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 

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.

, 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.

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

: 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.

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). 

. 2023;34(suppl 2):S337. doi:10.1016/j.annonc.2023.09.556

Articles

Peter Schmid, FRCP, MD, PhD, discusses the evaluation of combination of the datopotamab deruxtecan and durvalumab in patients with first-line triple-negative breast cancer, details safety and efficacy findings derived from the combination in the BEGONIA trial, and highlights ongoing efforts with this combination.

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

Findings From a Pooled Analysis of Trastuzumab Deruxtecan in HER2+ Breast Cancer

Dr Cortés on Findings From a Pooled Analysis of Trastuzumab Deruxtecan in HER2+ Breast Cancer

Javier Cortés, MD, PhD, head, International Breast Cancer Center, clinical investigator, Breast Cancer Research Program, Vall d’Hebron Institute of Oncology, discusses primary outcomes and safety findings from a pooled analysis of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with HER2-positive metastatic breast cancer who have brain metastases. These data were derived from the phase 3 DESTINY-Breast01 (NCT03248492), DESTINY-Breast02 (NCT03523585), and DESTINY-Breast03 (NCT03529110) trials.

Findings from the pooled analysis were presented at the 2023 ESMO Congress and showed that T-DXd exhibited strong intracranial responses in patients with treated/stable and active brain metastases vs the comparator agents. In patients with stable brain metastases, T-DXd generated an intracranial objective response rate (IC-ORR) of 45.2%, along with a median intracranial duration of response (IC-DOR) of 12.3 months (range, 9.1-17.9), compared with 27.6% and 11.0 months (range, 5.6-16.0), respectively, in the comparator groups.

In patients with untreated or active brain metastases, T-DXd elicited an IC-ORR of 45.5% and a median IC-DOR of 17.5 months (range, 13.6-31.6) vs 12.0% and an undefined duration, respectively, in the comparator groups. Additionally, T-DXd yielded a numerically longer median central nervous system progression-free survival (CNS-PFS) in patients with both stable and active brain metastases and maintained an acceptable and manageable safety profile consistent with that seen in the overall patient population.

A total of 44 patients with untreated or active brain metastases received T-DXd, and 25 patients received the standard of care (SOC), Cortés begins. Conversely, 104 patients with stable or treated brain metastases received T-DXd, and 58 patients were treated with physician's choice of SOC, he explains. The IC-ORR and IC-DOR outcomes in these cohorts indicate T-DXd's superior activity vs SOC, Cortés emphasizes.

An exploratory CNS-PFS analysis conducted in the subgroup of patients with untreated active brain metastases demonstrated a median CNS-PFS of 4.0 months (95% CI, 2.7-5.7) with SOC vs18.5 months (95% CI, 13.6-23.3) with T-DXd, again emphasizing the activity of T-DXd in this patient group, Cortés continues. In terms of safety, adverse events (AEs) in patients with brain metastases were comparable with those observed in the overall population, with T-DXd–related serious treatment-emergent AEs reported in 13.0% of patients with brain metastases compared with 12.4% of patients in the overall population, respectively, he notes. Overall, T-DXd exhibited an acceptable and manageable safety profile in the overall population, with no significant differences in toxicity observed in patients with altered brain metastases, Cortés concludes.

Videos

Javier Cortés, MD, PhD, discusses primary outcomes and safety findings from a pooled analysis of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer who have brain metastases. 


Dr Cortés on Pooled Data for Trastuzumab Deruxtecan in HER2+ Breast Cancer With Brain Metastases

Dr Modi on Updated OS Data From the DESTINY-Breast04 Trial of T-DXd in HER2-Low Breast Cancer  

Shanu Modi, MD, breast oncologist, Memorial Sloan Kettering Cancer Center, discusses updated survival data from the phase 3 DESTINY-Breast04 trial (NCT03734029) evaluating fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with HER2-low metastatic breast cancer.

The DESTINY-Breast04 study enrolled patients with unresectable and/or metastatic HER2-low breast cancer who were previously treated with 1 to 2 prior lines of chemotherapy in the metastatic setting, Modi details. Patients with both hormone receptor–positive and –negative breast cancer were included, she notes. A total of 373 patients were randomly assigned 2:1 to receive either T-DXd or physician’schoice of therapy.

