Trastuzumab Deruxtecan Elicits Activity in HER2-Expressing Solid Tumors

Funda Meric-Bernstam, MD

New data on fam-trastuzumab deruxtecan-nxki (Enhertu) has maintained clinically meaningful and durable responses in patients with HER2-expressing advanced solid tumors, according to the primary analysis of the ongoing phase 2 DESTINY-PanTumor02 trial (NCT04482309).¹

The median progression-free survival was 6.9 months (95% CI, 5.6-8.0) and the median overall survival was 13.4 months (95% CI, 11.9-15.5) in the overall trial population.² The confirmed objective response rate was 37.1% and the median duration of response was 11.3 months (95% CI, 9.6-17.8) in these patients with HER2-expressing advanced solid tumors, including biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic tumors, as assessed by investigator.

Further, the safety profile of trastuzumab deruxtecan was consistent with what has been seen in previous clinical trials, and no new safety concerns were identified. Findings showed that the most common grade 3 or greater treatment-emergent adverse events included neutropenia (19.1%), anemia (10.9%), fatigue (7.1%), and thrombocytopenia (5.6%).

“With meaningful clinical activity, this could represent a new treatment option. If it becomes available, this is something that I think our oncologists will be able to pursue as a true testing option,” Funda Meric-Bernstam, MD, told Targeted Oncology^TM, in an interview.

Breast Cancer Cells: © LASZLO- stock.adobe.com

In the interview, Meric-Bernstam, chair of the Department of Investigational Cancer Therapeutics at MD Anderson Cancer Center, further discussed the phase 2 DESTINY-PanTumor02 trial and the data on fam-trastuzumab deruxtecan-nxki for the treatment of patients with HER2-low breast cancer, HER2-positive breast cancer, HER2-positive gastric cancer, and HER2-mutant lung cancer.

Targeted Oncology: Can you give a brief overview of the DESTINY-PanTumor02 trial?

Meric-Bernstam: This is a study looking at the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing advanced solid tumors. Trastuzumab deruxtecan is already known to be active as an antibody-drug conjugate [ADC] and we already know that it has efficacy in the setting of HER2-low, as well as HER2-positive breast cancer, and in HER2-positive gastric cancer, as well as lung cancer. Here, our question was, can we assess if trastuzumab deruxtecan [has] antitumor activity? We asked this question by enrolling patients that had advanced solid tumors.

Who was included in the study?

We enrolled patients that had HER2-expression that was either 3+ or 2+ using immunohistochemistry. Patients were enrolled either with a central test or local test. If a local test was used for enrollment, we did several tests for confirmation. We enrolled 6 different tumor types, and we also enrolled all tumors in another tumor basket that allowed for patients that had diseases other than those that we enrolled, as well as those that had breast cancer, gastric cancer, colon cancer, and lung cancer. Overall, we enrolled 276 patients.

Please explain the findings of the trial.

We showed that the investigator-assessed objective response rate, which was the primary end point, was 37%, and this is a heavily pretreated patient population with a median of 2 prior lines of therapy. In addition, we saw that these were durable responses. Patients had a median duration of response of 11.8 months, and the objective response rate was also confirmed with central review.

We looked across tumor types and we saw that there were responses across a variety of tumors with objective response rates that were especially compelling in the gynecological tumors, but also very clinically meaningful in patients with biliary cancer and bladder cancer. The 1 cohort where we had less tumor activity was in pancreatic cancer. That study arm was closed a little early at 25 patients. We had 1 investigator assess objective response, and we also had a central review which actually showed a 12% response rate with 3 responses. Notably, however, in that patient population, around 68% of the patients had stable disease as well. This is a study that was conducted internationally, and we saw that with this study, the safety was similar to what we know.

What are the next steps for this research?

This is exciting activity. Notably, we looked at not just the overall population, but we also looked at patients that had HER2-expression tested centrally. That biomarker analysis is further ongoing. However, we have reported out the central 3+ patient population, and the 2+ patient population, especially in patients that were IC3, we saw that the objective response rate was quite high, it was around 61%. Also, the durability was even greater. They had a duration of response of 22.1 months. In many tumor types, the objective response rate was greater than 50% in that IC3+ patient population. This represents significant antitumor activity for patients with HER2-expressing tumors.

Were any of these findings particularly exciting or surprising?

This study was notable for many reasons. First, the antibody-drug conjugate serves as a next-generation treatment modality, and there is a lot of excitement surrounding this already. This is the first pan-tumor ADC trial to show tumor agnostic activity, so that was notable. We were excited to see each activity across tumor types, but also notable is the durability. This study is ongoing, and further follow-up with progression-free survival and overall survival and the duration of response median had not been reached yet. But what we saw with the 1.8 months overall and 22.1 months, especially in the 3+ population, is very compelling.

Down the line, if these are positive findings, how do you feel this will influence the space?

With meaningful clinical activity, this could represent a new treatment option for patients that are HER2-expressing. If it becomes available, this is something that I think our oncologists will be able to pursue as a true testing option. Notably, we use IC which is much easier to do and should be accessible more broadly.

REFERENCES:

1. ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated clinically meaningful survival across multiple HER2-expressing advanced solid tumors in DESTINY-PanTumor02 phase II trial. News release. Astrazeneca. October 23, 2023. Accessed November 1, 2023. https://tinyurl.com/23w52akp

2. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41(suppl 17):LBA3000.