Krop Highlights Durable Activity With ADC in HER2+ Breast Cancer

Ian E. Krop, MD, PhD

Trastuzumab deruxtecan (Enhertu) demonstrated efficacious and durable responses in later-line patients with HER2-positive metastatic breast cancer, according to Ian E. Krop, MD, PhD. Although the agent is associated with primarily manageable, low-grade adverse effects (AEs), the development of interstitial lung disease (ILD) can be problematic for some patients, which requires optimal management.

The FDA granted fam-trastuzumab deruxtecan-nxki an accelerated approval in December 2019 for the treatment of patients with metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. Findings from the phase 2 DESTINY-Breast01 trial were the basis for this approval.

In DESTINY-Breast01, trastuzumab deruxtecan demonstrated an objective response rate (ORR) of 60.9% (95% CI, 53.4%-68.0%) and a median progression-free survival (PFS) of 16.4 months (95% CI, 12.7 months-not reached) in this patient population.^1,2

“This was a very heavily pretreated population—there was a median of 6 prior lines of therapy in the metastatic setting for these patients. Despite that, there was an ORR of about 60% and the responses were durable,” said Krop. “The overall median duration of response was over 14 months, and the median PFS was about 16 months, which were numbers that we really haven't seen before in other trials with pretreated HER2-positive disease. Those were the standout characteristics. 

Updated data indicated that the agent is also effective in patients who had experienced prior brain metastases. Patients with brain metastases (n = 8) experienced an ORR of 58.3% (95% CI, 36.6%-77.9%) and a median PFS of 18.1 months (95% CI, 6.7-18.1).

Moreover, ILD was identified in 13.6% of patients, and were grade 1/2 in 10.9%, grade 3/4 in 0.5%, and grade 5 in 2.2%.3 The 4 deaths were attributed to ILD by independent adjudication and were initially reported as respiratory failure, acute respiratory failure, lymphangitis, and pneumonitis in 1 patient each by the treating investigators.

In an interview with OncLive, Krop, an associate professor of medicine with Harvard Medical School; associate chief, Division of Breast Oncology with Susan F. Smith Center for Women's Cancers; and a medical oncologist and clinical research director with the Breast Oncology Center at Dana-Farber Cancer Institute, discussed these pivotal data, the need for longer-term follow-up, and the proper management of ILD.

OncLive: How has the FDA approval of trastuzumab deruxtecan impacted the HER2-positive breast cancer treatment paradigm?

Krop: We've all been looking for effective therapies for patients with HER2-positive advanced breast cancer who have progressed on our standard-of-care agents, such as trastuzumab (Herceptin), pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). In the past, we've basically been using trastuzumab with other chemotherapies in those third-line and later line patients. There were options [in that setting], but they didn't tend to work very well; [other agents have had] relatively low response rates—typically less than 20%—and pretty short PFS. Trastuzumab deruxtecan has very nice characteristics in terms of its efficacy, benefitting the vast majority of patients, [who then experienced an] ORR of over 60% and a clinical benefit rate over 70%; it is very helpful in [the HER2-positive] setting. Plus, the responses tended to be durable, so it provided a very effective option for these later-line patients.

What some additional findings from the DESTINY-Breast01 trial?

[When] we look at the toxicity for most patients, there are typically some gastrointestinal toxicities, with nausea and vomiting being common, but these were almost all of low grade. In practice, they're quite manageable with our typical antiemetic regimens. About half the patients lost at least some of their hair, so that can be distressing for some. We have been exploring whether you can use things like cold caps to prevent that, but we don't we don't have any data on that yet. Neutropenia was seen, but again, mostly low grade and febrile neutropenia was very unusual in about 2% of patients. Myelosuppression is not a big issue with this drug for most patients.

The one important AE to recognize, which was seen in both the phase 1 study and in this trial, was that pneumonitis or ILD can happen with this agent. In the DESTINY-Breast01 trial, it occurred in about 13% of patients. Four patients, or 2% of patients, died of pneumonitis, which was felt to be related to the drug. Clearly, this is an important toxicity that both the providers, as well as the patients, need to be aware of. Patients need to be told that if they have symptoms of pneumonitis, such as dyspnea, fever, or cough, they need to let [their physician] know so that they can be evaluated. If you, as a provider, suspect pneumonitis, the drug should be held, the patient should be evaluated, and if pneumonitis does appear to be the cause, then steroids should be started. 

Are the safety data seen in the trial similar to what is being observed in clinical practice?

