Durvalumab Plus Tremelimumab and Trastuzumab Yields Clinical Activity in Trastuzumab-Resistant HER2+ Breast Cancer

Breast cancer- stock.adobe.com

Treatment with the combination of durvalumab (Imfinzi), tremelimumab (Imjudo), and trastuzumab (Herceptin) produced clinical activity in patients with advanced HER2-positive breast cancer that was resistant to trastuzumab, according to data from the phase 2 BCT1703 DIAmOND trial (ACTRN12617001325392).

Findings presented at the 2025 ESMO Breast Cancer Congress showed that patients with HER2-positive, estrogen receptor (ER)–positive breast cancer enrolled in cohort 1 (n = 22) achieved an overall response rate (ORR) of 27% (95% CI, 12%-50%) and a 12-month progression-free survival (PFS) rate of 16% (95% CI, 7%-39%). Patients with HER2-positive, ER-negative disease treated in cohort 2 (n = 23) experienced an ORR of 8.7% (95% CI, 2%-30%) and a 12-month PFS rate of 8% (95% CI, 2%-30%).

Notably, the trial was amended to include a third cohort, where patients received a single priming dose of tremelimumab prior to treatment with the combination. In this group (n = 18), the ORR and 12-month PFS rates were 11% (95% CI, 2%-36%) and 27% (95% CI, 12%-59%), respectively.

“[These are] the first data for efficacy of dual CTLA-4 and PD-L1 inhibition in trastuzumab-resistant advanced HER2-postive breast cancer,” lead study author Sherene Loi, MBBS (Hons), PhD, FRACP, FAHMS, GAICD, said in a presentation of the data. “[These findings] provide proof of concept that further investigation of dual checkpoint blockade plus HER2-targeted therapies is warranted.”

Loi is a consultant medical oncologist in the Breast Unit, head of the Translational Breast Cancer Genomics and Therapeutics Lab (Loi Lab), and the breast stream lead of the Parkville Precinct Cancer Clinical Trials Unit at Peter MacCallum Cancer Centre in Victoria, Australia.

BCT1703 DIAmOND Background

Loi explained that although immunotherapy-based regimens such as trastuzumab plus pembrolizumab (Keytruda) have demonstrated activity in trastuzumab-resistant, advanced HER2-positive breast cancer if patients have PD-L1–positive disease or a high level of tumor-infiltrating lymphocytes (TILs). However, she noted that dual checkpoint with both anti–PD-(L)1 and anti–CTLA-4 agents may be more effective than PD-(L)1 inhibition alone, particularly for patients with PD-L1–negative tumors.

The study enrolled patients with advanced, incurable HER2-positive breast cancer, irrespective of PD-L1 expression. In the original trial design, patients were assigned to the first 2 cohorts based on ER status. In the third cohort added with the protocol amendment, patients were enrolled irrespective of ER or PD-L1 status.

In the first 2 cohorts, patients received tremelimumab at 75 mg once every 4 weeks, durvalumab at 1500 mg once every 4 weeks, and trastuzumab at 2 mg/kg every week for weeks 1 to 16. Patients then received durvalumab at 1120 mg once every 3 weeks plus trastuzumab at 6 mg/kg once every 3 weeks for weeks 17 to 52. Notably, patients with ER-positive disease also received estrogen suppression.

In the amended cohort, patients were given a single priming dose of tremelimumab before receiving tremelimumab at 300 mg, durvalumab at 1120 mg, and a trastuzumab loading dose (if needed) on day 1 of cycle 1. Patients in this cohort then received durvalumab at 1120 mg once every 3 weeks and trastuzumab at 6 mg/kg once every 3 weeks for a total of 12 months.

In the original cohorts, 12-month PFS rate served as the trial’s primary end point. ORR per RECIST 1.1 criteria was the primary end point for the amended cohort.

The median age at baseline was 56 years (range, 48-63) for cohort 1 (n = 25), 55 years (range, 44-60) for cohort 2, and 57 years (range, 48-59) for cohort 3 (n = 18). The median time from metastatic diagnosis was 34 months (range, 22-70), 45 months (range, 19-63), and 28 months (range, 14-43) in the respective cohorts.

