DESTINY-Breast Data Add to Accolades for Trastuzumab Deruxtecan

Primary data from the phase 3 DESTINY-Breast02 trial, which is currently investigating trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate (ADC), vs the physician’s choice (TPC) of therapy, and updated analyses of the phase 3 DESTINY-Breast03 trial, comparing outcomes between T-DXd and trastuzumab emtansine (T-DM1), were presented this morning at the San Antonio Breast Cancer Symposium.

These new data continue to show survival, efficacy, and safety benefits of the ADC in the setting of HER2-positive (HER2+) metastatic breast cancer (mBC). The DESTINY-Breast02 findings were presented by Yale Cancer Center’s Ian Krop, MD, PhD, and the DESTINY-Breast03 findings by UCLA Health’s Sara A. Hurvitz, MD.

T-DM1 was first established for use in the second-line setting by the EMILIA trial, when it showed a 35% reduced risk of death compared with a lapatinib/capecitabine combo (median progression-free survival [PFS] of 9.6 vs 6.4 months; HR, 0.65; P < .001). DESTINY-Breast03 confirmed the anti-HER2 monoclonal antibody’s effect, with a median PFS that was not reached vs 6.8 months with T-DM1, for a 72% reduced mortality risk (HR, 0.28; P < .001). It was data from the latter, Krop explained, that solidified T-DXd’s place at “the recommended option in the second-line setting.”

DESTINY-Breast02: T-DXd vs Physician’s Choice¹

Designed as a confirmatory trial of DESTINY-Breast01, this first analysis of data from DESTINY-Breast02 reinforces the findings of that earlier investigation. The study cohort of 608 patients comprised 406 patients randomized to 5.4-mg/kg T-DXd every 3 weeks and 202 randomized to TPC of trastuzumab/capecitabine or lapatinib/capecitabine. All patients had confirmed HER2+ disease that had progressed after their most recent treatment and a history of T-DM1 treatment. The primary end point was PFS.

By the 12-month mark, the survival curves had separated significantly for PFS, for 62.3% in the T-DXd arm and 27.2% in the TPC arm. By 24 months, these totals were 42.2% and 13.9%, respectively. A median PFS was reached, and that was 17.8 vs 6.9 months, favoring T-DXd (HR, 0.3589; P < .000001).

An overall survival (OS) analysis was performed when PFS was shown to be statistically significant. “Here again,” Krop stated, “T-DXd was superior to TPC.”

There was a notable survival curve separation at 12 months for OS, for 89.4% in the T-DXd arm and 74.7% in the TPC arm, and this result persisted through 24 months, with corresponding OS rates of 65.9% and 54.3%. A median OS was reached, and this was 39.2 months with T-DXd vs 26.5 months with TPC, for a 34% reduced risk of death (HR, 0.6575; P = .0021). Of the exploratory and secondary efficacy end points, the confirmed best overall response was a partial response in 55.7% of the T-DXd arm and stable disease in 46.5% of the TPC arm.

Median duration of follow-up was 21.5 months in the treatment arm and 18.6 months in the TPC arm after median treatment durations of 11.3 and 4.5 months, respectively. Among those in the TPC arm who went on to additional treatment in the posttrial setting, 69.3% received a new systemic therapy and 25.7%, T-DXd.

At the June 30, 2022, data cutoff, 23.3% of patients receiving T-DXd (median age, 54.2 years; female patients, 99.3%) were still on treatment vs 2.6% of the TPC arm (median age, 54.7 years; female patients, 99.0%). The most common reason for treatment discontinuation was progressive disease (43.1% vs 72.3%, respectively). Among the treatment-emergent adverse events (AEs) that led to drug discontinuation, pneumonitis (6.2%) and interstitial lung disease (ILD; 3.2%) were most common in the T-DXd arm and palmar-plantar erythrodysesthesia (1.5%) in the TPC arm. AEs of special interest were ILD, with 10.4% of patients in the T-DXd arm experiencing any-grade ILD vs 0.5% in the TPC arm—median time to onset was 209.5 days—and left ventricular dysfunction, at 4.5% and 1.5%, respectively. ILD needs to be monitored, Krop stated, because although there were fewer grade 5 events compared with DESTINY-Breast01 (0.5% vs 2.7%), it remains a potentially serious AE.

“DESTINY-Breast02 confirms the favorable benefit/risk profile of T-DXd in patients with advanced HER2+ mBC,” Krop concluded. “Furthermore, these findings demonstrate that T-DXd is superior to conventional chemotherapy-based regimens in this patient population.”

