ASCO Kansas City: Dr Haideri Discusses the DESTINY-Breast06 Trial Findings in HER2-Low and Ultra-Low Advanced Breast Cancer
Presenter:
Nisreen Haideri, MD, HCA Health Midwest Kansas City VA Medical Center
Conference:
ASCO Direct™ Kansas City
The Bottom Line:
Human epidermal growth factor receptor 2 (HER2) is an important marker in breast cancer that has implications for treatment. A subset of breast cancer patients have HER2 expression that is considered “Low” or “Ultra-Low” and because of that, these patients are not candidates for other HER2-directed anti-cancer therapies. A new study called DESTINY-Breast06, suggests that trastuzumab deruxtecan (T-Dxd), an antibody-drug conjugate type therapy, may be more effective than other treatments like chemotherapy for patients with advanced breast cancer and HER2 Low or Ultra-Low status.
Background:
Treatment options for patients with advanced, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer that has spread beyond the primary tumor site (metastatic disease) include endocrine therapy (ET) in combination with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in the first line (1L) treatment setting, ET either alone or in combination with targeted therapy in the second line (2L) treatment setting, and chemotherapy or trastuzumab deruxtecan (T-Dxd) in the third line (3L) treatment setting. A subset of patients with HR+ metastatic breast cancer (mBC) may actually have HER2 expression that is not completely negative, but considered “Low” or “Ultra-Low”, as defined by specific molecular criteria. The DESTINY-Breast06 Trial compared the efficacy and safety of trastuzumab deruxtecan (T-Dxd) versus the physician’s choice of chemotherapy, specifically when used in patients with HER2-Low, or Ultra-Low status.
Patients and Trial Design
Patients in DESTINY-Breast06 had HR+, mBC that was HER2-Low or Ultra-Low, and they had not yet received chemotherapy for their mBC. The patients also had received 2 or more lines of ET with or without a targeted therapy for mBC, or had “early progression” of their mBC (defined as progression within 6 months of starting 1L ET + CDK4/6i, or progression within 2 years of starting ET). Dr Haideri noted that a majority of patients in the trial population (85% or more) had visceral disease (spread of their breast cancer to organs other than bone) and about 65% or more had metastases to the liver. Most patients (>88%) had received prior treatment with ET + CDK4/6i. Patients in the trial were randomized to receive either T-Dxd, or the treating physician’s choice of chemotherapy (TPC). The primary endpoint in the trial was progression-free survival (PFS) in the HER2-Low subgroup (n=713 patients), with secondary endpoints of PFS, and overall survival in the “intention-to-treat” or ITT population, which included both the HER2-Low, and the HER2 Ultra-Low patient subset (n= 153 patients).
Key Efficacy Findings:
Findings from DESTINY-Breast06 reported at this year’s American Society of Clinical Oncology (ASCO) Meeting demonstrated a significant improvement in PFS for patients on T-Dxd relative to those on TPC (median PFS, 13.2 vs. 8.1 months; P<0.0001), with a similar significant improvement observed in the ITT population (including the HER2 Ultra-Low patients). The secondary endpoint of OS also tended to be better with T-Dxd over TPC, both in the HER2-Low (87.6% vs. 81.7%) and ITT populations (87.0% vs. 81.1%), however, the results were not statistically significant. Dr Haideri cautioned that longer follow up is needed. Patients on TPC who had progression of their disease during the trial were allowed to “crossover” to the T-Dxd treatment arm, so this could have impacted the OS results. There was also a higher overall response rate (ORR) with T-Dxd over TPC in the HER2-Low (56.5% vs. 32.2%), ITT (57.3% vs. 31.2%), and Ultra-Low (61.8% vs. 26.3%) populations in the study, a result which Dr Haideri thought was “very impressive”.
Key Safety Findings
In terms of safety, Dr Haideri noted that pneumonitis (inflammation of the lung) occurred in 11.3% of patients in the T-Dxd arm, which was overall consistent with the previously reported safety profile for T-Dxd. She also noted other adverse events (AEs) such as fatigue, nausea, and hair loss (alopecia) that are important to consider when using T-Dxd. The most common AE leading to discontinuation was pneumonitis in the T-Dxd arm, and neuropathy in the TPC arm, and discontinuations due to any AE occurred in 14.3% and 9.4% of patients in the T-Dxd and TPC arms, respectively.
Conclusions and Faculty Insights:
Commenting on the overall results from DESTINY-Breast06, Dr Haideri noted the potential impact of crossover from TPC to T-Dxd, the need for longer term follow up to confirm the OS results, and the potential for AEs such as pneumonitis, when using T-Dxd. A lingering question coming from the trial, she suggested, is whether T-Dxd should be used sooner or later in the course of therapy. She noted, if no OS benefit is seen with longer follow up in the trial, then T-Dxd would be most appropriately used in the 2L setting for patients with HER2 Low or Ultra-Low disease. She also noted some benefits and drawbacks of using T-Dxd, as compared to another standard of care chemotherapy, such as capecitabine, in the 1L setting for HR+/HER2- mBC. For example, she thought T-Dxd might be most appropriately used in those patients who have ‘early’ progression as described above, or those with symptomatic, and clinically relevant metastatic disease (e.g. liver metastases), with the caveat of T-Dxd being an intravenous (IV) therapy and the risks for AEs such as fatigue, nausea, and pneumonitis. By comparison, she thought capecitabine might be more appropriate for patients without early recurrence, those with limited metastatic disease (e.g., bone metastases only), and those who might prefer an oral (versus IV) treatment, or a therapy that does not cause significant events like fatigue, nausea, and alopecia.
Speaker Disclosure Information:
Dr Haideri did not report any relevant disclosures for this presentation.