Previously reported data from the primary analysis of the trial led to the 

 in 2022 for patients with unresectable or metastatic HER2-low breast cancer. Patients with HER2-low breast cancer who had previously received at least 1 chemotherapy regimen in the metastatic setting experienced superior progression-free survival (PFS) and overall survival (OS) vs treatment with standard physician’schoice of chemotherapy.

Updated survival data from DESTINY-Breast04

, Modi states. The data confirmed that improvement in OS was clinically meaningful with T-DXd vs physician's choice in patients with hormone receptor–positive disease and the overall population, Modi reports.

At a median follow-up of 32.0 months (95% CI, 31.0-32.8), T-DXd (n = 373) resulted in a median OS of 22.9 months in the overall population vs 16.8 months with physician’s choice of chemotherapy (n = 184; HR, 0.69; 95% CI, 0.55-0.86). This translated to a 31% reduction in the risk of death for patients treated with T-DXd. In the hormone receptor–positive cohort, the median OS was 23.9 months (95% CI, 21.7-25.2) )with T-DXd vs 17.6 months (95% CI, 15.1-20.2) with the control. 

The median PFS was also consistent with results from the primary analysis, demonstrating a 63% reduction in the risk of disease progression or death with T-DXd vs physician’s choice of chemotherapy in the hormone receptor–positive cohort, and a 64% reduction with the antibody-drug conjugate in the overall population. The median PFS was 8.8 months (95% CI, 8.3-9.8) with T-DXd vs 4.2 months (95% CI, 3.0-4.5) with chemotherapy in the overall cohort (HR, 0.36; 95% CI, 0.29-0.45).

Exploratory analyses of the hormone receptor–negative cohort showed that T-DXd (n = 40) resulted in a median OS of 17.1 months (95% CI, 13.6-23.0) and median PFS of 6.3 months (95% CI, 4.2-8.5) vs 8.3 months (95% CI, 5.6-20.4) and 2.9 months (95% CI, 1.4-4.2), respectively, with treatment of physician’s choice (n = 18), Modi continues. Accompanying hazard ratios were 0.58 (95% CI, 0.31-1.08) for OS and 0.29 (95% CI, 0.15-0.57) for PFS, both in favor of T-DXd.

Regarding safety, the toxicity profile of T-DXd remained well tolerated, manageable, and generally consistent with what was reported in the primary analysis despite the prolonged duration of treatment.

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

Shanu Modi, MD, discusses updated survival data from the phase 3 DESTINY-Breast04 trial evaluating fam-trastuzumab deruxtecan-nxki in patients with HER2-low metastatic breast cancer.
 

Peter Schmid, FRCP, MD, PhD, professor, cancer medicine, centre lead, Centre of experimental Cancer Medicine, director, Barts Breast Cancer Centre, discusses key findings from the phase 1/2 BEGONIA trial (NCT03742102) in patients with unresectable, metastatic or locally advanced triple-negative breast cancer (TNBC), highlighting the clinical significance of these findings.

The BEGONIA trial is evaluating various combinations of the PD-L1 inhibitor durvalumab (Imfinzi) with other novel agents in the frontline setting in patients with advanced or metastatic TNBC. Findings from arm 7 of the trial, which evaluated datopotamab deruxtecan (Dato-DXd; DS-1062a) plus durvalumab in this patient population, were presented at the 2023 ESMO Congress.

Dato-DXd plus durvalumab elicited an overall response rate (ORR) of 79% (95% CI, 66.8%-88.3%), including 6 complete responses and 43 partial responses. Notably, investigators observed antitumor responses in patients regardless of PD-L1 expression level. In total, 87% of patients on arm 7 of BEGONIA had PD-L1–low or –negative disease, Schmid notes. Previously conducted phase 3 trials of chemotherapy plus immunotherapy in the first-line, metastatic TNBC setting have shown ORRs of approximately 40% to 45% in patients with PD-L1–negative tumors, Schmid explains. Therefore, the response rate seen with an antibody-drug conjugate plus an immune checkpoint inhibitor in this patient population is encouraging and warrants further evaluation, Schmid emphasizes. It is the highest ORR ever reported in a group of patients with first-line, metastatic TNBC with predominantly PD-L1–negative tumors, Schmid says.

