T-DXd’s Effect on Sensitivity to Subsequent Lines of Therapy
Trastuzumab deruxtecan (T-DXd) does not appear to compromise sensitivity to the therapies that follow it — a finding with direct implications for how clinicians weigh its use in earlier lines of metastatic breast cancer treatment. DESTINY-Breast04 post-trial therapy data shows comparable rates of chemotherapy, endocrine therapy, and CDK4/6 inhibitor use across the T-DXd and TPC arms, suggesting no cross-resistance penalty for patients who receive T-DXd first.
Chemotherapy
In the HR+ cohort, 47.1% of patients in the T-DXd arm and 45.4% in the TPC arm received chemotherapy as their first post-trial therapy. When considering any post-trial systemic treatment, 67.1% in the T-DXd arm and 66.9% in the TPC arm received chemotherapy. The near-identical rates across both arms indicate that prior exposure to T-DXd does not reduce a patient’s capacity to receive or respond to subsequent chemotherapy.
Endocrine Therapy
For the HR+ cohort, 15.1% of T-DXd patients and 12.3% of TPC patients received endocrine therapy as their first post-trial therapy. For any post-trial endocrine therapy, the rates were 30.8% for T-DXd and 34.4% for TPC. The similar rates indicate that T-DXd treatment does not preclude the use of subsequent endocrine therapy, an important consideration for HR+ patients who may cycle back to hormonal approaches after ADC treatment.
CDK4/6 Inhibitors
As a first post-trial therapy, 2.7% of T-DXd patients and 3.1% of TPC patients in the HR+ cohort received CDK4/6 inhibitors. For any post-trial use, these rates were 14.2% for T-DXd and 16.6% for TPC. The data suggest no significant impact of T-DXd on the subsequent use of CDK4/6 inhibitors, preserving this important targeted therapy option for later lines. According to the FDA, CDK4/6 inhibitors remain central to HR+ metastatic breast cancer management, making this finding clinically significant.
Other ADCs Including Sacituzumab Govitecan
As a first post-trial therapy, 2.4% of T-DXd patients and 0.6% of TPC patients in the HR+ cohort received ADCs. Specifically for sacituzumab govitecan, 0.6% in the T-DXd arm and 0.6% in the TPC arm received it as a first post-trial therapy in the HR+ cohort. For any post-trial ADC use, 4.8% of T-DXd patients and 9.2% of TPC patients in the HR+ cohort received ADCs. The data does not suggest T-DXd induces resistance to other ADCs.
PFS2 (second progression-free survival) is measured from randomization to progression on the next line of therapy after the trial treatment, or death. It captures not just the benefit of the trial drug itself but also the combined durability of the trial drug plus one additional line of therapy — making it a robust indicator of whether a drug preserves the effectiveness of subsequent treatment.
In the DESTINY-Breast04 HR+ cohort, 67.1% of T-DXd-treated patients and 66.9% of TPC-treated patients received chemotherapy as any post-trial systemic treatment, indicating trastuzumab deruxtecan (T-DXd) does not reduce sensitivity to subsequent chemotherapy in HER2-low metastatic breast cancer.
What PFS2 Data Reveal About T-DXd’s Impact on the Overall Treatment Trajectory
T-DXd delivers a consistently longer median PFS2 than TPC across all patient cohorts in DESTINY-Breast04, demonstrating that its benefit extends beyond the trial drug itself and into the next line of treatment. This is the most compelling evidence that T-DXd improves the overall treatment trajectory rather than simply borrowing time from future lines.
In the overall cohort, median PFS2 was 15.4 months (95% CI 13.6–16.5) in the T-DXd arm and 9.7 months (95% CI 8.3–10.8) in the TPC arm. In the HR+ cohort, PFS2 was 15.5 months (95% CI 13.8–17.2) for T-DXd versus 10.5 months (95% CI 8.3–11.4) for TPC. In the exploratory HR− cohort, median PFS2 was 12.9 months (95% CI 9.6–18.3) for T-DXd versus 6.7 months (95% CI 5.0–12.7) for TPC.
