Dato-DXd Plus Durvalumab Elicits Durable Responses in Metastatic TNBC Regardless of PD-L1 Status

Treatment with first-line datopotamab deruxtecan (Dato-DXd; DS-1062a) plus durvalumab (Imfinzi) elicited robust and durable responses in patients with unresectable, locally advanced/metastatic triple-negative breast cancer (TNBC), regardless of PD-L1 expression, according to updated data from the phase 1b/2 BEGONIA trial (NCT03742102) presented at the 2023 ESMO Congress.

Findings revealed that at a median follow-up of 11.7 months patients treated with the combination (n = 62) achieved a confirmed objective response rate (ORR) of 79% (95%CI, 66.8%-88.3%) which was comprised of 6 complete responses and 43 partial responses. The median duration of response (DOR) was 15.5 months (95% CI, 9.92–not calculable [NC]) and the median progression-free survival (PFS) was 13.8 months (95% CI, 11.0-NC).

Additionally, cohort 8 of the BEGONIA trial evaluating Dato-DXd plus durvalumab in patients with PD-L1–high disease is currently open for enrollment.

Regarding safety, the combination had a tolerable and manageable safety profile, and no new signals were observed. Grade 3 or 4 treatment-related adverse effects (TRAEs) occurred in 57% of patients treated with the combination and encompassed increased amylase (18%), stomatitis (11%), constipation (2%), fatigue (2%), vomiting (2%), and decreased appetite (2%). The most common any grade AEs included nausea (65%), stomatitis (65%), alopecia (50%), constipation (47%), and fatigue (45%); 11 patients required dose reductions due to stomatitis, which was the most common AE leading to dose reductions.

“The significance of the BEGONIA trial is that this is probably the combination with the highest response rates ever reported in a group of patients with first-line metastatic TNBC with predominantly PD-L1–negative tumors,” presenting author Peter Schmid, FRCP, MD, PhD, explained. Schmid is a professor of cancer medicine, lead at the Centre of Experimental Cancer Medicine, and the director of the Barts Breast Cancer Centre at Barts Cancer Institute in London.

In an interview with OncLive®, Schmid discussed the evaluation of combination of the antibody-drug conjugate (ADC) Dato-DXd with durvalumab, detailed safety and efficacy findings derived from the combination in the BEGONIA trial, and highlighted ongoing efforts with this combination.

OncLive: What were the key objectives and enrollment criteria of the BEGONIA trial?

Schmid: This trial explored different immunotherapy combinations in first-line setting for metastatic TNBC. The trial has several arms [evaluating] several combinations of ADCs or other agents in combination with the immune checkpoint inhibitor durvalumab. At the 2023 ESMO Congress we presented updated data on the combination of the TROP2-targeted ADC Dato-DXd in combination with durvalumab.

BEGONIA was focused on patients with untreated, and therefore first-line, metastatic TNBC. Patients were enrolled regardless of PD-L1 status and the majority of patients in this trial ended up being PD-L1 negative, which is interesting when we look at the trial data.

In the arm we presented at ESMO, which was the combination of Dato-DXd with durvalumab, we saw an ORR of 79%. To put this into context, nearly 90% of the patients were PD-L1 negative in this group.

If you look at the phase 3 trials of chemotherapy and immunotherapy in first-line metastatic TNBC, we [have seen] an ORR of approximately 40% to 45% in the group of patients with PD-L1–negative tumors, so having a response of nearly 80% with a combination of an ADC and immune checkpoint inhibitor in predominantly PD-L1–negative patients is a very powerful signal and warrants further investigation.

What were notable safety findings with the combination?

The safety profile of the combination of Dato-DXd and durvalumab is keeping with what we know for each of those drugs alone, and we didn’t see any significant additional toxicity when we combine both drugs. Both drugs can be combined safely and are well tolerated.

What next steps are planned for this trial and what are the significance of BEGONIA’s findings?

Dato-DXd is currently moving into earlier lines of therapy. There are ongoing first-line studies in metastatic TNBC in patients with PD-L1–negative disease. There’s a trial of Dato-DXd alone compared with standard chemotherapy in PD-L1–positive patients, and there will be a study starting very soon of Dato-DXd plus immunotherapy vs chemotherapy plus immunotherapy.

What will be interesting to see is whether we can expand on some of the experiences in patients with PD-L1–negative tumors and see whether we can explore if there is a benefit of immunotherapy in PD-L1–negative tumors when combined with the ADC Dato-DXd.

The early data of the BEGONIA study also showed that those responses are durable with an impressive median DOR and PFS at this point in time. Of course, the next step should be to see how this combination performs in a randomized disease setting, and those trials are in preparation or ongoing.

Reference

Schmid P, PJ Wysocki, CX Ma, YH Park, et al. Datopotamab deruxtecan (dato-dxd) + durvalumab (d) as first-line (1l) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC). Ann Oncol. 2023;34(suppl 2):S337. doi:10.1016/j.annonc.2023.09.556