The introduction of immune checkpoint inhibitors (ICIs) combined with vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) has substantially changed the first-line treatment of advanced clear-cell renal cell carcinoma (ccRCC). However, disease progression remains common, with median progression-free survival (PFS) generally remaining below two years despite these advances.
Additional immune checkpoint targets, including lymphocyte-activation gene 3 (LAG3) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT), have been investigated as potential approaches to improve treatment outcomes. Both pathways contribute to T-cell exhaustion and may play a role in resistance to PD-1 blockade.
Tobemstomig, a bispecific antibody targeting PD-1 and LAG3, was evaluated in combination with axitinib, with or without tiragolumab, an anti-TIGIT antibody, to determine whether additional immune checkpoint inhibition could improve outcomes compared with pembrolizumab plus axitinib.
On October 9, 2026, ESMO Open published a study titled “A randomised, open-label, phase II study of tobemstomig combinations in patients with previously untreated advanced clear-cell renal cell carcinoma.”
The study was authored by B.I. Rini, T. Powles, P. Tomczak, S.J. Shin, J. Guo, J. Molina-Cerrillo, X. Ren, J.L. Lee, P.J. Wysocki, J. Puente, A. Basu, N. Mar, S. Bernhard, O. Khan, J. Ha, L. Colley, H. Prizant, and L. Albiges.
This randomized phase II trial (BO43936; NCT05805501) evaluated the efficacy and safety of tobemstomig-based combinations compared with pembrolizumab plus axitinib in previously untreated advanced ccRCC.
Study Design and Patient Population
The randomized, open-label, phase II study enrolled adults with histologically confirmed, previously untreated, locally advanced unresectable or metastatic RCC containing a clear-cell component. Eligible patients had measurable disease according to RECIST v1.1 and intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification.
Patients were randomized 1:1:1 into three treatment arms:
- Arm A: Tobemstomig 600 mg intravenously every three weeks plus axitinib 5 mg orally twice daily.
- Arm B: Tobemstomig 600 mg plus tiragolumab 600 mg intravenously every three weeks, combined with axitinib 5 mg orally twice daily.
- Control arm: Pembrolizumab 200 mg intravenously every three weeks plus axitinib 5 mg orally twice daily.
Treatment was administered in 21-day cycles until disease progression, unacceptable toxicity, or a maximum of 24 months. The original primary endpoints were investigator-assessed PFS according to RECIST v1.1 and the incidence and severity of adverse events (AEs). Efficacy assessments included objective response rate (ORR), PFS, duration of response (DOR), and overall survival (OS).
Early Termination Following Futility Analysis
A protocol-specified interim futility analysis was conducted among the first 105 randomized patients with at least three months of follow-up. At the April 22, 2024, clinical cutoff, the tobemstomig plus axitinib arm crossed the predefined futility boundary, with an observed ORR difference of 11.44 percentage points favoring pembrolizumab plus axitinib. Neither experimental regimen demonstrated a meaningful efficacy advantage, while clinically relevant adverse events were numerically more frequent with the experimental combinations.
Consequently, enrollment was stopped across all three arms after 199 patients had been randomized, and the sponsor subsequently discontinued the development of tobemstomig. Following these decisions, the primary endpoint was amended to the incidence and severity of AEs only. Efficacy outcomes were therefore assessed descriptively rather than through the originally planned formal analysis.
Efficacy Outcomes
Between April 21, 2023, and July 11, 2024, 199 patients were randomized. The final descriptive analysis had a data cutoff of February 1, 2025, with a median follow-up of approximately 11 months across treatment arms. The efficacy-assessable population included 197 patients: 66 in the tobemstomig plus axitinib arm, 65 in the triplet arm, and 66 in the pembrolizumab plus axitinib control arm. Most patients had intermediate IMDC risk (81.7%), and 88.3% had metastatic disease at enrollment.
Objective Response Rate
Confirmed ORRs were similar across the three treatment groups:
- Tobemstomig plus axitinib: 51.5% (34/66).
- Tobemstomig plus tiragolumab plus axitinib: 53.8% (35/65).
- Pembrolizumab plus axitinib: 51.5% (34/66).
Two complete responses (3.1%) occurred in the triplet arm, whereas no complete responses were observed in either the tobemstomig plus axitinib or control arm. The median DOR was 12.4 months (95% CI 8.5–not estimable) with tobemstomig plus axitinib and 14.7 months (95% CI 9.45–not estimable) with the triplet combination. Median DOR was not estimable (95% CI 9.6–not estimable) in the control arm.
