Trastuzumab Deruxtecan Represents Potential New Second-Line Standard in HER2+ Metastatic Gastric/GEJ Cancer

John Marshall, MD

Updated data from the phase 2 DESTINY-Gastric02 trial (NCT04014075) showed that fam-trastuzumab deruxtecan-nxki (Enhertu) elicited promising response rates as a second-line therapyin Western patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancer, further underscoring the need for molecular profiling to determine who are the best candidates to receive the antibody-drug conjugate (ADC), according to John Marshall, MD.

Results from the study presented during the 2021 ESMO Congress showed that among 79 evaluable patients, trastuzumab deruxtecan elicited an overall response rate of 38% (95% CI, 27.3%-49.6%); this was comprised of 3 complete responses (3.8%) and 27 partial responses (34.2%). Moreover, the median duration of response was 8.1 months (95% CI, 4.1–not evaluable), and the median progression-free survival was 5.5 months (95% CI, 4.2-7.3).

“This is a breakthrough in [that we saw a] very high response rate in [patients who received trastuzumab deruxtecan in later] lines [of] therapy,” Marshall said. “This is what we wanted to see: it is a potent HER2-targeted treatment. [These findings] further emphasize the need for all of us to have good molecular profiling on our patients with gastric cancer, so we know whether they are HER2 positive [and they can receive this treatment].”

In an interview with OncLive^®, Marshall, chief of the Division of Hematology/Oncology at Georgetown University Hospital, and associate director of Clinical Research at Georgetown Lombardi Comprehensive Cancer Center, discussed the results of the DESTINY-Gastric02 trial with trastuzumab deruxtecan in patients with HER2-positive gastric/GEJ cancer, the importance of molecular profiling, and future considerations for the ADC.

OncLive^®: To start, could you speak to the data we saw from the DESTINY-Gastric02 trial that read out at the 2021 ESMO Congress?

Marshall: We must [first] remember what the phase 2 DESTINY-Gastric01 trial [NCT03329690] showed. This was a randomized study looking at trastuzumab deruxtecan, which is as a monoclonal antibody of trastuzumab [Herceptin] that is enriched with a toxic, potent TOP1 inhibitor that binds to HER2 receptors.

[The agent] was first approved in breast cancer, and then tested in the DESTINY-Gastric01 study in gastric cancer, in second- and third-line [setting for patients with] HER2-positive disease [vs chemotherapy], primarily in an Asian population. [The study] showed [that treatment with trastuzumab deruxtecan led to] significant improvement in really all parameters and was the justification for the FDA approval in gastric cancer [in the United States].

The DESTINY-Gastric02 trial is an extension of that study, in the Western population. [The study examined patients with] metastatic HER2-positive gastric cancer who already had HER2-targeted treatments; they already received trastuzumab in the frontline setting, which is where our current indication is, and then they received trastuzumab deruxtecan in the second- or [later]-line setting.

The findings were that there was a significant response rate of 38%, and several complete responses [were observed]. This is a big deal because we have tried [many times] to do HER2 targeting after first-line therapy in gastric cancer, and we have never really shown anything that worked, so this was a breakthrough, in that regard.

How do these data compare with what has been reported with its use in the third-line setting?

In the third-line setting, in the Asian population, the response rates were in a similar ballpark. Essentially, [we saw a] consistency through [different] lines of therapy. In every case, there were patients who had only seen 1 prior HER2-targeted therapy, so it was not as if they had already received 2 or 3 lines.

Those data are consistent in both the second- and third-line [setting]. In Asia, interestingly, the approval [for trastuzumab deruxtecan] was only [for use] in the third-line setting, whereas in the United States the FDA [decided that it would be for use in the] second or third line. We have a bit of a distinction there, and the DESTINY-Gastric02 study supports that.

Do you foresee an approval for trastuzumab deruxtecan in the second-line setting across the board for this patient population? How might such an approval impact the treatment paradigm?

I fully anticipate having access to this medicine in this patient population, and I fully anticipate that it will become one of the new standards of care. Currently, our second-line therapies include single-agent taxanes, ramucirumab [Cyramza] and paclitaxel, or irinotecan. Those drugs are effective, and they do have a place in the treatment paradigm, but if [a patient] is HER2 positive, these results [with trastuzumab deruxtecan are] obviously going to be of more interest.

This not a non-toxic drug. This drug does have adverse effects [AEs], and one of the scarier ones, interstitial lung disease, is fortunately rare. However, it is not a perfectly simple [approach]. We sometimes consider biologics [to be] easier, but this is a combination of a biologic and a chemotherapy connected to it, so we are going to need to monitor these patients. However, with a response rate that approaches 40% in this patient population, those trade-offs will be in favor of trying the medicine.

The biggest [take-home] for me is that we now have [HER2-targeted treatment] beyond progression. After many trials, and failures, we now have that. What we will want to know [moving forward] is, do we have to re-biopsy? Are we going to need repeat profiling? This was not required in these studies, but some of the patients did have repeat testing. Increasingly, I believe we will have that as a standard, but for now, that is not a requirement.

We will learn more as we go forward as to who are the right patients to receive this HER2-targeted approach in the second- and third-line [settings].

Reference

1. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Primary analysis of a phase 2 single-arm trial of trastuzumab deruxtecan (T-DXd) in Western patients with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Ann Oncol. 2021;32(5): S1283-S1346. doi:10.1016/annonc/annonc741