T-DXd Elicits Durable Responses in HER2-Expressing, Advanced Solid Tumors

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Trastuzumab deruxtecan (T-DXd; Enhertu) showed an improved overall response rate (ORR) and response durability across multiple HER2-expressing advanced solid tumors in heavily pretreated patients, according to findings from the phase 2 DESTINY-PanTumor02 trial (NCT04482309).¹

In addition to efficacy, the safety profile observed in the study was consistent with prior studies. No new safety signals were observed. Further data from the study will be presented at an upcoming medical meeting and shared with regulatory authorities.

DESTINY-PanTumor02 is an open-label, multi-center, multi-cohort study in which anti-HER2 therapy is being evaluated for the treatment of urothelial bladder cancer, biliary tract cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and rare tumors.1According to investigators led by Funda Meric-Bernstam, MD, HER2 is an established biomarker for treatment in patients with breast cancer and gastric cancer, but there is limited research for other tumors that express HER2.²

“Enhertu has already demonstrated its potential to improve outcomes for patients with HER2-targetable breast, gastric and lung cancers, and these positive initial results in other tumor settings with significant unmet need are very encouraging. The DESTINY-PanTumor02 results mark an important step forward in our understanding of the potential role of Enhertu across multiple HER2-expressing tumor types,” said Cristian Massacesi, chief medical officer and Oncology chief development officer, AstraZeneca, in a press release.

T-DXd, an antibody-drug conjugate of an anti-HER2 antibody, specifically showed preliminary activity in patients with heavily pretreated HER2-expressing or HER2-mutant solid tumors in a phase 1 dose-expansion trial (NCT02564900).³

Sixty patients with HER2-expressing or HER2-mutated tumors were enrolled in the study. Of the patients enrolled, 20 had colorectal cancer, 18 had non–small cell lung cancer (NSCLC), and 21 had other cancers. Eight of the other cancer were salivary gland tumors, 2 were HER2-mutant breast cancers, 2 were endometrial cancers, 2 were Paget disease[TB1] , 2 were biliary tract cancer. There was also 1 patient each with pancreatic cancer, uterine cervix carcinoma, extraskeletal myxoid chondrosarcoma, and small-intestine adenocarcinoma.

At baseline, the study population had a median age of 58.0 years (range, 23-83 years). The majority of the population was female (51.7%) and lived in Japan (63.3%). Patients from the United States made up the remainder of the study population (36.7%).

In terms of disease characteristics, patients had an ECOG performance status of either 0 (48.3%) or 1 (50.0%). Patients had received a median of 3.0 (range, 0-10) prior anticancer regimens, and 33.3% received 5 or more prior anticancer regimens. Moreover, 66.7% of the study population had prior surgery for cancer, and 51.7% had previous radiotherapy.

HER2 expression was identified by local assessment in all but 48.3% of patients. HER2 expression by central laboratory assessment was identified in all patients, and of those 31.7% had HER2 mutations.

Patients were treated with T-DXd 6.4 mg/kg, which was the recommended part 2 dose of the agent. A total of 59 patients received at least 1 dose of T-DXd. Treatment lasted for a median of 6.3 months (range, 0.7-29.0 months).

At a median follow-up of 7.8 months (95% CI, 0.1-28.6), the ORR per investigator assessment was 36.7% (95% CI, 24.6%-50.1%). Responses consisted of complete responses in 1.7% of patients, partial response in 35.0%, and stable disease in 43.3%. Fifteen percent of patients had progressive disease, and 5.0% were not evaluable for response.

The disease control rate with T-DXd was 80.0% (95% CI, 67.7%-89.2%), and the median time to response was 1.4 months (95% CI, 1.4–2.9).

In all 59 patients, the most common grade 1/2 treatment-emergent adverse events (TEAEs) were anemia, decreased platelet count, decreased neutrophil count, and decreased white blood cell count decreased. Grade ≥ 3 TEAEs occurred in 62.7% of patients, with the most common being anemia (25.4%), decreased neutrophil count (20.3%), decreased white blood cell count (11/59; 18.6%), decreased platelet count (15.3%), decreased appetite (6.8%), increased aspartate aminotransferase (5.1%), febrile neutropenia (5.1%), and hyponatremia (5.1%). Serious TEAEs were seen in 30.5% of patients.

The occurrence of TEAEs led to treatment discontinuation in 8.5% of patients, and 23.7% required dose reductions. Treatment discontinuation mainly resulted from pneumonitis (3.4%) and interstitial lung disease (1.7%).Dose reductions were caused by cases of platelet count decrease (10.2%), anemia (6.8%), and fatigue (5.1%).

The clinically meaningful responses seen in the DESTINY-PanTumor02 trial reaffirm our belief in the potential of Enhertu across multiple HER2-expressing cancers. The results seen so far across multiple cohorts of the trial will inform next steps of our broad development program as we look to bring this important medicine to as many patients as quickly as possible, said Ken Takeshita, global head, Research & Development, Daiichi Sankyo, in the press release.¹

_REFERENCES:

_{1. AstraZeneca and Daiichi Sankyo’s Enhertu met prespecified criteria for objective
response rate and duration of response. News release. AstraZeneca and Daiichi Sankyo. March 6, 2023. Accessed March 7, 2023. https://bit.ly/3IZo0Pe}

_{2. Meric-Bernstam, Anoka C, Dobrowlska A, et al. A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02). J Clin Oncol. 2022;40(suppl 4). doi: 10.1200/JCO.2022.40.4_suppl.TPS623}

_{3. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase i study in multiple advanced solid tumors. Cancer Discov. 2020;10(5): 688–701. doi: 10.1158/2159-8290.CD-19-1014}