I don't think we've seen any surprises. We obviously were involved in the trial, so we've been using the drug for a few years. We actually were involved in the phase 1 trial as well, so we're pretty comfortable with the drug and, in practice, the toxicities are generally quite manageable.

The only point that is paramount to get out to [patients] as they start to use this agent is to be aware of the pneumonitis; just as we have to be cognizant of [toxicities] with immune checkpoint inhibitors, it's important here, as well. In addition to the symptoms that patients need to be reminded to report back on, you can also typically see radiographic changes associated with pneumonitis. Often, it can be picked up as part of routine staging. With any new toxicity found in a new drug, we, as providers, need to learn about it and be comfortable with it. That's going to go a long way in terms of preventing serious sequelae from this AE.

How does the clinical activity hold up across various subgroups?

There were a couple of interesting findings, both at the 2020 ASCO Virtual Scientific Program this year, as well as the 2020 ESMO Breast Cancer Virtual Meeting. The 2 things [of importance] were that if you look at the subgroups by line of prior therapy, there certainly was good activity across all lines of therapy. It did look like there were perhaps even greater levels of activity in very early line patients with response rates over 70% in that group. Even if you go out to [those with multiple lines of therapy], there still was a very high response rate. That uniformity of response doesn't seem to be greatly affected by the line of treatment.

Another interesting point that was presented at these meetings was just further reinforcing that this drug, at least in the limited data we have, seems to be effective in patients with brain metastases. This is relevant, particularly in HER2-positive disease, because brain metastases are such a common manifestation of this disease. The response rate in the patients who had brain metastases was essentially the same as the overall population at 58%. The median PFS in those patients was 18 months.

An important new piece of data was that the number of patients who developed progressive brain metastases while on the study was very low; about 1% of patients who didn't have brain metastases at baseline and a small percentage of patients who did had progression in the CNS. It certainly does suggest that the presence of brain metastases, at least treated brain metastases, doesn't compromise the efficacy of trastuzumab deruxtecan. It suggests that we now can further explore how this drug can work in the brain.

One of the questions that I was asked at the 2019 San Antonio Breast Cancer Symposium was, “Why didn't we allow patients who had progressive brain metastases on the trial?” The reason was that we, at that point, had no data on the efficacy of the drug in patients with brain metastases, so we didn't think it was safe to allow patients with progressive disease onto the study.

Now that we do data supporting efficacy in patients with stable brain metastases, and at least relatively low rates of progression in the brain while on trial, that opens the door to further exploration as to how this drug could work in patients with progressive brain metastases.

What would you like to see with longer follow-up?

[Questions regarding sequencing and combination regimens] are important. Can you get even more efficacy from this drug if you move it into less pretreated populations? There are certainly interesting combinations. There's already a trial going on right now combining the antibody-drug conjugate with an immune checkpoint inhibitor. There's a lot of interest in combining [trastuzumab deruxtecan] with a TKI since there are certainly other data suggesting combinatorial activity with antibody-based HER2 therapies plus TKIs. Then, of course, as we like to do with any drug that looks very efficacious in the metastatic setting, we wonder whether this drug prevent recurrences in the early disease setting? There are trials under way to look at that, as well.

This drug also now has impressive data in other types of cancer, such as gastric, colon, and lung cancers that express HER2. There are plenty of opportunities for this drug to hopefully improve outcomes across a number of cancer types.

Is there anything regarding trastuzumab deruxtecan that you wanted to emphasize?

There are phase 3 trials underway now looking at trastuzumab deruxtecan compared with TDM-1 in the second-line setting. There's a confirmatory trial comparing it with

physician's choice of HER2-directed therapy in the third- and later-line settings. We will have more data in large data sets about this drug and then hopefully we can learn more about how the pneumonitis plays out now that people are aware of it. And, in a head-to-head comparison, how does it look [compared with] our current standards?

References

1. Modi S, Andre F, Krop IE, et al. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. J Clin Oncol. 2020;38(suppl 15; abstr 1036). doi:10.1200/JCO.2020.38.15_suppl.1036
2. Jerusalem G, Park YH, Yamashita T, et al. TCNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(suppl 2; abstr 138O). doi:10.1016/annonc/annonc122
3. Modi S, Saura C, Yamashita T, et al. trastuzumab deruxtecan in previously treated her2-positive breast cancer. N Eng J Med. 2020;382:610-621. doi:10.1056/NEJMoa1914510