Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Author(s): Funda Meric-Bernstam, MD¹; Vicky Makker, MD^2,3; Ana Oaknin, MD⁴; Do-Youn Oh, MD⁵; Susana Banerjee, PhD⁶; Antonio González-Martín, MD⁷; Kyung Hae Jung, MD⁸; Iwona Ługowska, MD⁹; Luis Manso, MD¹⁰; Aránzazu Manzano, MD¹¹; Bohuslav Melichar, MD¹²; Salvatore Siena, MD¹³; Daniil Stroyakovskiy, MD¹⁴; Anitra Fielding, MBChB¹⁵; Yan Ma, MSc¹⁶; Soham Puvvada, MD¹⁵; Norah Shire, PhD¹⁵; Jung-Yun Lee, MD¹⁷

Source: https://doi.org/10.1200/JCO.23.02005

Dr. Anjan Patel's Thoughts

This is a study showing tumor agnostic activity of trastuzumab deruxtecan (T-DXd) with an all-comer overall response rate (ORR) of 37.1%, duration of response (DOR) of 11.3 months and an overall survival (OS) of 13.4 months in an otherwise heavily pre-treated group. Those with IHC-3+ derived larger benefit than 2+. Patients with ERBB2 mutations who had no expression of HER2 were excluded from the trial.

PURPOSE

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.

METHODS

This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS).

RESULTS

At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.

CONCLUSION

Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.

Author Affiliations

¹Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX; ²Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY; ³Department of Medicine, Weill Cornell Medical College, New York, NY; ⁴Gynaecologic Cancer Programme, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; ⁵Seoul National University Hospital; Cancer Research Institute, Seoul National University College of Medicine; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea; ⁶Gynaecology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom; ⁷Medical Oncology Department and Programme in Solid Tumours-CIMA, Cancer Center Clínica Universidad de Navarra, Madrid, Spain; ⁸Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; ⁹Early Phase Clinical Trials Unit and Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland; ¹⁰Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain; ¹¹Experimental Therapeutics in Cancer (UTEC), Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain; ¹²Department of Oncology, Palacký University Medical School and University Hospital, Olomouc, Czech Republic; ¹³Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda and the Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Piazza dell’Ospedale Maggiore, Milan, Italy; ¹⁴Healthcare Department, Moscow City Oncology Hospital No. 62, Moscow, Russia; ¹⁵Oncology R&D, AstraZeneca, Gaithersburg, MD; ¹⁶Oncology R&D, AstraZeneca, Cambridge, United Kingdom; ¹⁷Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, South Korea

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