Progression-Free and Overall Survival
Median PFS was similar across the three treatment arms, with no meaningful improvement observed for either experimental regimen. Median PFS was 12.4 months (95% CI 8.4–16.3) with tobemstomig plus axitinib, 12.5 months (95% CI 7.3–17.2) with the triplet combination, and 12.5 months (95% CI 9.5–not estimable) with pembrolizumab plus axitinib. Median OS was not reached in any treatment arm. The descriptive OS hazard ratios compared with pembrolizumab plus axitinib were:
- Tobemstomig plus axitinib: HR 1.8 (95% CI 0.6–4.9).
- Tobemstomig plus tiragolumab plus axitinib: HR 2.1 (95% CI 0.8–5.6).
At six months, landmark event-free survival rates were 93.8% (95% CI 87.9–99.7) with tobemstomig plus axitinib, 90.6% (95% CI 83.5–97.8) with the triplet regimen, and 96.9% (95% CI 92.6–100.0) in the control arm. Overall, neither tobemstomig-containing regimen demonstrated an efficacy advantage over pembrolizumab plus axitinib in the descriptive analysis.
Safety and Treatment Discontinuation
The safety-assessable population included 198 patients who received at least one dose of study treatment. Although nearly all patients experienced at least one AE, higher rates of clinically relevant toxicity were observed with the tobemstomig-containing regimens, particularly the triplet combination.
Grade 3–4 AEs occurred in 62.1% of patients receiving tobemstomig plus axitinib, 67.7% receiving tobemstomig plus tiragolumab plus axitinib, and 56.7% receiving pembrolizumab plus axitinib. Serious AEs occurred in 42.4%, 61.5%, and 31.3% of patients, respectively.
Treatment-related serious AEs were reported in 22.7% of patients in the tobemstomig plus axitinib arm, 29.2% in the triplet arm, and 13.4% in the control arm. Treatment-related AEs leading to discontinuation of any study treatment occurred in 12.1%, 29.2%, and 11.9% of patients, respectively.
Immune-mediated AEs were also numerically more frequent with the experimental combinations, occurring in 75.8% with tobemstomig plus axitinib and 80.0% with the triplet regimen, compared with 70.1% in the control arm. Seven grade 5 AEs were reported across the study population, including three in each experimental arm and one in the control arm. None were considered treatment-related. These findings indicate a higher toxicity burden with tobemstomig-based treatment, particularly when tiragolumab was added, without an accompanying meaningful improvement in efficacy.
Clinical Implications and Future Directions
The findings highlight the challenges of intensifying established PD-1/VEGF-TKI combinations through additional immune checkpoint inhibition in advanced ccRCC.
Despite the addition of LAG3 inhibition through tobemstomig, with or without TIGIT inhibition through tiragolumab, the experimental regimens produced response rates and median PFS comparable to those observed with pembrolizumab plus axitinib. The triplet combination was associated with higher rates of serious adverse events and treatment discontinuation. These observations are consistent with challenges reported in other studies evaluating intensified immunotherapy combinations in advanced RCC.
In the phase Ib STELLAR-002 study, the combination of zanzalintinib, nivolumab, and relatlimab demonstrated a lower ORR than zanzalintinib plus nivolumab (33% vs 63%), with higher toxicity-related discontinuation.
Similarly, the phase III COSMIC-313 trial demonstrated improved PFS with cabozantinib plus nivolumab and ipilimumab compared with nivolumab plus ipilimumab, but did not demonstrate an OS benefit and was associated with increased toxicity. However, the present study’s early termination, limited follow-up, and descriptive efficacy analyses restrict definitive conclusions about survival differences between treatment arms.
The findings support a greater focus on biomarker-guided treatment development and the identification of resistance mechanisms that could inform more effective therapeutic combinations.
Conclusion
In the final descriptive analysis of this randomized phase II study, tobemstomig plus axitinib, with or without tiragolumab, did not demonstrate meaningful efficacy improvement over pembrolizumab plus axitinib in patients with previously untreated advanced clear-cell RCC and intermediate- or poor-risk disease.
Both experimental combinations were associated with numerically higher rates of clinically relevant adverse events, particularly the triplet regimen, which also resulted in more treatment discontinuations. Although efficacy comparisons were limited by early study termination and descriptive analysis, the results did not support further development of the investigated tobemstomig-based regimens.
The findings emphasize that adding further immune checkpoint inhibition to established treatment backbones does not necessarily translate into improved outcomes and reinforce the importance of biologically informed strategies in advanced RCC.
