patients with metastatic renal cell carcinoma: a multi-center, retrospective analysis. Front Immunol. 2025;16 doi: 10.3389/fimmu.2025.1668406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Takamatsu K., Tanaka N., Hakozaki K., et al. Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy. Nat Commun. 2021;12(1):5547. doi: 10.1038/s41467-021-25865-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Compagno S., Casadio C., Galvani L., et al. Novel immune checkpoint inhibitor targets in advanced or metastatic renal cell carcinoma: state of the art and future perspectives. J Clin Med. 2024;13(19):5738. doi: 10.3390/jcm13195738. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zelba H., Bedke J., Hennenlotter J., et al. PD-1 and LAG-3 dominate checkpoint receptor-mediated T-cell inhibition in renal cell carcinoma. Cancer Immunol Res. 2019;7(11):1891–1899. doi: 10.1158/2326-6066.CIR-19-0146. [DOI] [PubMed] [Google Scholar]
- 8.Bi K., He M.X., Bakouny Z., et al. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma. Cancer Cell. 2021;39(5):649–661.e5. doi: 10.1016/j.ccell.2021.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhang J., Peng Q., Xiang X., et al. LIMD2 is associated with an exhausted CD8+ T cell state linked to ICI response in clear cell renal cell carcinoma. Sci Rep. 2025;15(1) doi: 10.1038/s41598-025-27315-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Tawbi H.A., Schadendorf D., Lipson E.J., et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24–34. doi: 10.1056/NEJMoa2109970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Nadal E., Rittmeyer A., De Marinis F., et al. 7MO: a phase II trial of tobemstomig (tobe) + platinum-based chemotherapy (chemo) vs pembrolizumab (pembro) + chemo in patients (pts) with untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) J Thorac Oncol. 2025;20(3):S11–S12. [Google Scholar]
- 12.Long G.V., Nair N., Marbach D., et al. Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 morpheus-melanoma trial. Nat Med. 2025;31(11):3700–3712. doi: 10.1038/s41591-025-03967-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Motzer R.J., Porta C., Eto M., et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC) J Clin Oncol. 2023;41(16 suppl):4502. [Google Scholar]
- 14.Chahoud J., McGregor B.A., Torras O.R., et al. Zanzalintinib (zanza) + nivolumab (nivo) ± relatlimab (rela) in patients (pts) with previously untreated clear cell renal cell carcinoma (ccRCC): results from an expansion cohort of the phase 1b STELLAR-002 study. J Clin Oncol. 2025;43(16 suppl) 4515-4515. [Google Scholar]
- 15.Albiges L., Motzer R., Trevino Aguirre S.A. Presented at: Kidney Cancer Research Summit (KCRS25); July 17-18, 2025; Boston, MA. Final results of the phase 3 COSMIC-313 study comparing first-line cabozantinib plus nivolumab and ipilimumab with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma. [Google Scholar]
- 16.Socinski M.A., Rodriguez Abreu D., Lee D.H., et al. LBA2 SKYSCRAPER-06: efficacy and safety of tiragolumab plus atezolizumab plus chemotherapy (tira + atezo + chemo) vs pembrolizumab plus chemotherapy (pembro + chemo) in patients (pts) with advanced non-squamous non-small cell lung cancer (NSq NSCLC) IOTECH. 2024;24 [Google Scholar]
- 17.Braun D.A., Hou Y., Bakouny Z., et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909–918. doi: 10.1038/s41591-020-0839-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Braun D.A., Street K., Burke K.P., et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell. 2021;39(5):632–648.e638. doi: 10.1016/j.ccell.2021.02.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chen Y.W., Rini B.I., Beckermann K.E. Emerging targets in clear cell renal cell carcinoma. Cancers (Basel) 2022;14(19):4843. doi: 10.3390/cancers14194843. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Choi S.H., Chen Y.W., Panian J., Yuen K., McKay R.R. Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma. Oncologist. 2025;30(3) doi: 10.1093/oncolo/oyae276. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Qualified researchers may request access to individual patient-level data through the clinical study data request platform: https://vivli.org/. Further details on Roche’s criteria for eligible studies are available here: https://vivli.org/members/ourmembers/. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.