The antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS) vs standard-of-care trastuzumab emtansine (T-DM1; Kadcyla) for patients with previously treated HER2positive metastatic breast cancer, according to data from DESTINY-Breast03 (NCT03529110), the first randomized headto-head trial of the ADC, presented at the 2021 European Society for Medical Oncology Congress.

The median PFS for patients treated with trastuzumab deruxtecan was not reached (95% CI, 18.5 months to not estimable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; 

 = 7.8 x 10–22). Among the 261 patients in the trastuzumab deruxtecan arm, the 12-month PFS rate was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%) among 263 patients treated in the T-DM1 arm.

“These data support trastuzumab deruxtecan becoming the standard of care for the second-line treatment of HER2-positive metastatic breast cancer,” said Javier Cortés, MD, PhD, in a presentation of the data. Cortés is head of breast cancer and gynecological cancers at Hospital Universitario Ramón y Cajal in Madrid, Spain, and a clinical investigator for the breast cancer research program at Vall d’Hebron Institute of Oncology in Barcelona, Spain.

In reference to the Kaplan-Meier curves for PFS, Cortés said there is a “clear and early separation of the curves starting at time of first scan after treatment and proceeding throughout.”

In a discussion of the abstract, Shanu Modi, MD, called attention to the early separation as well. “If the waterfall plot from DESTINY-Breast01 was dramatic, I think these PFS curves from DESTINY-Breast03 are startling, as is the hazard ratio of 0.28 and the P value of 10

,” said Modi, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

The median overall survival (OS) was NE in both arms (HR, 0.56; 95% CI, 0.36-0.86; 

 = .007172). The 12-month OS rates were 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%89.7%) in the investigative and control arms, respectively.

The OS data did not cross the prespecified boundary of 

 <.000265; however, Cortés noted that this is likely because of immature follow-up of the OS data. Investigators observed relatively few events in each arm at the time of analysis (33 and 53 with trastuzumab deruxtecan and T-DM1, respectively).

DESTINY-Breast03 randomized 524 patients with HER2positive metastatic breast cancer, previously treated with trastuzumab and taxane, to receive either trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks or T-DM1 at 3.6 mg/kg every 3 weeks. Patients with brain metastases were eligible for enrollment if those metastases were treated and clinically stable.

The primary end point was PFS by blinded independent central review (BICR). A key secondary end point was OS; other secondary end points included objective response rate (ORR) by BICR and investigator assessment, duration of response by BICR, PFS by investigator assessment, and safety. Stratification factors for the analysis included hormone receptor status, prior treatment with pertuzumab (Perjeta), and history of visceral disease. The median follow-up was 16.2 months for the trastuzumab deruxtecan group and 15.3 months for the T-DM1 group.

Baseline characteristics were well balanced between the treatment arms: 50.2% in the trastuzumab deruxtecan group vs 51% in the T-DM1 group were hormone receptor positive, 23.8% vs 19.8%, respectively, had brain metastases, and 70.5% vs 70.3% had visceral disease. The median age was 54.3 years (range, 27.9-83.1) vs 54.2 years (range, 20.2-83).

Nearly half of the patients enrolled to the study had only 1 line of prior therapy in the metastatic setting (49.8% in the investigative group vs 46.8% in the control group). The percentage of patients who had received 2 prior therapies was 21.5% vs 24.7%, respectively. Of note, both groups included a handful of patients who had received 5 or more prior lines of therapy (8.8% vs 6.8%).

In the trastuzumab deruxtecan arm, 62.1% of patients had prior pertuzumab and 16.1% received another anti-HER2 tyrosine kinase inhibitor; these rates were 60.1% and 13.7%, respectively, in the T-DM1 arm.

The data cutoff for the interim PFS analysis was May 21, 2021.

 Of note, on July 30, 2021, the independent drug monitoring committee recommended that investigators unblind the study.

“At the time of this analysis, more than 50% of patients remain on trastuzumab deruxtecan [n = 132] compared with 18% of patients on T-DM1 [n = 47],” Cortés said.

In a PFS analysis by investigator assessment, the median PFS was 25.1 months (95% CI, 22.1-NE) in the trastuzumab deruxtecan arm vs 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (HR, 0.26; 95% CI, 0.20-0.35; 

). The 12-month PFS rates were 76.3% (95% CI, 70.4%-81.2%) vs 34.9% (95% CI, 28.8%-41.2%), respectively.

“Improved efficacy with trastuzumab deruxtecan exists across all prespecified subgroups including hormone receptor status, prior pertuzumab treatment, the presence of visceral disease, number of prior lines of therapy, and presence or absence of brain metastases,” Cortés said.

