Trastuzumab Deruxtecan, Tucatinib Generate Excitement in Metastatic HER2+ Breast Cancer

The regulatory approvals of fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa) have significantly moved the needle in the realm of HER2-positive breast cancer treatment, according to Erika P. Hamilton, MD, who added that other emerging agents, such as CDK4/6 inhibitors and bispecific antibodies are also generating excitement in the space.

In December 2019, trastuzumab deruxtecan was granted an accelerated approval from the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting. The decision was based on data from the phase 2 DESTINY-Breast01 trial, which showed that the antibody-drug conjugate (ADC) resulted in a confirmed objective response rate (ORR) of 60.3% per independent central review.¹

Tucatinib also joined the list of approved agents in this setting in April 2020, when the FDA approved it for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) in patients with unresectable locally advanced or metastatic HER2-positive disease, including those with brain metastases, following 1 previous anti–HER2-based therapy in the metastatic setting.

The approval was based on findings from the phase 2 HER2CLIMB trial, which showed that the triplet led to a 34% reduction in the risk of death in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive disease.^2,3 Updated data presented during the 2020 ASCO Virtual Scientific Program showed that the tucatinib triplet also significantly improved response rates and showed a 68% reduction in the risk of central nervous system progression-free survival in those with brain metastases.⁴

“We’ve made several advances in HER2-positive metastatic breast cancer over the past couple of years. A few notable drugs are neratinib (Nerlynx), trastuzumab deruxtecan, and tucatinib. Moving forward, we must think about optimal sequencing our therapies. Oftentimes, pertuzumab (Perjeta) and T-DM1 are used in both the neoadjuvant and adjuvant settings, respectively,” Hamilton explained. “This underscores the fact that although we have great drugs in the HER2 setting, we still need more.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer on Breast Cancer, Hamilton, director of the Breast Cancer and Gynecologic Cancer Research Program and principal investigator at the Sarah Cannon Research Institute, discussed the pivotal data that led to the approvals of trastuzumab deruxtecan and tucatinib in metastatic HER2-positive breast cancer, factors considered in terms of treatment selection, and emerging agents under exploration.

OncLive: Could you shed light on new therapies in the HER2-positive breast cancer space?

Hamilton: Currently, there are 2 drugs in the HER2-positive metastatic space that everyone is talking about, both of which were recently approved: trastuzumab deruxtecan and tucatinib. Trastuzumab deruxtecan is an ADC, which we're all familiar with; this is not unlike T-DM1, although, it does have some differences. Tucatinib is a TKI, another a class of molecules that we're familiar with. However, unlike neratinib and lapatinib (Tykerb), tucatinib is specific and blocks only HER2; it does not block HER1 or EGFR. This translates to less rash and diarrhea and interesting data with this drug have been released with regard to brain metastases.

What are some of the data that have read out with trastuzumab deruxtecan?

This agent was analyzed in a heavily pretreated patient population. It was examined in the single-arm DESTINY-Breast01 trial and because of the incredible activity observed, the ADC was approved. Patients received a median of 6 prior lines of therapy but in that setting, they saw an ORR of over 60%. Additionally, over 90% of patients experienced tumor shrinkage while on the drug.

The median duration of response to the agent was really quite impressive, at about 14.8 months, and the median progression-free survival (PFS) was 16.4 months. These patients who received the drug did quite well for some time.

The biggest adverse effect (AE) that we worry about with trastuzumab deruxtecan is interstitial lung disease, which is sometimes referred to as pneumonitis; that occurred in over 13% of patients on the trial. Unfortunately, in about 2.2% of patients, this effect proved to be fatal. We are very in tune with this and monitor our patients closely [for this toxicity].

How is trastuzumab deruxtecan being explored in the HER2-low setting?

A lot of data have been presented here and they have been really impressive. This is not the first time we've looked at HER2-low disease. A couple of years ago, we saw trastuzumab deruxtecan data in this setting and those data were negative. This truly speaks to the mechanism of trastuzumab deruxtecan; it’s a unique molecule that has a lot of power behind it.

In the HER2-low space, trastuzumab deruxtecan has a bystander effect. Even if just a little bit of trastuzumab deruxtecan binds, it can kill other cells around the cell that may not have much HER2 expression at all. We've seen quite impressive response rates in this space. We're even participating in some of those trials at Sarah Cannon Research Institute. Another exciting point is that the minority of patients have HER2-overexpressing disease, meaning amplified or 3+. There are a lot more patients who are 1+, 2+, and FISH negative, so I’m excited about how many patients that may reach.

