Highlights
- Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg monotherapy demonstrates significant clinical activity in pretreated patients with HER2-overexpressing (IHC 3+/2+) non-small cell lung cancer (NSCLC).
- The combination of T-DXd with durvalumab and platinum chemotherapy (cisplatin or carboplatin) resulted in substantial dose-limiting toxicities (DLTs), including Grade 5 hematologic events.
- Observed Objective Response Rates (ORR) were 44.4% for T-DXd monotherapy and 37.5% for the carboplatin-combination arm, suggesting monotherapy remains the more viable path for this population.
- DESTINY-Lung03 findings suggest that the overlapping toxicities of ADCs, immunotherapy, and platinum doublets present a significant barrier to intensive combination regimens in metastatic NSCLC.
Background
Human epidermal growth factor receptor 2 (HER2) has emerged as a critical therapeutic target in non-small cell lung cancer (NSCLC). While HER2 mutations (predominantly exon 20 insertions) occur in approximately 2% to 4% of NSCLC cases and have successful targeted therapies like trastuzumab deruxtecan (T-DXd), HER2 overexpression (HER2-OE)—defined by immunohistochemistry (IHC) scores of 3+ or 2+—represents a larger and more heterogenous population. Historically, traditional HER2-targeted agents such as trastuzumab and lapatinib failed to show significant benefit in HER2-OE NSCLC, creating a substantial unmet clinical need for patients who have progressed on standard-of-care platinum-based chemotherapy and immune checkpoint inhibitors (ICIs).
Trastuzumab deruxtecan is a next-generation antibody-drug conjugate (ADC) comprising a humanized anti-HER2 monoclonal antibody, a cleavable tetrapeptide-based linker, and a potent topoisomerase I inhibitor payload. Its high drug-to-antibody ratio (DAR ~8) and unique bystander effect, which allows the payload to kill neighboring cancer cells regardless of their HER2 expression levels, make it a promising candidate for HER2-OE tumors. However, the optimal integration of T-DXd into the treatment landscape—whether as a monotherapy or in combination with ICIs and chemotherapy—requires rigorous clinical validation, leading to the initiation of the DESTINY-Lung03 study.
Key Content
Study Design and Patient Population
DESTINY-Lung03 (NCT04686305) is an open-label, multicenter, multi-arm Phase 1b trial designed to evaluate the safety, tolerability, and efficacy of T-DXd-based regimens in patients with pretreated metastatic HER2-OE NSCLC. Part 1 of the trial focused on dose-finding and safety across several cohorts:
- Arm 1A: T-DXd (4.4 or 5.4 mg/kg) + Durvalumab (1120 mg) + Cisplatin (60 or 75 mg/m²).
- Arm 1B: T-DXd (4.4 or 5.4 mg/kg) + Durvalumab (1120 mg) + Carboplatin (AUC 4 or 5).
- Arm 1D: T-DXd Monotherapy (5.4 mg/kg).
Patients were required to have documented HER2 overexpression (IHC 3+ or 2+) and must have received prior systemic therapy. The primary endpoints for the combination arms (1A and 1B) were the incidence of dose-limiting toxicities (DLTs) and adverse events (AEs). For the monotherapy arm (1D), the primary focus was safety, with efficacy serving as a secondary endpoint for all arms.
Safety and Dose-Limiting Toxicities (DLTs)
The safety profile in the combination arms revealed significant challenges. In Arm 1A (cisplatin combination), DLTs included febrile neutropenia (Grade 5 at the lower dose level) and decreased platelet counts (Grade 4 and Grade 5 at the higher dose level). Arm 1B (carboplatin combination) also reported febrile neutropenia (Grade 3 and 4) and decreased platelet counts (Grade 4).
Drug-related serious adverse events (SAEs) occurred with high frequency in the triple-combination arms: 63.6% in Arm 1A and 37.5% in Arm 1B. In contrast, T-DXd monotherapy (Arm 1D) was significantly better tolerated, with drug-related SAEs occurring in only 16.7% of patients. These results highlight a narrow therapeutic index for T-DXd when combined with platinum doublets and durvalumab, largely due to overlapping myelosuppression.
Efficacy Outcomes
Despite the safety concerns in combination arms, T-DXd demonstrated promising clinical activity. As of the April 2024 data cutoff:
- Arm 1D (Monotherapy): Confirmed Objective Response Rate (ORR) was 44.4% (95% CI: 27.9–61.9). This result aligns with findings from the DESTINY-Lung01 trial, reinforcing the efficacy of T-DXd in HER2-OE populations.
- Arm 1B (Carboplatin combo): Confirmed ORR was 37.5% (95% CI: 18.8–59.4).
- Arm 1A (Cisplatin combo): Small sample sizes and early terminations due to toxicity precluded robust efficacy assessment for this cohort.
The data suggest that the addition of chemotherapy and PD-L1 inhibition to T-DXd did not result in a synergistic efficacy signal that justified the increased toxicity burden in this pretreated population.
Expert Commentary
The results of DESTINY-Lung03 Part 1 provide a critical cautionary tale for the development of ADC-based combination therapies. While the biological rationale for combining T-DXd with durvalumab (to enhance immunogenicity through the release of tumor antigens) and platinum chemotherapy (to maximize initial cytoreduction) is sound, the clinical reality is dictated by hematologic toxicity. The occurrence of Grade 5 (fatal) febrile neutropenia and thrombocytopenia in the cisplatin arm is particularly concerning and suggests that the 5.4 mg/kg dose of T-DXd—which is the standard for lung cancer—cannot be safely combined with standard doses of platinum doublets and durvalumab.
From a mechanistic perspective, T-DXd’s topoisomerase I inhibitor payload (DXd) is inherently myelosuppressive. When combined with cisplatin or carboplatin (which also cause bone marrow suppression) and durvalumab (which can induce immune-related cytopenias), the synergistic marrow toxicity appears to exceed the compensatory capacity of most pretreated patients.
Furthermore, the efficacy of T-DXd monotherapy (44.4% ORR) remains highly competitive in the second-line setting for HER2-OE NSCLC, where standard docetaxel typically yields ORRs of less than 15%. These findings suggest that for HER2-OE NSCLC, the future may lie in refining T-DXd as a monotherapy or exploring more sequential approaches rather than simultaneous intensive combinations.
Conclusion
DESTINY-Lung03 confirms that T-DXd monotherapy at 5.4 mg/kg is a potent and relatively safe therapeutic option for patients with pretreated HER2-overexpressing NSCLC. However, the study does not support the use of T-DXd in combination with durvalumab and platinum-based chemotherapy due to prohibitive hematologic toxicities. These results guide the oncology community toward a more cautious approach to triple-combination regimens involving high-DAR ADCs. Future research should focus on identifying the specific IHC thresholds that best predict T-DXd response and investigating novel, less toxic combinations, such as T-DXd with targeted inhibitors or alternate immunotherapy dosing schedules.
Reference：
Li BT, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022;386(3):241-251. PMID: 34534430; Goto K, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase 2 DESTINY-Lung02 Trial. J Clin Oncol. 2023;41(31):4852-4863. PMID: 37699478.
