Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2023 Oct 23
Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial.
Abstract
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.
Related Questions
Are you planning to start running IHC HER2 testing on all tumor types, even those where HER2 overexpression is less typical, in light of tumor agnostic approval of trastuzumab deruxtecan?
In my practice, I recommend HER2 IHC testing for all patients with advanced cancers, especially for those with epithelial cancers. For patients in whom HER2 positivity is rare, I also take into account any concerns about tissue availability as well as clinical eligibility for HER2-targeted therapy.
Would you use T-DXd as a first-line agent for a patient who developed early metastatic relapse of HER2+ urothelial cancer shortly after standard perioperative chemo/immunotherapy, over other standard non-targeted treatments?
Currently, for first-line therapy in the metastatic setting, I would recommend enfortumab vedotin in combination with pembrolizumab, with T-DXd as a potential next-line option for patients with HER2 3+ IHC. However, there is still a need to see if HER2-targeted ADCs have a role in first-line.
In a patient with HER2+ advanced endometrial cancer, do you include IO(+/- olaparib) in their treatment regimen, or only trastuzumab in addition to carboplatin/paclitaxel?
This is a data-free zone and an excellent question. We don't yet know the efficacy of checkpoint inhibitor therapy in pMMR, HER2-positive, p53 mutated tumors, although the ad hoc RUBY data presented at ESMO suggest that p53 mutated tumors are responsive to immunotherapy. I eagerly await the histolog...