DESTINY-Breast03: T-DXd vs T-DM1²

An interim analysis of DESTINY-Breast03 data published in March in The New England Journal of Medicine showed reduced risks of mBC disease progression and death following treatment with T-DXd vs T-DM1, with the study authors noting, “the efficacy of T-DXd substantially exceeded that of currently available HER-2 directed regimens.”

This updated OS analysis encompassed findings from 524 patients with unresectable or metastatic HER2+ disease randomized 1:1 to 5.4-mg/kg T-DXd (n = 261; median age, 54.3 years) or 3.6-mg/kg T-DM1 (n = 263; median age, 54.2 years) every 3 weeks, with PFS again the primary end point and OS, the key secondary end point. Data cutoff was July 25, 2022. Median study follow-ups were 28.4 months for T-DXd and 26.5 months for T-DM1, most patients (99.6% in each arm) were female patients, trastuzumab and pertuzumab were the most common prior systemic therapies, and most patients had 1 or 2 prior lines of therapy in the metastatic setting.

When the data cutoff occurred, 4 times as many patients in the T-DXd arm were still undergoing treatment compared with the T-DM1 arm: 29.2% vs 6.9%. As with DESTINY-Breast02, the most common reason for treatment discontinuation was progressive disease, in 36.6% and 68.2%, respectively.

By the 12-month mark after treatment initiation with either T-DXd or T-DM1, the PFS survival curves between the 2 regimens again had noticeably separated, with 75.2% and 33.9%, respectively, experiencing this outcome. Data at 2 years echo the 1-year results, with 53.7% receiving T-DXd and 26.4% receiving T-DM1 having PFS. Median PFS was reached and was approximately 4 times longer with T-DXd vs T-DM1: 28.8 vs 6.8 months, for a 67% reduced risk (HR, 0.33; P < .000001).

PFS2, too, favored T-DXd significantly, coming in at 40.5 months compared with 25.7 months seen with T-DM1, with fewer patients in the former arm discontinuing treatment (70.8% vs 93.1%).

Superior outcomes were also seen with new data on OS. Most patients in the T-DXd arm (94.1%) and the T-DM1 arm (86.0%) experienced this outcome at 12 months, but there again was a noticeable survival curve separation by this point. This separation was ongoing at 2 years, with corresponding OS rates of 77.4% and 69.9%. Median OS was not reached in either arm.

“However, the hazard ratio of 0.64 was statistically significantly in favor of T-DXd,” Hurvitz said, “with a P value crossing that prespecified threshold, .013, being at .0037.”

In the posttrial setting, 35.3% of the T-DXd arm received T-DM1 and 17.3% of the T-DM1 arm received T-DXd.

The confirmed overall response rate was 78.5% with T-DXd and 35.0% with T-DM1, with most patients receiving T-DXd achieving a partial response (57.5%) and most receiving T-DM1 achieving stable disease (41.8%). The clinical benefit rate overwhelmingly favored T-DXd (89.3% vs 46.4%).

Most patients in each arm experienced any-grade treatment-emergent AEs: 21.4% of the T-DXd arm and 9.2% of the T-DM1 arm. Among the treatment-emergent AEs that led to drug discontinuation, pneumonitis (5.8%) and ILD (5.1%) were again most common from T-DXd and decreased platelet count (1.5%), while pneumonitis and thrombocytopenia (1.1% each) were most common with T-DM1.

ILD/pneumonitis was an AE of special interest, with 15.2% of the T-DXd arm and 3.1% of the T-DM1 arm experiencing any-grade ILD. Kovitz stated. There were more grade 1 and grade 2 events, grade 3 events remained the same as in the interim analysis, and there were no grade 4 or 5 events.

These most recent data announced at SABCS, which encompass a longer treatment duration, show that treatment with T-DXd continues to be safe and manageable, with “remarkable OS and PFS benefit, further supporting the use of T-DXd as the second-line standard of care in patients with HER2+ MBC,” Hurvitz noted. “T-DXd demonstrated clinically meaningful and statistically significant improvement in OS over T-DM1; a consistent OS benefit was observed; and with a longer treatment duration, T-DXd continues to demonstrate a manageable and tolerable safety profile.”

References

1. Krop I, Park YH, Kim S-B, et al. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized phase 3 study DESTINY-Breast02. Presented at: SABCS; December 6-10, 2022; San Antonio, TX. Abstract GS2-01.

2. Hurvitz SA, Hegg R, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER-2 positive metastatic breast cancer: updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: SABCS; December 6-10, 2022; San Antonio, TX. Abstract GS2-02.