In the discussion, Modi called attention to the PFS data for patients with treated, stable brain metastases: In this group, the median PFS was nearly 3 times longer with trastuzumab deruxtecan (n = 62) compared with T-DM1 (n = 52). The median PFS was 15.0 months (95% CI, 12.6-22.2) with trastuzumab deruxtecan vs 5.7 months (95% CI, 2.9-7.1) with T-DM1 (HR, 0.3796; 95% CI, 0.2267-0.6357). “This is a very clinically important difference to highlight between these 2 agents,” Modi said.

The ORR and best overall response data also favored trastuzumab deruxtecan. Specifically, the confirmed ORR in the trastuzumab deruxtecan arm was 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%) in the T-DM1 arm (

Of the responders in the trastuzumab deruxtecan arm, 16.1% had a complete response (CR) and 63.6% had a partial response (PR). Among responders in the T-DM1 arm, 8.7% had a CR and 25.5% had a PR. Stable disease was reported for 16.9% and 42.6% of patients, respectively. The disease control rate (CR plus PR plus stable disease) was 96.6% with trastuzumab deruxtecan vs 76.8% with T-DM1.

Modi noted that the ORR with trastuzumab deruxtecan was comparable with that seen with pertuzumab/trastuzumab/ docetaxel (80.2%) in the first-line setting in results from the phase 3 CLEOPATRA study (NCT00567190).3 “It’s exciting to see that 16% of patients on trastuzumab deruxtecan had a CR,” Modi said. “We recall in CLEOPATRA that number was 5.5%, so it’s interesting to speculate if we will see a larger proportion of patients with long-term disease remission in the trastuzumab deruxtecan arm.”

In terms of safety, the incidence of grade 3/4 drug-related treatment-emergent adverse effects (TEAEs) was 45.5% with trastuzumab deruxtecan vs 39.8% with T-DM1. This difference extended to incidence of serious drug-related TEAEs (10.9% vs 6.1%, respectively), drug-related TEAEs associated with discontinuation (21.4% vs 12.6%), and drug-related TEAEs associated with dose reductions (21.4% vs 12.6%).

The median treatment duration was 14.3 months (range, 0.7-29.8) for patients who received trastuzumab deruxtecan vs 6.8 months (range, 0.7-25.1) for those who received T-DM1.

Interstitial lung disease (ILD)/pneumonitis was the most common TEAE associated with treatment discontinuation for trastuzumab deruxtecan (8.2%); thrombocytopenia was the most common TEAE that led to discontinuation of T-DM1 (2.7%).

TRAEs associated with dose reduction for trastuzumab deruxtecan were nausea (6.2%) and neutropenia (3.5%). For T-DM1, they were thrombocytopenia (4.2%), alanine aminotransferase increase (2.7%), and aspartate aminotransferase increase (2.7%).

No drug-related deaths occurred in either arm, and most drugrelated TEAEs were gastrointestinal or hematologic. The most common grade 3 or higher TRAEs with trastuzumab deruxtecan were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%), and anemia (5.8%). For T-DM1, the most common TEAEs grade 3 or higher were thrombocytopenia (24.9%), aspartate aminotransferase increase (5.0%), alanine aminotransferase increase (4.6%), and anemia (4.2%).

“If the efficacy was impressive, I would say the safety [data] from DESTINY-Breast 03 were reassuring,” Modi said, adding that “there were no bad surprises in this trial. T-DM1 certainly sets a high bar for antibody-drug conjugate safety, and I think that is one of its great strengths.”

Modi said that in terms of treatment discontinuation because of TEAEs, lung toxicity with trastuzumab deruxtecan was expected. “Lung toxicity was 1 of the highly anticipated outcomes from this trial, and T-DM1 [had an approximate] 2% incidence of low-grade events,” Modi said. “In comparison, trastuzumab deruxtecan had a risk of [10.5%]—so, 5-fold higher than T-DM1—but lower than that seen in DESTINY-Breast01 [NCT03248492].”

Most importantly, Modi added, no grade 4 or 5 ILD/ pneumonitis events were observed, “a major difference from DESTINY-Breast01 and a major relief.”

Less lung toxicity may have been observed in DESTINYBreast03 because the trial included a patient population that was less heavily pretreated and therefore exposed to few lines of cancer therapy and stricter patient selection; however, Modi said this rationale is only a hypothesis at this time.

“Of course, there was also greater awareness [concerning ILD],” Modi said. “There was a large education campaign around the lung toxicity of trastuzumab deruxtecan. If you look at the rates of ILD, the rates were consistent until 2019 when updated management guidelines were implemented. Following this, incidence rates started to come down.”

Specifically, Modi presented pooled data demonstrating that the incidence of any-grade ILD over time was 24.3% (n = 18/74) in 2016; 19.6% (n = 33/168) in 2017; 15.3% (n = 87/569) in 2018; 15.6% (n = 28/179) in 2019; and 6.9% (n = 11/160) in 2020.

