Trastuzumab Deruxtecan Generates PFS, OS Benefit Vs Capecitabine-based Regimens in Pretreated HER2+ Breast Cancer

Ian Krop, MD, PhD

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated a clinically meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with treatment of physician's choice (TPC) in patients with advanced HER2-positive unresectable and/or metastatic breast cancer who received prior treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla), according to the primary analysis of the phase 3 DESTINY-Breast02 trial (NCT03523585).¹

The median PFS by blinded independent central review (BICR) was 17.8 months (95% CI, 14.3-20.8) for patients who received trastuzumab deruxtecan (n = 406) compared with 6.9 months (95% CI, 5.5-8.4) with TPC (n = 202; HR, 0.3589; 95% CI, 0.2840-0.4535; P < .0000001), demonstrating a 64% reduction in the risk of disease progression or death.¹

A key secondary end point was OS. The median OS was 39.2 months (95% CI, 32.7-not evaluable [NE]) and 26.5 months in the trastuzumab deruxtecan and TPC arms, respectively (HR, 0.6575; 95% CI, 0.5023-0.8605; P = .0021).¹

The findings, which were presented at the 2022 San Antonio Breast Cancer Symposium (SABCS), are consistent with findings from the 2019 phase 2 DESTINY-Breast01 trial (NCT03248492), which demonstrated trastuzumab deruxtecan as a viable treatment for patients with HER2-positive breast cancer and led to its accelerated approval for patients with metastatic or unresectable breast cancer.² DESTINY-Breast02 is the confirmatory trial for the approval.¹

“[Findings from] the phase 3 DESTINY-Breast02 trial demonstrated a statistically significant and clinically meaningful improvement in both progression-free and OS compared [with] TPC in the post–T-DM1 setting,” study author Ian Krop, MD, PhD, a chief clinical research officer at the Yale Cancer Center in New Haven, Connecticut, said in a presentation of this data. “DESTINY-Breast02 confirms the favorable benefit-risk ratio of trastuzumab deruxtecan in patients with advanced HER2-positive breast cancer.”

The 12-month and 24-month PFS rates were 62.3% (95% CI, 57.0%-67.1%) and 42.2% (95% CI, 36.5%-47.8%) of patients who received trastuzumab deruxtecan. These rates were 27.2% 95% CI, 20.1%-34.8%) and 13.9% (95% CI, 7.9%-21.6%) for patients who received TPC.¹ The PFS benefit was consistent across all subgroups.

The 12-month OS rate for patients who received trastuzumab deruxtecan was 89.4% vs 74.7% with TPC. The 24-month OS rates were 65.9% vs 54.3%, respectively.¹

In the trial, 608 patients with pathologically confirmed HER2-positive metastatic breast cancer who had previously received T-DM1 were randomly assigned to receive trastuzumab deruxtecan or a physician-recommended combination of capecitabine with either trastuzumab (Herceptin) or lapatinib (Tykerb).

The median age of patients in the trastuzumab deruxtecan arm was 54.2 years (range, 22.4-88.5) and 18.2% had brain metastases at baseline. The patients who received TPC had a median age of 54.2 years (range, 24.7-86.5) and 17.8% had baseline brain metastases. HER2 expression by immunohistochemistry (IHC) was mostly IHC 3+ (80.3% and 78.7%, respectively). More than half of patients in the trastuzumab deruxtecan (58.6%) and TPC (58.4%) arms had hormone receptor–positive disease. The median number of prior lines of therapy was 2 in both arms.

Objective response rate (ORR) was a secondary end point for the study. Patients in the trastuzumab deruxtecan arm has a confirmed ORR by BIRC of 69.7% (95% CI, 65.0%-74.1%) compared with 29.2% (95% CI, 23.0%-36.0%) in the TPC arm (P <.0001). Among responders in the trastuzumab deruxtecan arm the confirmed complete response (CR) rate was 14% and the partial response (PR) rate was 55.7%. In the TPC arm, CR and PR rates were 5.0% and 24.3%, respectively. At data cutoff, 23.4% and 46.5% of patients had stable disease in the trastuzumab deruxtecan and TPC arms, respectively, with 4.7% and 12.9% of patients experiencing progressive disease.¹

The median duration of response was 19.6 months (95% CI, 15.9-NE) vs 8.3 months (95% CI, 5.8-9.5) in the trastuzumab deruxtecan and TPC arms, respectively.

Clinical benefit rate (CBR), investigator-assessed PFS, and time to second disease progression (PFS2) were exploratory end points for the study. The CBR with trastuzumab deruxtecan was 82.3% (95% CI, 78.2%-85.9%) and was 46.0% (95% CI, 39.0%-53.2%) with TPC. The median PFS by investigator was 16.7 months (95% CI, 14.3-19.6) vs 5.5 months (95% CI, 4.4-7.0). Finally, median PFS2 was 35.8 months (95% CI, 14.3-19.6) vs 15.8 (95% CI, 13.5-21.0).¹

Of note, in the TPC arms 140 patients (69.3%) received a new systemic anticancer treatment and 52 patients (25.7%) received trastuzumab deruxtecan in the posttrial setting.

In the safety analysis included 404 patients who received trastuzumab deruxtecan and 195 who received TPC. The percentage of patients who discontinued therapy due to a treatment-related adverse event (TRAE) to the drug was 14.4% with trastuzumab deruxtecan vs 5.1% with TPC. Krop noted that the most common noted that most common drug-related discontinuations associated with trastuzumab deruxtecan were pneumonitis (6.2%) and interstitial lung disease (ILD; 3.2%). Palmar-plantar erythrodysesthesia was attributed to discontinuation in 1.5% of patients who receive TPC.

Fewer grade 5 ILD events were observed in DESTINY-Breast02 (0.5%) compared with DESTINY-Breast01 (2.7%).

Another AE of special interest was left ventricular (LV) dysfunction. In the trastuzumab deruxtecan arm, 18 (4.5%) patients experienced an LV dysfunction event with 2 (0.5%) patients experiencing a grade 3 or higher event. In the TPC arm, 3 (1.5%) patients experienced an LV dysfunction, and 1 (0.5%) patient had a grade 3 or higher event. Other safety events were consistent with what were previously reported.¹

The median treatment duration was 11.3 months for patients who received trastuzumab deruxtecan and approximately 4.5 months for patients who received TPC.

“Trastuzumab deruxtecan should be used in the second-line setting in virtually all patients [with advanced HER2-positive breast cancer],” Krop concluded.

References

1. Krop, Ian et al T-DXd yields superior outcomes over chemotherapy-based regimens in patients previously treated with T-DM1 participating in the phase III DESTINY-Breast02 trial. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. News release. FDA. Updated December 23, 2019. Accessed December 7, 2022. bit.ly/3FDn2Yp