DESTINY-Breast03 and DESTINY-Breast06 Data Shape Metastatic Breast Cancer Treatment

Paolo Tarantino, MD

During the 2024 ASCO Annual Meeting, investigators shared preliminary and updated findings from 2 phase 3 studies evaluating the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) against different comparators in patients with metastatic breast cancer with differing HER2 status with the potential to expand the use of the agent: DESTINY-Breast06 (NCT04494425) and DESTINY-Breast03 (NCT03529110).

In August 2022, the FDA approved T-DXd for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer following prior treatment with an anti–HER2-based regimen in either the metastatic setting or the neoadjuvant or adjuvant setting who have experienced disease recurrence during or within 6 months of completing treatment. The approval was supported by previous findings from DESTINY-Breast03.¹

“I expect that the use of the [T-DXd] will expand across categories of HER2 expression; it will expand and will be used in earlier settings when it’s needed and required,” Paolo Tarantino, MD, a researcher at the European Institute of Oncology in Milan, Italy, and a clinical research fellow at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with OncologyLive. “I was impressed when I saw the first phase 1 trial of T-DXd when it was still called DS-8201, and I’m still impressed every time I see a new clinical trial with this drug. It’s extremely effective, both for HER2-positive metastatic breast cancer [and] HER2-low and even ultralow [disease].”

Updated Findings From DESTINY- Breast03 Further Solidify T-DXd in HER2+ Disease

The open-label, multicenter DESTINY-Breast03 trial enrolled patients with unresectable or metastatic HER2-positive breast cancer who had previously received trastuzumab (Herceptin) and a taxane. Eligible patients needed to have documented radiographic disease progression and adequate renal and hepatic function. Those who had previously received a HER2-directed ADC in the metastatic setting, had uncontrolled or significant cardiovascular disease, or had a history of or current interstitial lung disease were excluded. Prior therapy with ado-trastuzumab emtansine (T-DM1; Kadcyla) was not permitted (Figure 1).^2,3

After enrollment, patients were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks or 3.6 mg/kg T-DM1 every 3 weeks. Patients were stratified by hormone receptor status, prior treatment with pertuzumab (Perjeta), and history of visceral disease.

At the November 20, 2023, data cutoff, updated survival findings from DESTINY- Breast03 presented during ASCO 2024 showed that patients who received T-DXd (n=261) achieved a median investigator-assessed PFS of 29.0 months (95% CI, 23.7-40.0) compared with 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (n=263; HR, 0.30; 95% CI, 0.24- 0.38). The 36-month PFS rates were 45.7% (95% CI, 38.9%-52.2%) and 12.4% (95% CI, 8.1%- 17.7%), respectively.³

DESTINY-Breast03 Phase 3 Trial Design

The median investigator-assessed OS in the T-DXd arm was 52.6 months (95% CI, 48.7-not evaluable [NE]) compared with 42.7 months (95% CI, 35.4-NE) in the T-DM1 arm (HR, 0.73; 95% CI, 0.56-0.94). The 36-month OS rates were 67.6% (95% CI, 61.3%-73.0%) and 55.7% (95% CI, 49.2%-61.7%), respectively. The respective 42-month OS rates were 62.5% (95% CI, 56.2%- 68.3%) and 50.1% (95% CI, 43.6%-56.2%).

“What we knew already was that T-DXd improved both PFS and OS compared with T-DM1, but at the prior presentations of this study, we never had an actual amount of improvement in OS because it was not reached in the treatment arms,” Tarantino explained. “Now, at this ASCO, we had the final presentation of the OS that was published concurrently in Nature Medicine. It showed that the use of T-DXd in the second line compared with T-DM1 prolonged OS by 10 months. This is highly relevant and highly clinically impactful to see almost a 1-year improvement in OS, the most meaningful end point.”

The median follow-up was 43.0 months (range, 0.0-62.9) in the T-DXd arm vs 35.4 months (range, 0.0-60.9) in the T-DM1 arm. The median treatment duration was 18.2 months (range, 0.7-56.6) vs 6.9 months (range, 0.7-55.2), respectively.

Additional results demonstrated that the confirmed investigator-assessed ORR was more than doubled with T-DXd vs T-DM1, at 78.9% (95% CI, 73.5%-83.7%) vs 36.9% (95% CI, 31.0%- 43.0%), respectively. The complete response (CR) rates were 12.6% and 4.2%, respectively. The respective median DOR rates were 30.5 months (95% CI, 23.0-NE) and 17.0 months (95% CI, 14.1-23.7); the 36-month DOR rates were 48.9% (95% CI, 41.3%-56.1%) and 28.7% (95% CI, 18.9%-39.2%), respectively.

In terms of safety, patients in the T-DXd and T-DM1 arms experienced any-grade drug-related treatment-emergent adverse effects (TEAEs) at rates of 98.1% and 87.4%, respectively. Patients in both arms experienced drug-related TEAEs of at least grade 3 severity (48.6% vs 42.5%), serious drug-related TEAEs (13.6% vs 7.7%), drug-related TEAEs associated with dose interruption (44.0% vs 18.4%), drug-related TEAEs associated with dose reduction (28.0% vs 15.3%), and drug-related TEAEs associated with treatment discontinuation (22.6% vs 7.3%). No patients in either arm experienced drug-related TEAEs leading to death.

“These data reinforced what we already knew and reinforced the position of T-DXd in patients whose disease progressed after chemotherapy and trastuzumab in earlier lines for HER2-positive metastatic breast cancer,” Tarantino said. “We await [results from] the first-line trial, [the phase 3] DESTINY-Breast09 study [NCT04784715], which is ongoing, [results of which] we may hear about within the next year.”