Both Cortés and Modi stated that the unmatched efficacy and reduced risk of lung toxicity with trastuzumab deruxtecan support its use in the second-line setting.

Trastuzumab deruxtecan is approved for patients with unresectable, HER2-positive, metastatic breast cancer who have received 2 or more prior lines of anti–HER2-based regimens in the metastatic setting.

Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract LBA1.

Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. News release. AstraZeneca and Daiichi Sankyo Company; August 9, 2021. Accessed September 18, 2021. bit.ly/3tRh5zG

Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Investigators. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. 

. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216

Powell CA, Modi S, Iwata H, et al. Analysis of study drug-related interstitial lung disease (ILD) inn patiennts (pts) with HER+ metastatic breast cancer (mBC) treated with trastuzumab deruxtecan (T-DXd). 

 2021;32(suppl 2):S61-S62. doi:10.1016/j.annonc.2021.03.106

Enhertu. Prescribing information. Daiichi Sankyo; 2021. Accessed September 18, 2021. bit.ly/3CtlWKm

Sponsored in part by Daiichi Sankyo. Content independently developed by 

Articles

Fam-trastuzumab deruxtecan-nxki demonstrated a clinically meaningful and statistically significant improvement in progression-free survival vs standard of care trastuzumab emtansine for patients with previously treated HER2-positive metastatic breast cancer. 

Trastuzumab Deruxtecan Bests T-DM1 in First Head-to-Head Study for HER2+ Breast Cancer

The addition of carboplatin to neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide significantly improved pathological complete response (pCR) rates and event-free survival (EFS) in patients with treatment-naïve triple-negative breast cancer (TNBC), according to 4-year follow-up data from the phase 3 BrighTNess trial (NCT02032277) presented during the 2021 ESMO Congress.

 However, the addition of veliparib to carboplatin had no impact on either end point.

At a median follow-up of 4.5 years, the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel resulted in a 37% reduction in the risk of events or death compared with paclitaxel alone (HR, 0.63; 95% CI, 0.43-0.92; 

 = .02). However, when the veliparib regimen was compared with carboplatin/paclitaxel, no event-free survival (EFS) benefit was observed (HR, 1.12; 95% CI, 0.72-1.72; 

 = .62). Post-hoc analyses showed that EFS was most improved with carboplatin/paclitaxel compared with paclitaxel (HR, 0.57; 95% CI, 0.36-0.91; 

“Adding carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pathologic complete response significantly, and this translated into an improved EFS by an absolute 11% after a median follow-up of 4.5 years,” Sibylle Loibl, MD, lead study author and chair of the German Breast Group in Germany, said in a virtual presentation on the findings. “The addition of veliparib did not impact pCR, EFS, or [overall survival]. These findings, overall, support the inclusion of carboplatin into neoadjuvant chemotherapy for stage II to III TNBC, regardless of germline BRCA status.”

TNBC is known to have the highest risk of recurrence and a worse overall prognosis for survival compared with other breast cancers. Standard treatment is comprised of neoadjuvant chemotherapy followed by surgery.

In the double-blind, placebo-controlled, phase 3 BrighTNess trial, 634 patients with treatment-naïve stage II/III TNBC were randomized 2:1:1 to receive paclitaxel at 80 mg/m

weekly for 12 doses in up to 16 weeks plus carboplatin at area under the curve (AUC) 6 mg/mL every 3 weeks for 4 cycles plus veliparib at 50 mg orally twice daily (arm A; n = 316); carboplatin plus paclitaxel plus placebo (arm B; n = 160); or paclitaxel plus placebo (arm C; n = 158).

 dose with cyclophosphamide at 600 mg/m2 every 2 or 3 weeks for 4 cycles. Patients underwent surgery 2 to 8 weeks following the last dose of chemotherapy. A postsurgical assessment was done every 3 months until 1 year after surgery, followed by every 6 months until 2 years after surgery, and then annually until 4 years after surgery or until an EFS event.

To be eligible for enrollment, patients had to be at least 18 years old, have histologically or cytologically confirmed invasive stage II/III TNBC, have an ECOG performance status of 0 or 1, and be eligible for potentially curative surgery with documented germline 

Those who received prior anticancer therapy, had prior or concurrent cancer, or were on ovarian hormonal replacement therapy were excluded from study enrollment.

Patients were stratified based on germline BRCA status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration.

The primary end point of the trial was pCR; secondary end points were EFS and OS using a fixed testing procedure that ordered arm A vs arm C; and then arm A vs arm B. Both coprimary end points had to be statistically significant to continue formally testing secondary end points, Loibl noted.

