Trastuzumab Deruxtecan May Represent Potential Option for HER2-Expressing Solid Tumors

Clinically meaningful responses were broadly observed with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) across advanced HER2-expressing solid tumor types in the phase 2 DESTINY-PanTumor02 trial (NCT04482309). These data suggest that this agent could provide a new therapeutic option for patients who have historically difficult-to-treat diseases and lack effective targeted treatments, according to Funda Meric-Bernstam, MD.

Interim results presented at the 2023 ASCO Annual Meeting showed that in the overall population (n = 267), patients treated with T-DXd experienced an objective response rate (ORR) of 37.1% with a median duration of response (DOR) of 11.8 months (95% CI, 9.8-not evaluable). The 12-week disease control rate (DCR) was 68.2%.

When broken down by tumor type, patients with cervical (n = 40), endometrial (n = 40), ovarian (n = 40), biliary tract (n = 41), bladder (n = 41), pancreatic (n = 25), and other (n = 40) cancers experienced ORRs of 50.0%, 57.5%, 45.0%, 22.0%, 39.0%, 4.0%, and 30.0%, respectively.

“We’ve seen that patients, across tumor types, who have HER2 expression may be sensitive to T-DXd,” said Meric-Bernstam in an interview with OncLive®. “[As such,] this may be a new treatment option for patients who [have] HER2-expressing [tumors].”

Meric-Bernstam is chair of the Department of Investigational Cancer Therapeutics–the Phase I Program, medical director of the Institute for Personalized Cancer Therapy (IPCT), and the Nellie B. Connally Chair in Breast Cancer at the University of Texas MD Anderson Cancer Center, in Houston, Texas.

In the interview, Meric-Bernstam discussed the design of the DESTINY-PanTumor02 trial, detailed the antitumor activity and safety of T-DXd in HER2-expressing solid tumors, and shared additional analyses that will be coming down the pike.

OncLive: Please summarize the rationale for investigating T-DXd in hard-to-treat, HER2-positive solid tumors in the DESTINY-PanTumor02 study.

Meric-Bernstam: T-DXd is a potent antibody-drug conjugate that’s already in use for patients who have HER2-low or HER2-overexpressing breast cancers, HER2-positive gastric cancer, and HER2-mutant lung cancer. Several other tumor types express HER2, so there’s an interest to see whether T-DXd [has] antitumor efficacy in these other tumor types.

When the early-phase clinical trials were being done with T-DXd, an efficacy signal was seen in tumor types such as salivary cancer, endometrial cancer, and biliary tumors. Thus, this phase 2 study was conducted [to determine] whether we will see antitumor activity [with T-DXd] if we specifically select patients [whose tumors] are [classified as HER2] 3+ or 2+ using immunohistochemistry [IHC].

What is the design of the study, and which tumor types were evaluated?

This is an interesting study design. We had disease-specific cohorts, as well as a basket cohort. [Specifically,] we had 6 disease-specific cohorts. We had 3 gynecological tumor cohorts, [consisting of] patients with cervical cancer, endometrial cancer, and ovarian cancer. We had 2 gastrointestinal cohorts, [including] patients with biliary tumors and pancreatic tumors, and we had a bladder cancer cohort. In addition, we had a basket cohort of other tumors. [For the basket cohort,] we excluded the tumor types listed [above], and excluded breast cancer, gastric cancer, lung cancer, and colon cancer. Thus, [the trial involved] both the basket and disease-specific assessments in diseases where HER2 expression was already known to be more frequent.

What efficacy findings from this trial were presented at the 2023 ASCO Annual Meeting? How did the agent’s activity vary by tumor type?

We presented [data on] the primary end point, which was investigator-assessed ORR, as well as some of the secondary end points, which included DOR and DCR. It was quite notable that we had responses across tumor types. Of the 267 patients enrolled, our ORR was [37.1%]. These were durable responses; the [overall] median DOR was 11.8 months. For the overall patient population, the ORR by [independent central review] was also found to be [about] 37%.

We also looked across tumor types and found several tumor cohorts that had quite high ORRs, especially the patients who had gynecological diseases. Almost all cohorts had clinically meaningful response rates.

The 1 cohort that experienced the least activity [with T-DXd] was the patients with pancreatic cancer; this wasn’t as much of a surprise because that’s a challenging disease. We had 1 [response] out of 25 by investigator assessment, and 3 [responses] based on central review. In the pancreatic cancer cohort, [patients] had a stable disease rate of 68%.

What adverse effects (AEs) were observed with T-DXd? Does the safety profile of this agent appear to differ by tumor type?

We’re going to do a deeper analysis over the next several months, but the overall safety profile that we saw was very similar to what we’ve previously observed with T-DXd. The most common grade 3 or greater AEs were neutropenia and anemia. One of the AEs we always worry about with T-DXd is interstitial lung disease [ILD]. When the drug was initially developed, it took some time for oncologists to learn how to manage [this AE], but now, a lot of people are very familiar with how to [do this].

[In our study], we had a 7.5% ILD rate, and most of these [cases] were low grade. However, we did have 1 ILD-related death. We want to continue to highlight the importance of education and monitoring patients [with HER2-expressing tumors who receive this agent] for low-grade ILD.

Looking to the future, what next steps are planned for this research?

We presented this interim analysis highlighting the overall ORR, but we also have already done a central assessment of IHC. One of the important things that we found is that the ORR was especially high in patients whose tumors highly expressed HER2. The ORR in patients [whose tumors] were [HER2] 3+ centrally confirmed was 61%. These were even more durable responses, [with] a median DOR of 22.1 months.

We will continue to assess the antitumor activity [of T-DXd] with further follow-up, reviewing overall survival and progression-free survival. We are also going to do an additional biomarker analysis, where we will look at some variability in concordance with central and local assessment. We’ll be examining the role of amplification using in situ hybridization as well as circulating tumor [DNA].

Reference
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.