Adam M. Brufsky, MD, PhD, further discusses the utility of trastuzumab deruxtecan in HER2-positive breast cancer, ongoing research efforts examining the antibody–drug conjugate, and how he approaches sequencing in the paradigm.
Fam-trastuzumab deruxtecan-nxki (Enhertu) is a treatment paradigm–altering agent available for patients with HER2-positive breast cancer, although it must be monitored closely due to adverse effects (AEs), such as interstitial lung disease (ILD), according to Adam M. Brufsky, MD, PhD.
The December 2019 FDA approval of trastuzumab deruxtecan was based on data from the phase 2 DESTINY-Breast01 trial (NCT03248492), in which the antibody-drug conjugate (ADC) had resulted in a progression-free survival rate of 16.4 months in patients who were heavily pretreated with ado-trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-targeted treatments.1
Results from a subgroup analysis presented during the 2020 ASCO Virtual Scientific Program showed that the ADC continued to show strong clinically significant objective response rate (ORR) and durable responses in all clinical subgroups evaluated.2 Specifically, the ORR with the ADC was 60.9% (95% CI, 53.4%-68.0%), the median progression-free survival was 16.4 months, and the median duration of response was 14.8 months.
The ADC also showed continued benefit in patients with HER2-positive breast cancer who had stable, treated brain metastases at baseline in a subgroup analysis of the DESTINY-Breast01 trial presented during the 2020 ESMO Breast Cancer Virtual Meeting. The analysis of the central nervous system also showed a consistent safety profile when compared with the overall population.
The next steps for this research will be the phase 3 DESTINY-Breast03 trial (NCT03529110) will compare the antitumor activity, safety, and efficacy of trastuzumab deruxtecan versus T-DM1 in patients with HER2-positive, unresectable and/or metastatic breast cancer. “I believe [the trial] has completed accrual, but nonetheless, this is a paradigm-changer for us in terms of how we think about ADCs in this disease,” noted Brufsky. Additionally, the DESTINY-Breast 04 (NCT03734029) will examine the ADC versus investigator’s choice of standard treatment in patients with HER2-low breast cancer that has spread or is unresectable.
“[This is] a disease that, 20 years ago, was universally devastating. We didn’t have trastuzumab back then and we couldn’t really do much [for our patients],” said Brufsky. “Now, it's 2 decades later and we're having discussions on what the best third-line therapy is for [this disease]. We see about one-third of women living about 8 years. We're getting a much better understanding of what HER2-positive metastatic disease is, and when you start to discuss what the best third-line treatment for a particular disease entity is, you know you've made progress.”
In an interview with OncLive, Brufsky, a professor of medicine, associate chief of the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer Center, and associate director of clinical investigation at the University of Pittsburgh Department of Medicine, further discussed the utility of trastuzumab deruxtecan in HER2-positive breast cancer, ongoing research efforts examining the ADC, and how he approaches sequencing in the paradigm.
OncLive: How has the DESTINY-Breast01 trial impacted the HER2-positive breast cancer treatment paradigm in the metastatic setting?
Brufsky: [Results are] really going to change [the treatment paradigm] dramatically. Even though it's a phase 2 trial, we have to take the results with a grain of salt because it is not a randomized [trial]. The overall PFS was around 16.4 months and the median survival had not been reached. This is a group of patients who have been heavily pretreated and had trastuzumab- and pertuzumab (Perjeta)-based therapies, as well as T-DM1-based therapies. To see such a dramatic improvement is pretty impressive. Now we [need to] wait for the randomized study to come out, which is [the phase 3] DESTINY-Breast03.
What are your thoughts on the safety profile of the agent?
There's a lot of attention being paid to ILD. In a gastrointestinal trial [examining the agent, investigators] carefully monitored this and they found a treatment discontinuation rate of around 7.4% or 7.6%; no toxic deaths [were reported]. [Initially,] the toxic death rate was about 2.2% in the breast trials and that was because we really didn't know what was going on. Now, we're much more aware of [these toxicities, and] if [a patient] gets shortness of breath at any time that they’re on trastuzumab deruxtecan, we know that we have to stop [treatment] and do a CT [scan]. If there is visual evidence of ILD, we need to start [the patient on] steroids immediately and get pulmonary involved. Now that we're doing that, the hope is that the toxic death rate will continue to be very low with this agent, especially as we start doing these larger trials with the drug.
How did the activity of trastuzumab deruxtecan hold up in the subgroup analyses that we saw at this year’s ASCO and ESMO Breast meetings? What other research is being done with this agent?
Not unsurprisingly, [the data with the agent] held up perfectly. I don’t believe there was a subgroup that didn't have a substantial response rate benefit. The only subgroup [in whom the response rate to the ADC] was a little bit [lower] were those who were HER2 1+ or 2+, even though they had to be FISH-positive. That is very encouraging for the DESTINY-Breast04, which [will examine the agent in a] HER2-low [population]. Investigators are now evaluating trastuzumab deruxtecan in a randomized trial in patients with estrogen receptor–positive breast cancer or triple-negative breast cancer with low HER2 expression. It’s going to be really exciting to see those data.
There are also very encouraging phase 1b/2 data from Daiichi Sankyo that suggest there is going to be a reasonable response in the 40% to 50% range with this agent. Again, those patients in that trial, just like the DESTINY-Breast01 trial, were heavily pretreated. It's really encouraging to see those data and to understand that there may be some randomized data in the near future that could be very promising.
Have any sequencing concerns come up within the past year with the approvals of neratinib (Nerlynx) and tucatinib (Tukysa)?
Fifty percent of patients within the later lines of HER2-positive metastatic breast cancer are going to develop brain metastases. It's very interesting to figure out what to do [for these patients]; for them, I will predominantly give TKI-based drugs, either tucatinib or neratinib. The major difference between tucatinib and neratinib, at the end of the day, is not going to be efficacy, but rather toxicity. How we manage the toxicity [associated with these agents is important]. The toxicity observed with neratinib can actually be quite manageable if you pay a lot of attention to dose escalation—in other words, start low [then] go high—and use a lot of antidiarrheals. Diarrhea [that stems from the use of] neratinib is [now] controllable. Nonetheless, tucatinib has some benefits in that it doesn't bind to the EGFR. As a result, patients should experience less diarrhea with these 2 drugs.
When a patient comes in with chronic brain metastasis progression, I'll probably reach for tucatinib. I can also reach for tucatinib and maybe neratinib if the patient doesn’t want to lose their hair because many patients [experience that] with trastuzumab deruxtecan. However, if [I’m seeing a patient with] predominantly systemic progression, I'll probably reach for trastuzumab deruxtecan.
The good thing is that most patients with HER2-positive metastatic disease are probably going to live long enough to receive [all options]. I'm not sure at the end of the day whether [one is better to start with than the other]; we won't know [until we] see the studies with real-world data on this, which will take a few years. Although this is how I am managing it right now, this approach may change as we see more data with both agents.
Was there anything else that you wanted to emphasize?
We didn't have trastuzumab back then and we really couldn't do much [for our patients]. Now, we see one-third of the women with the disease living almost 8 years; that is probably the most encouraging thing I have seen around all these discussions we've been having.