“The increased median PFS2 seen with T-DXd suggests that T-DXd may not cause treatment resistance to subsequent therapies compared with TPC.”
The consistently longer median PFS2 in the T-DXd arm across all cohorts confirms that T-DXd not only extends the initial progression-free period but also does not negatively impact the efficacy of subsequent therapies. The 5.7-month PFS2 advantage in the overall cohort (15.4 vs 9.7 months) reflects a genuine improvement in the overall treatment trajectory — not a redistribution of benefit from future lines to the trial drug.
In DESTINY-Breast04, median PFS2 (progression-free survival from randomization to progression on the next line of therapy or death) was 15.4 months in the T-DXd arm versus 9.7 months in the TPC arm for the overall cohort, representing a 5.7-month improvement that indicates T-DXd enhances the overall treatment trajectory in HER2-low metastatic breast cancer without compromising subsequent therapy effectiveness.
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The low rates of subsequent ADC use after DESTINY-Breast04 — 4.8% in the T-DXd arm and 8.2% in the TPC arm for the overall cohort — do not indicate a lack of clinical rationale for ADC sequencing; rather, they reflect the limited availability of approved ADCs specifically for HER2-low disease at the time of the March 1, 2023 data cutoff.
In the HR+ cohort, 4.8% of T-DXd patients and 9.2% of TPC patients received any post-trial ADC therapy. For sacituzumab govitecan specifically, just 0.6% in each arm received it as a first post-trial therapy in the HR+ cohort. These figures capture a moment in the treatment landscape before the widespread adoption or regulatory approval of other ADCs in the HER2-low setting.
T-DXd was the first HER2-directed therapy to demonstrate clinical efficacy in HER2-low breast cancer, identifying a new targetable patient population previously classified as HER2-negative. The 2023 ASCO/CAP guidelines updated their recommendations to recognise new ADCs like T-DXd for breast cancers lacking HER2 protein overexpression or gene amplification, reflecting how rapidly the classification and treatment of this population has evolved.
Several factors explain the low post-trial ADC utilisation. First, patients transitioning off trial more commonly moved to established therapies — chemotherapy was the most frequent first post-trial treatment at 47.1% (T-DXd arm) and 45.4% (TPC arm) in the HR+ cohort. Second, the data cutoff predates the broader availability of clinical evidence supporting ADC use after T-DXd. Third, the HER2-low category itself was only formally recognised as a clinically actionable designation through DESTINY-Breast04’s own results, meaning the infrastructure for subsequent ADC use in this population was still developing at the time of analysis.
As noted by ASCO and other oncology bodies, the ADC landscape in breast cancer is evolving rapidly. The low post-trial ADC rates observed in DESTINY-Breast04 are expected to change as more agents receive approval and as data from sequencing studies mature.
In DESTINY-Breast04, only 4.8% of T-DXd-treated patients and 8.2% of TPC-treated patients in the overall cohort received any antibody-drug conjugate (ADC) as post-trial anticancer therapy, with the data cutoff of March 1, 2023 predating widespread availability of other approved ADCs for HER2-low metastatic breast cancer.
Optimal Sequencing: DESTINY-Breast04, DESTINY-Breast06, DESTINY-Breast15, and the Broader Treatment Algorithm
T-DXd is now established as the standard of care after prior chemotherapy in patients with HER2-low metastatic breast cancer — a position confirmed by DESTINY-Breast04. However, evidence from DESTINY-Breast06 and the ongoing DESTINY-Breast15 trial is pushing T-DXd’s optimal position progressively earlier in the treatment sequence, with implications for how all subsequent therapies are ordered.