Furthermore, early data from the BEGONIA trial demonstrate that the responses seen with Dato-DXd plus durvalumab are durable, with a median duration of response of 15.5 months (95% CI, 9.92–not calculable [NC]) and a median progression-free survival of 13.8 months (95% CI, 11.0-NC). In the future, this combination should be investigated in a randomized clinical trial setting, Schmid concludes. Arm 8 of the BEGONIA trial is currently enrolling and will evaluate Dato-DXd plus durvalumab in patients with PD-L1–high metastatic TNBC.

Dr Schmid reports honoraria from AstraZeneca, Daiichi, Gilead, Merck, Novartis, Pfizer, Roche, Sanofi, and Seagen; consulting or advisory roles with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Daiichi, Eisai, Genentech, Gilead, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sanofi, and Seagen; and institutional research funding from Astellas Pharma, AstraZeneca, Genentech, Gilead, Medication Inc, Merck, Novartis, OncoGenex, and Roche.

Peter Schmid, FRCP, MD, PhD, discusses key findings from the phase 1/2 BEGONIA trial in patients with unresectable, metastatic or locally advanced triple-negative breast cancer, highlighting the clinical significance of these findings.

Dr Schmid on Key Efficacy Findings With Dato-DXd in Metastatic TNBC

Datopotamab deruxtecan (Dato-DXd; DS-1062a) elicited a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs chemotherapy for patients with hormone receptor–positive, HER2-low or -negative metastatic breast cancer, according to data from the phase 3 TROPION-Breast01 trial (NCT05104866) presented the 

“Overall results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” Aditya Bardia, MD, MPH, the director of the Breast Cancer Research Program at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, in Boston, said during a presentation of the data.

Patients who received Dato-DXd (n = 365) achieved a median PFS of 6.9 months (95% CI, 5.7-7.4) compared with 4.9 months (95% CI, 4.2-5.5) for those treated with investigator’s choice of chemotherapy (ICC; n = 367), reducing the risk for disease progression by 37% (HR, 0.63; 95% CI, 0.52-0.76; 

 < .0001), meeting the trial’s coprimary end point.

“After a small initial drop, there’s a separation between the curves in favor of Dato-DXd; [PFS is] maintained over time and, if anything, increases over time,” Bardia said, adding that the 9-month PFS rates were almost double with Dato-DXd compared with ICC. The 6-, 9-, and 12-month PFS rates with Dato-DXd were 53.3%, 37.5%, and 25.5%, respectively, compared with 38.5%, 18.7%, and 14.6% with ICC, respectively.

PFS benefit was seen across all subgroups, including those examining age, race, ECOG performance status, geographic region, number of previous lines of chemotherapy, prior use of CDK4/6 inhibitors, and prior use of taxane and/or anthracyclines.

Objective response rate was also superior with Dato-DXd at 36.4%, including a 0.5% complete response (CR) rate, compared with 22.9% in the ICC arm, which had no CRs.

Although the overall survival (OS) data are not mature at a median follow-up of 9.7 months, there was a trend that favored Dato-DXd over ICC (HR, 0.84; 95% CI, 0.62-1.14). “The study is continuing to the next planned analysis for overall survival,” Bardia added.

Additional Findings and Patient Baseline Characteristics

Median treatment duration was 6.7 months in the Dato-DXd arm and 4.1 months in the ICC arm. After a median follow-up of 10.8 months, 93 patients in the Dato-DXd arm and 39 in the ICC arm were still receiving study treatment. In both arms, treatment was discontinued (267 vs 240 patients) as a result of progressive disease (229 vs 240), adverse effects (AEs; 11 vs 10), patient decision (13 vs 32), death (2 vs 7), or other (12 vs 23).

“Two important points to note—as of data cutoff, approximately 3 times the number of patients are still [receiving] Dato-DXd as compared with the standard chemotherapy arm. [Additionally, the] majority of patients who discontinued the study had disease progression,” Bardia said.