What were the findings that led to the approval of tucatinib?

This decision was based on the HER2CLIMB trial, which randomized patients to either the combination of capecitabine, trastuzumab, and placebo or capecitabine, trastuzumab, and tucatinib. These were third-line patients who had previously seen taxane, trastuzumab, and pertuzumab in the first-line setting, and then T-DM1; this was a common third-line trial. Patients who received tucatinib] experienced benefit with regard to PFS [in the overall population] and in those with brain metastases, overall survival (OS), and ORR. Those data are not new.

Newer data presented during the 2020 ASCO Virtual Scientific Program were focused on patients with brain metastases who were enrolled on the trial; they were split into different categories. HER2CLIMB was different in the fact that investigators didn't only allow the enrollment of patients with stable, treated brain metastases; they also permitted those with untreated, asymptomatic brain metastases or treated and then progressive brain metastases.

These patients were grouped into 2 categories: the active group consisted of patients who had untreated or treated and then progressive metastases, while the stable group consisted of stable, treated metastases. About 40% of patients were stable and about 60% had active disease. In those patients with active brain metastases, we saw an improvement in PFS, going from 4.1 months to 9.5 months. We also saw an improvement in OS, going from 11.6 months up to 20.7 months. In a very challenging subset of patients with very aggressive disease and active brain metastases, this was incredibly encouraging.

Most of the AEs we see with tucatinib really come from the backbone of capecitabine, with the most common toxicities being diarrhea and hand-foot syndrome. We also have to watch out forliver function abnormalities, but [patients who experience these effects] are typically asymptomatic and can be managed with dose holds or reductions.

What does your current treatment algorithm look like with these new therapies?

The current treatment algorithm is a little bit tricky. I don't believe there is an 100% right answer in the third-line space. I make my decision based on each individual patient. If someone has brain metastases, we have to remember that tucatinib is actually approved even in the second line and beyond, not just in the third-line setting. As such, if a patient presents with brain metastases, I would be inclined to use tucatinib whenever I could, whether that’s in the second or third lines of treatment.

In the absence of that, I take a few other factors into consideration. When treating a patient with lung disease, I would avoid trastuzumab deruxtecan. However, if a patient is in visceral crisis, or if we only have 1 shot to get a response in a patient, I would probably use trastuzumab deruxtecan just because the ORR is so impressive. Similarly, if someone does not have an incredibly high burden of disease and they're doing pretty well, I would probably use the tucatinib regimen.

It’s not a one-size-fits-all answer for our patients; it’s going to take more of a conversation with the patient in addition to assessing some of the subtle differences in their presentation to optimally decide between these drugs.

Looking at investigational agents, what are your thoughts on CDK4/6 inhibitors?

This area of research is very exciting. I believe we may have done a disservice by classifying all patients with HER2-positive disease as HER2, and ignoring whether they are hormone receptor positive or not. Over the past couple of years, we've seen some exciting data with CDK4/6 inhibitors or aromatase inhibitors in combination with HER2 agents. I find these [data to be] very encouraging. For a patient with estrogen receptor–positive disease, a hormonal backbone may make a lot of sense than just using chemotherapy.

Are any other exciting agents emerging in this space?

Some new agents, such as new ADCs, are being developed by several companies. Bispecific antibodies are also emerging, and these come in a couple of different flavors. We have the bispecific antibodies that bind to extracellular domains 2 and 4; this is essentially a combination between pertuzumab and trastuzumab. We also have bispecific molecules that bind to HER2 on 1 side and then bind to a component of the immune system on the other side, so this is almost targeted immunotherapy to the HER2 cell. I believe that's a really novel mechanism of action and 1 that I'm quite interested in.

What is the biggest unmet need that you hope to see addressed with future research efforts?

It's hard to say that there's a bigger unmet need than brain metastases. For patients with metastatic HER2-positive disease, we know that up to 50% will go on to develop brain metastases at some point in their lifetime. I'm particularly excited about tucatinib, not only where it's approved right now, but [I would love] to see whether we can incorporate it into earlier lines of therapy to prevent brain metastases. This is important, rather than just being reactionary and treating patients when something is wrong, [we would be able to take action beforehand].

References

1. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. December 20, 2019. Accessed August 27, 2019. https://bit.ly/2tzcabv.
2. Murthy R, Loi S, Okines A, et al. Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-01.
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. 2020;382(7):597-609. N Engl J Med. doi:10.1056/NEJMoa1914609
4. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005