Data From DESTINY-Breast06 to Establish T-DXd in Earlier-Line HER2-Low Disease

The open-label, multicenter DESTINY-Breast06 study enrolled patients with hormone receptor–positive, HER2-low metastatic breast cancer, with HER2-low status being defined as an immunohistochemistry (IHC) of 1+ or 2+/in situ hybridization negative and HER2- ultralow status being an IHC of 0. Patients needed to have received at least 2 prior lines of endocrine therapy with or without targeted therapy for metastatic breast cancer or 1 prior line for metastatic breast cancer with progression at or before 6 months of initiating frontline endocrine therapy plus a CDK4/6 inhibitor or disease recurrence at or before 24 months of initiating adjuvant endocrine therapy. Other inclusion criteria included being at least 18 years old and not having received prior chemotherapy for advanced or metastatic breast cancer (Figure 2).^4,5

After enrollment, patients were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd every 3 weeks or physician’s choice of capecitabine (Xeloda), nab-paclitaxel (Abraxane), or paclitaxel. Patients were stratified by prior CDK4/6 inhibitor use, HER2 expression, and prior treatment with a taxane in the nonmetastatic setting.

The primary end point was PFS in the population with hormone receptor–positive, HER2-low disease. Secondary end points included OS, ORR, DOR, and PFS in the intention-to-treat (ITT) population, which comprised the HER2-low and HER2-ultralow populations, as well as safety. Figure 2.

DESTINY-Breast06 Phase 3 Trial Design

“DESTINY-Breast06 was a trial that [intended to] extend the footprint of T-DXd. This is a drug that’s now been FDA approved for a few years; it was initially [approved for] patients who have HER2- positive disease that is relatively late line, so these are patients whose cancers are actually driven by the HER2 oncogene,” V. K. Gadi, MD, PhD, a professor in the Department of Medicine, Division of Hematology/Oncology, at the University of Illinois College of Medicine and the deputy director of the University of Illinois Cancer Center in Chicago, said in an interview with OncologyLive. “However, [with T-DXd] being an ADC, the question was, Could we get the active molecule—the chemotherapy portion of it—into cells that have lower levels of HER2 and see efficacy there?”

At the March 18, 2024, data cutoff, primary findings from DESTINY-Breast06 presented during ASCO 2024 demonstrated that patients with HER2-low disease who received T-DXd (n=359) achieved a median PFS by blinded independent central review of 13.2 months compared with 8.1 months in the physician’s choice arm (n=354; HR, 0.62; 95% CI, 0.51-0.74; P<.0001). Similarly, the median PFS in the ITT population was 13.2 months vs 8.1 months in the T-DXd (n = 436) and the physician’s choice (n=430) arms (HR, 0.63; 95% CI, 0.53-0.75; P < .0001).

“When you look at the PFS curves, they separate early, they stay separated, and that translated into a median difference of 5.1 months. At different time points [on the PFS curves], T-DXd is comfortably above standard-of-care chemotherapy,” Gadi noted.

Moreover, the 12-month OS rates among patients with HER2-low disease who received T-DXd and physician’s choice of treatment were 87.6% and 81.7%, respectively (HR, 0.83; 95% CI, 0.66-1.05; P =.118). In the ITT population, the 12-month OS rates were 87.0% and 81.1%, respectively (HR, 0.81; 95% CI, 0.65-1.00).

Notably, the median PFS improvement observed with T-DXd (n=76) vs physician’s choice of therapy (n=76) in the population with HER2-ultralow disease was consistent with the overall findings, at 13.2 months vs 8.3 months, respectively (HR, 0.78; 95% CI, 0.50-1.21). The 12-month OS rates among these patients were 84.0% and 78.7%, respectively (HR, 0.75; 95% CI, 0.43-1.29).

In the safety population in the T-DXd (n=434) and physician’s choice (n=417) arms, patients experienced any-grade TEAEs at respective rates of 98.8% and 95.2%. Patients in both arms experienced treatment-related TEAEs (96.1%vs 89.4%), serious TEAEs (20.3% vs 16.1%), TEAEs associated with treatment discontinuation (14.3% vs 9.4%), TEAEs associated with dose interruptions (48.4% vs 38.4%), TEAEs associated with dose reductions (24.7% vs 38.6%), and TEAEs leading to death (2.5% vs 1.4%).
“There’s a chance that [T-DXd] gets regulatory approval to move up into this line [of therapy],” Gadi said.

“Then the other question [comes down to safety because] T-DXd is, in some ways, more toxic than what we use otherwise [in this setting].

Capecitabine is an exceptionally well-tolerated drug for most patients; T-DXd is less so. However, the efficacy margin is big enough that it’s tempting to look at this [as a treatment option]. It will be an individualized patient decision.”

“This was a positive trial, and we’re all excited about it. Now, how do we put this into play? How are we going to individualize [treatment] decisions? There are a lot of thoughtful things that we must move through as the next phase of things,” Gadi added in conclusion.

References

1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. May 4, 2022. Updated May 11, 2022. Accessed June 19, 2024. bit.ly/3ybhZLL
2. DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. ClinicalTrials.gov. Updated June 12, 2024. Accessed June 19, 2024. https://classic.clinicaltrials.gov/ct2/ show/NCT03529110
3. Hamilton EP, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated survival results of DESTINY- Breast03. J Clin Oncol. 2024;42(suppl 16):1025. doi:10.1200/ JCO.2024.42.16_suppl.1025
4. Study of trastuzumab deruxtecan (T-DXd) vs investigator’s choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). ClinicalTrials.gov. Updated April 12, 2024. Accessed June 19, 2024. https://classic. clinicaltrials.gov/ct2/show/NCT04494425
5. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_ suppl.LBA1000