Abstract CT572: Phase 1b dose-escalation and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd) in combination with durvalumab and cisplatin, carboplatin, or pemetrexed in advanced or metastatic, HER2-overexpressing, nonsquamous non-small cell lung cancer (NSCLC): DESTINY-Lung03
Authors: Planchard David , Brahmer Julie R. , Yang James C. , Chen Yuh-Min , Lee Kang-Yun , Suksombooncharoen Thatthan , Viglianti Natasha , Gustavson Mark , Ragone Alejandra , Hernandez Amaya Gasco 
Published: June 2022

Background: HER2 overexpression is an established molecular target in breast and gastric cancer therapy, but no HER2-targeted therapies are currently available for NSCLC. In studies of NSCLC and lung cancer overall, the prevalence of HER2 overexpression has been reported to be anywhere from &lt;5% to 35% (Cox et al. Int J Cancer. 2001;92:480-483; Hirsch et al. Lancet. 2017;389:299-311). T-DXd is an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. Interim results from the DESTINY-Lung01 trial showed encouraging efficacy in extensively pretreated patients (pts) with unresectable/metastatic, HER2-overexpressing, nonsquamous NSCLC, with a confirmed objective response rate (ORR) of 24.5% and median overall survival (OS) of 11.3 months (Nakagawa et al. WCLC 2020. Abstract OA04.05). Preclinically, the combination of T-DXd and an anti-programmed cell death 1 antibody was more effective than either therapy alone. The DESTINY-Lung03 trial is evaluating the safety and tolerability of T-DXd in combination with durvalumab and chemotherapy in pts with unresectable/metastatic, HER2-overexpressing, nonsquamous NSCLC.

Methods: DESTINY-Lung03 (NCT04686305) is a phase 1b, open-label, multicenter, dose-escalation (part 1) and dose-expansion (part 2) study in pts with HER2-overexpressing (≥25% immunohistochemistry 2+/3+ tumor cells), unresectable, locally advanced or metastatic, nonsquamous NSCLC. In part 1, pts with progression after 1 or 2 lines of systemic therapy in the recurrent/metastatic setting are enrolled to receive T-DXd and durvalumab in combination with cisplatin (arm 1A), carboplatin (arm 1B), or pemetrexed (arm 1C), or T-DXd monotherapy (arm 1D). In part 2, pts who have not received prior curative treatment in the locally advanced setting or systemic treatment in the metastatic setting are enrolled to receive T-DXd and durvalumab in combination with cisplatin (arm 2A), carboplatin (arm 2B), or pemetrexed (arm 2C), or T-DXd plus durvalumab (arm 2D); pts in part 2 must not have activating EGFR mutations, an EML4-ALK fusion, or other targetable alterations. The primary endpoint is the frequency of adverse events (AEs) and serious AEs (SAEs) with T-DXd plus durvalumab plus chemotherapy combinations to assess safety and tolerability and determine the recommended phase 2 dose. Secondary endpoints include confirmed ORR, duration of response, disease control rate, progression-free survival, OS, frequency of AEs and SAEs with T-DXd monotherapy (part 1) and T-DXd plus durvalumab (part 2), pharmacokinetics, and immunogenicity.

Citation Format: David Planchard, Julie R. Brahmer, James C. Yang, Yuh-Min Chen, Kang-Yun Lee, Thatthan Suksombooncharoen, Natasha Viglianti, Mark Gustavson, Alejandra Ragone, Amaya Gasco Hernandez. Phase 1b dose-escalation and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd) in combination with durvalumab and cisplatin, carboplatin, or pemetrexed in advanced or metastatic, HER2-overexpressing, nonsquamous non-small cell lung cancer (NSCLC): DESTINY-Lung03 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT572.