The open-label, global TROPION-Breast01 trial randomly assigned patients 1:1 to receive either 6 mg/kg Dato-DXd intravenously every 3 weeks or ICC. ICC was comprised of eribulin mesylate on days 1 and 8 every 3 weeks (n = 220), vinorelbine on days 1 and 8 every 3 weeks (n = 38), gemcitabine on days 1 and 8 every 3 weeks (n = 33), or capecitabine on days 1 through 14 every 3 weeks (n = 76). Treatment in both arms continued until progressive disease, unacceptable tolerability, or other discontinuation criteria.

Patients were stratified by prior CDK4/6 inhibitor exposure (yes vs no), lines of chemotherapy received (1 vs 2), and geographic location (United States, Canada, and Europe vs rest of world).

Patients with hormone receptor–positive, HER2-negative (defined as immunohistochemistry 0/1+/2+; ISH negative) breast cancer who previously received 1 to 2 lines of chemotherapy were eligible for the trial. Additionally, patients enrolled had an ECOG performance status of 0 or 1 and either experienced progression on endocrine therapy (ET) or had ET deemed an unsuitable treatment option.

PFS by blinded independent central review per RECIST 1.1 criteria and OS served as the primary end points, while secondary end points included investigator-assessed PFS and safety.

Baseline characteristics were well balanced between arms. In the Dato-DXd arm, the median age was 56 years (range, 29-86) and the majority of patients were White (49%). In total, 63% of patients had received 1 prior line of chemotherapy and 37% had received 2 lines, 82% had received a CDK4/6 inhibitor, and 90% had received a taxane and/or anthracycline.

Of the 1003 patients screened, 732 underwent treatment randomization. “After screening approximately 1000 patients over the period of 1 year, the study enrolled rapidly. In a span of 1 year there were 732 patients who were randomly assigned. It highlights the interest in the study and the unmet need,” Bardia explained.

Dato-DXd Demonstrates Favorable Safety Profile

Treatment-related AEs (TRAEs) occurred in 94% and 86% of the Dato-DXd (n = 360) and ICC (n = 351) safety populations. However, the rate of grade 3 or higher TRAEs was less than half with the TROP2-directed antibody–drug conjugate (ADC) vs ICC (21% vs 45%, respectively).

TRAEs led to dose reductions in 21% of the Dato-DXd arm compared with 30% in the ICC arm; dose interruptions in 12% and 25%, respectively; and treatment discontinuation in 3% of each arm. One patient death occurred in the ICC group due to a TRAE. Serious TRAEs occurred in 6% of the Dato-DXd arm and 9% of the ICC arm.

Bardia highlighted that most TRAEs were grade 1 or 2. In the Dato-DXd and ICC arms, any grade TRAEs included anemia (11% vs 20%, respectively), neutropenia (11% vs 42%), dry eye (22% vs 8%), nausea (51% vs 24%), stomatitis (50% vs 13%), vomiting (20% vs 8%), constipation (18% vs 9%), fatigue (24% vs 18%), and alopecia (36% vs 21%). Oral mucositis/stomatitis and dry eye led to treatment discontinuation in 1 patient each in the Dato-DXd group; however, adjudicated drug-related interstitial lung disease rate rates were low and mostly grade 1 or 2 in this arm.

Bardia noted that despite the availability of newer treatment options in breast cancer, an unmet need remains for those with endocrine-resistant, metastatic disease. Although chemotherapy is widely used for this patient population, it is associated with a low response rate, poor prognosis, and significant toxicity; similarly, TROP2-directed ADCs that are either approved or are in development have demonstrated efficacy but may have toxicities leading to treatment limitations.

“From a field perspective, there’s an unmet need, both from an efficacy perspective as well as a toxicity perspective. We need agents that are better and less toxic,” Bardia said, adding that Dato-DXd may have unique properties to address these needs, such as its optimized drug to antibody ratio, stable linker payload, tumor-selective cleavable linker, and bystander antitumor effect.

Editor’s Note: Dr Bardia has participated in advisory boards for Pfizer, Novartis, Genentech, Merck, Radius Health/Menarini, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Mersana, and Foundation Medicine. He has also received research grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health/Menarini, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Natera, and Eli Lilly.

Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor–positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. 

. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015

Datopotamab deruxtecan elicited a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy for patients with hormone receptor-positive, HER2-low or -negative, metastatic breast cancer.

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Dato-DXd Provides PFS Benefit in HR+/HER2– Breast Cancer