Efficacy evaluations were done in all randomized patients; safety was analyzed in those who received at least 1 dose. In the primary pCR analyses, arm A was found to be superior to arm C, but not to arm B.

Baseline characteristics were similar across all 3 arms. The median age was 50 years (range, 22-79), and 46.6% of patients were from North America compared with 38.6% from Europe and 15% from Asia-Pacific. Moreover, 14.6% of patients had deleterious germline BRCA mutations; most patients (71.3%) had T2 stage tumors and 58% had N0 stage disease. Additionally, 55.3% of patients received doxorubicin/cyclophosphamide every 2 weeks. When breaking down patients by histological primary tumor grade, 59.6% had high grade, 20.3% had intermediate, 5.3% had low grade, and 14.3% of patients’ data were unknown/not reported.

Previously reported findings from the double-blind, placebo-controlled, phase 3 trial showed that the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pCR rates in this patient population, but there was no benefit to adding veliparib to carboplatin and paclitaxel alone.

At that time point, the pCR rates were higher in the paclitaxel, carboplatin, and veliparib group, at 53% compared with 31% in patients who received paclitaxel alone (

 <.0001) but was not superior vs the patients who received carboplatin/paclitaxel at 58% (

However, the impact of neoadjuvant carboplatin on long-term outcomes remained uncertain, explained Loibl, who added that based on the primary analyses, the subsequent secondary analyses are descriptive with nominal P values.

At the 4.5-year median follow-up, additional results from a statistical analysis of OS showed that there were 38 deaths in arm A (12%), 16 in arm B (10%), and 22 deaths in arm C (14%). OS was not statistically significant different with the addition of veliparib to carboplatin/paclitaxel vs paclitaxel alone (HR, 0.82; 95% CI, 0.48-1.38; 

 = .45), but there was a trend for the carboplatin/paclitaxel (HR, 1.25; 95% CI, 0.70-2.24; 

 = .46). Carboplatin plus paclitaxel also showed a trend toward improved OS vs paclitaxel (HR, 0.63; 95% CI, 0.33-1.21; 

Additionally, the 4-year EFS rates were 78.2% (95% CI, 73.5%-83.2%) in arm A, 79.3% (95% CI, 72.9%-86.2%) in arm B, and 68.5% (95% CI, 61.3%-76.6%) in arm C.

In the patients who experienced events in arm A (n = 65), arm B (n = 30), and arm C (n = 47), few patients experienced progressive disease prior to surgery; this occurred in 1, 1, and 4 patients, respectively. Sixteen percent of patients in both arms A and B experienced any recurrence compared with 22% of patients in arm C. Secondary non-breast cancer malignancies occurred in 4% of patients on arm A, 2% on arm B, and 3% on arm C.

Investigators also studied the impact of pCR on EFS in all patients and subgroups by germline 

 status. pCR had a positive correlation with EFS in all patients (HR, 0.26; 95% CI, 0.18-0.38; 

 = .0004), and those whose tumors were germline 

 wild-type (HR, 0.29; 95% CI, 0.19-0.44; 

Death as the first event occurred in 13 patients on arm A, 3 on arm B, and 6 on arm C.

Regarding safety, the rates of treatment-emergent and posttreatment-emergent myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and secondary malignancies were similar between all treatment arms. Pancytopenia occurred in 4, 3, and 0 patients on arms A, B, and C, respectively, and MDS occurred in 1, 0, and 1 patient(s), respectively.

In arm A with veliparib, secondary malignancies included acute leukemia (n = 1), AML (n = 2), chronic myeloid leukemia (n = 1), lung neoplasm (n = 1), and malignant melanoma (n = 1). In arm B with carboplatin/paclitaxel, these included AML (n = 3), basal cell carcinoma (n = 1), and colon cancer (n = 1). In the paclitaxel-alone arm, these were MDS (n = 1) and pancreatic carcinoma (n = 2).

Loibl S, Sikov W, Huober J, et al. Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after 4 years of follow-up: BrighTNess, a randomized phase 3 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 119O.

Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. 

. 2018;19(4):497-509. doi:10.1016/S1470-2045(18)30111-6

The addition of carboplatin to neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide significantly improved pathological complete response rates and event-free survival in patients with treatment-naïve triple-negative breast cancer. 

Neoadjuvant Carboplatin Plus Paclitaxel, Without Veliparib, Improves pCR, EFS in TNBC

The 2021 ESMO Congress priority report focuses on updates in breast cancer presented at the virtual conference, which was held September 16 to 21, 2021. 

2021 ESMO Congress: Breast Cancer | Supplements and Featured Publications

Trastuzumab Deruxtecan Bests T-DM1 in First Head-to-Head Study for HER2+ Breast Cancer

Neoadjuvant Carboplatin Plus Paclitaxel, Without Veliparib, Improves pCR, EFS in TNBC