DESTINY-Breast04: The Post-Chemotherapy Standard
DESTINY-Breast04 firmly establishes T-DXd as the standard of care after one or two prior lines of chemotherapy in the metastatic setting for HER2-low patients. The PFS2 advantage of 5.7 months in the overall cohort (15.4 vs 9.7 months) and the preservation of subsequent therapy sensitivity make a compelling case for T-DXd over TPC at this line. The data also confirms that T-DXd does not compromise the ability to use chemotherapy, endocrine therapy, or CDK4/6 inhibitors in subsequent lines.
DESTINY-Breast06: Moving Earlier — Post-Endocrine, Pre-Chemotherapy
DESTINY-Breast06 evaluated T-DXd in HR+, HER2-low and HER2-ultralow breast cancer patients who received prior endocrine therapy but not chemotherapy in the metastatic setting. The trial demonstrated a significant improvement in median PFS for T-DXd compared to TPC in the HER2-low population (13.2 versus 8.1 months). Consistent efficacy was also observed in HER2-ultralow cohorts. This positions T-DXd as an option before chemotherapy for HR+/HER2-low and HER2-ultralow patients who have progressed on endocrine therapy — expanding both the eligible patient population and the treatment window.
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DESTINY-Breast15 is an ongoing phase 3b trial evaluating T-DXd in an even earlier treatment setting — up to two prior lines of therapy in the metastatic setting — for HR+ or HR−, HER2-low or HER2 IHC 0 unresectable or metastatic breast cancer. Results from this trial will further refine the optimal positioning of T-DXd, potentially moving it to even earlier lines and broadening eligibility to patients with HER2 IHC 0 disease.
HER2-Ultralow and HER2-Independent Activity
The DAISY trial (NCT04132960) showed antitumor activity of T-DXd across all HER2 expression levels, including HER2 IHC 0, suggesting that even ultralow levels of HER2 expression might be sufficient for T-DXd uptake and that HER2-independent mechanisms may also contribute to its efficacy. This broadens the understanding of T-DXd’s mechanism and the potential patient population that could benefit — a finding with significant implications for how HER2 testing and patient selection are conducted. As highlighted by WHO and international oncology bodies, accurate biomarker classification is central to optimal ADC deployment.
The recognition of HER2-low and HER2-ultralow categories, and the challenges in their accurate identification, are crucial to realising the full potential of T-DXd across the metastatic breast cancer population. The updated 2023 ASCO/CAP guidelines recognising new ADCs for breast cancers lacking HER2 protein overexpression or gene amplification reflect this evolving classification landscape. Research published through NEJM and other peer-reviewed journals continues to refine the evidence base for these distinctions.
DESTINY-Breast06 demonstrated that trastuzumab deruxtecan (T-DXd) improved median progression-free survival to 13.2 months versus 8.1 months for TPC in HR+/HER2-low metastatic breast cancer patients who had received prior endocrine therapy but not chemotherapy, positioning T-DXd as a treatment option before chemotherapy in this population.
Synthesising the Sequencing Evidence
Based on the cumulative evidence from DESTINY-Breast04, DESTINY-Breast06, and the DAISY trial, the optimal treatment sequencing for HER2-low and HER2-ultralow metastatic breast cancer is becoming more nuanced. For HR+ patients with HER2-low or HER2-ultralow disease who have progressed on endocrine therapy, T-DXd can be considered before chemotherapy. For HER2-low patients who have received prior chemotherapy in the metastatic setting, T-DXd is established as a standard of care. Across both scenarios, the PFS2 data from DESTINY-Breast04 confirms that subsequent therapies — including chemotherapy, endocrine therapy, and CDK4/6 inhibitors — remain available and effective after T-DXd. As ADC sequencing data matures and DESTINY-Breast15 reports, the treatment algorithm will continue to evolve, with T-DXd’s position potentially extending to HER2 IHC 0 disease and even earlier metastatic lines. PatSnap’s life sciences intelligence platform and Insights hub track the patent and clinical trial landscape for T-DXd and competing ADCs in real time.