Frontline Datopotamab Deruxtecan/Durvalumab Combo Elicits Encouraging Responses in TNBC

Peter Schmid, FRCP, MD, PhD

The combination of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (DS-1062) and durvalumab (Imfinzi) showcased early activity with acceptable safety when used as first-line treatment in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to data from the phase 1b/2 BEGONIA trial (NCT03742102).¹

The findings, which were presented during the 2022 ESMO Breast Congress, showed that at a median follow-up of 3.9 months (range, 2-6), the doublet elicited a confirmed objective response rate (ORR) of 74% (95% CI, 54%-89%) among 27 patients who were evaluable for response; this included a complete response rate of 7% and a partial response rate of 67%. Notably, responses were observed irrespective of PD-L1 expression.

“Preliminary results of BEGONIA show that datopotamab deruxtecan plus durvalumab demonstrated a robust response rate in first-line locally advanced or metastatic TNBC in a biomarker-unselected population,” lead study author Peter Schmid, FRCP, MD, PhD, of Barts Cancer Institute, Queen Mary University of London, said in a presentation on the data. “The combination…had a manageable safety profile consistent with the known profile of the individual agents, with no new safety signals.”

Although the combination of immune checkpoint inhibitors and frontline chemotherapy has been found to improve outcomes in patients with advanced or metastatic TNBC, this is only true for those who have PD-L1–positive disease. In heavily pretreated patients with recurrent disease, datopotamab deruxtecan has showcased antitumor activity.

The 2-part, open-label platform trial enrolled patients with unresectable advanced or metastatic TNBC who were at least 18 years of age, had an ECOG performance status of 0 or 1, acceptable organ function, and measurable disease per RECIST v1.1 criteria. At least 12 months must have passed since previous taxane therapy was received.

Moreover, patients could not have previously received treatment for stage IV disease, nor could they have previously received a checkpoint inhibitor or a topoisomerase I inhibitor–based ADC.

In part 1 of the trial, the first 20 patients received paclitaxel plus durvalumab (n = 20) while the other patients were randomized to 1 of 4 open cohorts: datopotamab deruxtecan plus durvalumab given every 3 weeks until disease progression (n = 30), capivasertib (AZD5363) plus paclitaxel and durvalumab (n = 30), oleclumab (MEDI9447) plus paclitaxel/durvalumab (n = 30), or fam-trastuzumab deruxtecan-nxki (Enhertu) plus durvalumab (n = 30).

The primary end points for each combination cohort were safety and tolerability, and key secondary end points included ORR, progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

Prior data from the trial showed that the paclitaxel/durvalumab combination elicited an ORR of 58.3%, and responses were noted to be durable.² Moreover, the median PFS in this cohort was 7.3 months (95% CI, 5.4-13.8), which proved to be consistent with what has been observed with the frontline combination of immune checkpoint inhibitors and single-agent chemotherapy in patients with metastatic TNBC.

Additionally, an ORR of 66.7% was observed in the cohort of patients who received trastuzumab deruxtecan plus durvalumab. Notably, the majority of the responders, or 87.5%, continued to respond at the time of data cutoff.³

Data from the first part of the trial were shared during the meeting. At a data cutoff of November 15, 2021, a total of 29 patients received treatment with datopotamab deruxtecan plus durvalumab. Of these patients, 17% discontinued treatment; reasons for discontinuation included progressive disease (7%), toxicity (7%), or another unspecified reason (7%). Eighty-three percent of patients were still receiving treatment at the time of data cutoff.

The median age of those in this cohort was 51 years (range, 33-72). Thirty-one percent of patients did not receive prior treatment. Those who did previously receive treatment for early-stage disease had received radiotherapy (59%), cytotoxic chemotherapy (66%), taxane therapy (48%), an anthracycline (55%), a platinum compound (17%), hormonal therapy (21%), or targeted therapy (7%).

More than half of patients had visceral metastases (69%) and lymph node metastases (76%). Regarding PD-L1 expression, 72.4% had a low expression of less than 5%, 17.2% had a high expression of 5% or more, and 10.3% had missing data.

Additional data showed that the median time to response with the combination regimen was 1.4 months (95% CI, 1.35-1.58). All responders were still responding at the time of data cutoff. The median DOR was not yet reached with the combination.

Regarding safety, all participants experienced all-grade adverse effects (AEs); 28% of patients experienced effects that were grade 3 or 4 in severity. Moreover, any-grade AEs related to treatment were experienced by 93%; grade 3 or 4 TRAEs occurred in 28% of patients. Serious toxicities were reported in 17% of patients.

The toxicities reported in 15% or more of patients included stomatitis (grade 1, 28%; grade 2, 28%; grade 3, 14%), alopecia (grade 1, 45%; grade 2, 21%), nausea (grade 1, 45%; grade 2, 21%), constipation (grade 1, 28%; grade 2, 10%), fatigue (grade 1, 31%; grade 2, 6.9%), rash (grade 1, 28%; grade 2, 3%), and vomiting (grade 1, 10%; grade 2, 6.9%).

Notably, low rates of diarrhea were reported with the combination; 14% of patients experienced this toxicity and all cases were grade 1. No cases of interstitial lung disease/pneumonitis or neutropenic events were observed.

Fourteen percent of patients required dose reductions of datopotamab deruxtecan; 13.7% of patients needed a dose reduction because of stomatitis. Updated trial management guides and prophylaxis for this toxicity are in the process of being implemented.

Moreover, 3% of patients needed a dose delay of datopotamab deruxtecan, and 14% needed a dose delay of durvalumab. Toxicities resulted in death in 3% of patients, and 7% of patients experienced AEs that resulted in discontinuation of all treatments.

A Simon 2-stage futility analysis was utilized for the part 2 expansion portion of the trial. In this part, investigators will continue to evaluate datopotamab deruxtecan plus durvalumab every 3 weeks until disease progression or trastuzumab deruxtecan plus durvalumab. An additional 27 patients will be enrolled to each arm. The primary end point is ORR, and secondary end points included PFS, DOR, PFS6, and OS.

Enrollment to part 2 is currently ongoing.

“Follow-up continues in order to determine DOR and PFS/OS,” Schmid concluded.

References

1. Schmid P, Jung KH, Wysocki PJ, et al. Datopotamab deruxtecan + durvalumab as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): initial results from BEGONIA, a phase Ib/II study. Ann Oncol. 2022;33(suppl 3):S199. doi:10.1016/j.annonc.2022.03.185
2. Schmid P, Nowecki Z, Im S-A, et al. BEGONIA: phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC): results from arm 1 D + paclitaxel (P), arm 2 D+P + capivasertib (C), and arm 5 D+P + oleclumab (O). Presented at: 2021 San Antonio Breast Cancer Symposium; December 9, 2021; San Antonio, TX. Abstract PD10-03. https://bit.ly/3t6RwvB
3. Schmid P, Im S-A, Armstrong AC, et al. BEGONIA: phase 1b/2 of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd). J Clin Oncol. 2021;39(suppl 15):1023. doi:10.1200/JCO.2021.39.15_suppl.1023