The median number of lines of prior therapy was 4 (range, 2-5) in cohort 1, 3 (range, 2-5) in cohort 2, and 3 (range, 2-4) in cohort 3. All patients received prior trastuzumab, and the majority of patients in all arms received prior treatment with pertuzumab (Perjeta; cohort 1, 92%; cohort 2, 100%; cohort 3, 93%) and ado-trastuzumab emtansine (Kadcyla; 68%; 72%; 67%). Other prior treatments included fam-trastuzumab deruxtecan-nxki (Enhertu; 0%; 4%; 17%) and lapatinib (Tykerb; 20%; 12%; 6%). Most patients had PD-L1–positive disease (59%; 79%; 81%), and a smaller proportion of patients had a TIL level of at least 5% (39%; 50%; 31%).

Additional Efficacy and Safety Data

In cohort 1, patients achieved a mean duration of response (DOR) of 23.6 months (95% CI, 7.5-74.2), a clinical benefit rate (CBR) of 40% (95% CI, 22%-61%), and a 12-month PFS per iRECIST criteria of 64% (95% CI, 48%-86%). In cohort 2, the mean DOR was 11 months (95% CI, 6.7-17.9), a CBR of 28% (95% CI, 13%-50%), and a 12-month PFS rate per iRECIST criteria of 32% (95% CI, 18%-57%). In cohort 3, the mean DOR was 30 months (95% CI, 2.7-339), a CBR of 33% (95% CI, 14%-59%), and a 12-month PFS rate per iRECIST criteria of 65% (95% CI, 46%-92%).

Findings from an exploratory analysis showed that the ORR in PD-L1–positive patients was 36% (95% CI, 12%-68%) in cohort 1 (n = 11), 6% (95% CI, 0%-29%) in cohort 2 (n = 18), and 15% (95% CI, 3%-46%) in cohort 3 (n = 13). The respective 12-month PFS rates in these subgroups were 15% (95% CI, 4%-55%), not evaluable (NE), and 21% (95% CI, 7%-64%).

The ORRs in patients with a TIL level of at least 5% were 63% (95% CI, 26%-90%) in cohort 1 (n = 8), 9% (95% CI, 0.5%-43%) in cohort 2 (n = 11), and 0% (95% CI, 0%-54%) in cohort 3 (n = 5). The 12-month PFS rates for these subgroups were 22% (95% CI, 7%-75%), 8% (95% CI, 1%-54%), and NE, respectively.

Safety data from the first two cohorts (n = 50) showed that any-grade adverse effects (AEs) occurred in all patients, and 66% had grade 3/4 AEs. Twenty percent of patients discontinued treatment with tremelimumab and durvalumab due to AES. Six percent of patients complete 12 months of durvalumab, and 10% continued treatment with trastuzumab after ending treatment with the other two agents.

In the priming cohort, all patients had any-grade AEs, and 53% had grade 3/4 AEs. AEs led to discontinuation of durvalumab and tremelimumab in 11% of patients. Eleven percent of patients complete 12 months of treatment with durvalumab, and no patients continued with trastuzumab after ending treatment with durvalumab and tremelimumab.

Disclosures: Dr Loi reported receiving research funding to her institution from Novartis, Merck, Roche-Genentech, Seattle Genetics, Pfizer, BMS, Eli Lilly, Nektar, and Puma Biotechnology; and serving as a consultant or on an advisory board for Novartis, Roche-Genentech, Seattle Genetics, AstraZeneca, Pfizer, BMS, Merck, Mersana, Daiichi-Sankyo, Bicycle Therapeutics, Silverback, Amaroq, and Eli Lilly.

Reference

Loi S, Zdenkowski N, Gebski V, et al. Primary efficacy results of tremelimumab and durvalumab in combination with trastuzumab in trastuzumab resistant advanced HER2-positive breast cancer: BCT1703 DIAmOND. Presented at: 2025 ESMO Breast Cancer Congress; May 14-17, 2025; Munich, Germany. Abstract 301MO.