A signal-seeking phase 2 study of tremelimumab in advanced cancers with high tumour mutational burden

Subotheni Thavaneswaran^{1

2

3

4}, Frank Lin^{5

6

7

8}, David Espinoza⁵, John Grady⁹, Peey-Sei Kok⁵, Sarah Chinchen⁵, Nick Pavlakis¹⁰, Vladimir Andelkovic¹¹, Michail Charakidis¹², Paul Craft¹³, Michael Brown¹⁴, Jayesh Desai¹⁵, Peter Lau¹⁶, Maya Kansara⁹, John Simes⁵, David Thomas¹⁷

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
² The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
³ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
⁴ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
⁵ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
⁶ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia.
⁷ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
⁸ Kinghorn Centre for Clinical Genomics, Darlinghurst, Sydney, NSW, Australia.
⁹ Centre for Molecular Oncology, University of NSW, Sydney, NSW, Australia.
¹⁰ Royal North Shore Hospital, Sydney, NSW, Australia.
¹¹ Princess Alexandra Hospital, Brisbane, QLD, Australia.
¹² Royal Darwin Hospital, Darwin, NT, Australia.
¹³ The Canberra Hospital, Canberra, ACT, Australia.
¹⁴ Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁵ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁶ Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
¹⁷ Centre for Molecular Oncology, University of NSW, Sydney, NSW, Australia. dmthomas@unsw.edu.au.

PMID: 41272153
PMCID: PMC12639129
DOI: 10.1038/s41698-025-01156-5

A signal-seeking phase 2 study of tremelimumab in advanced cancers with high tumour mutational burden

Subotheni Thavaneswaran et al. NPJ Precis Oncol. 2025.

. 2025 Nov 21;9(1):372.

doi: 10.1038/s41698-025-01156-5.

Authors

Affiliations

¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
² The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
³ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
⁴ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia. s.thavaneswaran@garvan.org.au.
⁵ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
⁶ School of Clinical Medicine, Faculty of Medicine and Health, University of NSW, Sydney, NSW, Australia.
⁷ Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
⁸ Kinghorn Centre for Clinical Genomics, Darlinghurst, Sydney, NSW, Australia.
⁹ Centre for Molecular Oncology, University of NSW, Sydney, NSW, Australia.
¹⁰ Royal North Shore Hospital, Sydney, NSW, Australia.
¹¹ Princess Alexandra Hospital, Brisbane, QLD, Australia.
¹² Royal Darwin Hospital, Darwin, NT, Australia.
¹³ The Canberra Hospital, Canberra, ACT, Australia.
¹⁴ Royal Adelaide Hospital, Adelaide, SA, Australia.
¹⁵ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁶ Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
¹⁷ Centre for Molecular Oncology, University of NSW, Sydney, NSW, Australia. dmthomas@unsw.edu.au.

PMID: 41272153
PMCID: PMC12639129
DOI: 10.1038/s41698-025-01156-5

Abstract

This single-arm phase II trial (ACTRN12620000918921) evaluated the clinical activity of tremelimumab (10 mg/kg intravenously every 4 weeks for 6 cycles) in advanced cancers with a high tumour mutational burden (TMB), defined as TMB > 10 mutations/megabase (mut/Mb) on standard platforms (TSO500 panel, F1CDx), or >20 mut/Mb on the TST170 panel. The primary objective was 6-month progression-free survival rate (PFS6) by iRECIST. Secondary objectives included objective response; the ratio of time to progression (TTP) on study to TTP on prior therapy (TTP2:TTP1); overall survival (OS); and safety. After minimum followup of 12 months, the PFS6 was 6% (95% CI 0-24%), with a median PFS and OS of 1.9 (95% CI 1.4-2.8) and 6.3 (2.8-10.3) months, respectively. Amongst 19 evaluable patients, two partial responses occurred in an endometrial adenocarcinoma and an undifferentiated pleomorphic sarcoma, maintained for 3.8 and 15.9 months respectively, both with TMB >20 mut/Mb. Adverse events were experienced by 19 patients (90%), with 15 patients (72%) experiencing grade 3-5 adverse events. Seven tremelimumab-related serious adverse events (grade 2-3) occurred in 5 patients. While the primary PFS6 endpoint was not met, there were two durable objective responses in rare cancers and a favourable change in disease trajectory for an additional five patients based on TTP ratio $\geq$ 1.3.

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Conflict of interest statement

Competing interests: D.T. as CEO of Omico, a non-profit organisation has received grants, consultancies or research support from Roche, Astra Zeneca, Pfizer, Eisai, Illumina, Beigene, Elevation Oncology, RedX Pharmaceuticals, Sun-Pharma, Bayer, Abbvie, George Clinical, Janssen, Merck, Kinnate, Microba, BioTessellate, Australian Unity, Foundation Medicine, Guardant, Intervenn, Amgen, Seattle Genetics and Eli Lilly. D.T. also serves on the advisory boards or committees for Canteen, UNSW SPHERE and NSW government in respect to genomics and translational medicine. The authors otherwise declare no competing financial or non-financial interests.

Figures

Fig. 1. Swimmer plot capturing best response, time to progression (TTP) on study (TTP2), time to progression on prior therapy (TTP1), TTP ratio, and status at last follow-up on an individual patient basis.
TR0195 does not display a TTP2 bar as the patient did not experience progression on study. TTP ratio has been calculated using the censor date for TTP2. EOT end of treatment, PR partial response, SD stable disease, PD progressive disease.

**Fig. 2. Kaplan-Meier curves of clinical outcomes.**
A Progression free survival (PFS), including 6 month PFS. B Overall survival (OS).

**Fig. 3. Kaplan–Meier curve of overall survival (OS) by tumour mutational burden (TMB).**
Intermediate TMB < 20 mutations/ megabase (mut/Mb) versus high TMB $\geq$ 20 mut/Mb.

See this image and copyright information in PMC

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A signal-seeking phase 2 study of tremelimumab in advanced cancers with high tumour mutational burden

Affiliations

A signal-seeking phase 2 study of tremelimumab in advanced cancers with high tumour mutational burden

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

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