Combination Approaches Are on the Horizon in Later-Line HER2+ Breast Cancer Management

Ado-trastuzumab emtansine (Kadcyla) plus tucatinib (Tukysa), as well as the phase 2 monarcHER trial (NCT02675231) regimen, are among potential future directions in the later-line treatment of patients with HER2-positive breast cancer who have previously received fam-trastuzumab deruxtecan-nxki (Enhertu) in the second line, according to Adrienne G. Waks, MD.

The monarcHER trial investigated the efficacy of fulvestrant (Faslodex), abemaciclib (Verzenio), and trastuzumab (Herceptin) in patients with hormone receptor (HR)–positive, HER2-positive breast cancer who had received at least 2 prior therapies. The median progression-free survival was 8.3 months (95% CI, 5.9-12.6) with the triplet vs 5.7 months (95% CI, 5.4-7.0) with standard-of-care chemotherapy plus trastuzumab.¹

In addition, the ongoing phase 3 HER2CLIMB-02 trial (NCT03975647) is investigating the efficacy and safety of tucatinib plus trastuzumab emtansine vs trastuzumab emtansine alone in patients with HER2-positive disease who have previously received trastuzumab or a taxane in any setting.²

“When we’re faced with a patient who’s asking us their likelihood of responding to [these agents] in the third, fourth, or fifth line, and how long their benefit will last from that regimen if they do benefit, we unfortunately don’t have those answers right now, and we need to get them,” Waks said in an interview with OncLive^®.

In the interview, Waks, associate director of Clinical Research at Dana-Farber Cancer Institute, as well as an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts, spotlighted the need to understand mechanisms of resistance to second-line HER2-positive breast cancer therapies, chemotherapy-free regimens with later-line treatment potential, and the future of HER2-positive disease management.

OncLive: What unmet research needs in the later-line management of HER2-positive metastatic breast cancer, if addressed, may fuel treatment developments for this patient population?

Waks: We’re using trastuzumab deruxtecan in the second line for many patients, and if not trastuzumab deruxtecan, then largely a tucatinib-based regimen. However, with few exceptions, we have little data on how any other regimens perform after trastuzumab deruxtecan and certainly after trastuzumab deruxtecan and tucatinib.

Regarding what we can expect and tell patients about how they will respond to [different] regimens in the later-line setting, we don’t have any data to [support] that we expect, [for instance], 6 months or 12 months [of survival]. That’s an important area for future investigation.

Tied into that, we are at an early point in understanding the mechanisms of resistance to trastuzumab deruxtecan. We have a bit more understanding of the mechanisms of resistance to TKIs, because those have been around longer. It will be important to understand how patients develop resistance to agents like trastuzumab deruxtecan, how we can figure that out in real time when we’re treating a patient clinically, and whether and how we should use that information to decide between our long list of options we have in the later-line settings.

What third- and later-line treatment options are available for patients with HER2-positive disease?

With those caveats, because we will still use these regimens even if we’re not sure exactly how they perform, a nice option to consider is margetuximab-cmkb [Margenza], a novel monoclonal anti-HER2 antibody in place of trastuzumab. I always describe margetuximab to patients as [an agent that’s] trying to be an immunologically supercharged version of trastuzumab; it’s trying to be more immune activating then trastuzumab. We all get to a point with our patients with HER2-positive metastatic disease where we partner a chemotherapy agent that we know is active with an anti-HER2 antibody. Once you get to that point, substituting in margetuximab makes sense at one point or another.

A nice option for patients with HR-positive and HER2-positive disease is the triplet regimen that was studied in the monarcHER trial, which was fulvestrant, abemaciclib, and trastuzumab. Those weren’t registrational data. This was not a phase 3 trial. Nonetheless, these are all FDA-approved agents in their own rights. The triplet regimen looked tolerable, and it’s a nice option because it is completely chemotherapy-sparing; there’s only the CDK4/6 inhibitor, the endocrine therapy, and the anti-HER2 therapy. This is attractive because in many cases, these patients have been on pure chemotherapy with different targeted agent combinations for many years that being able to offer a chemotherapy-sparing [regimen] at some point is always a nice idea.

Then, we have trastuzumab emtansine, which is at this point the oldest available antibody-drug conjugate. With HER2CLIMB-02, maybe we’ll see that we can combine trastuzumab emtansine with tucatinib and get efficacy there. We don’t know yet how that will look. Then, we have other HER2-directed TKIs like neratinib [Nerlynx] that can also be used in the later-line settings, though again, we don’t know how those will perform after tucatinib and especially after tucatinib and trastuzumab deruxtecan.

What upcoming or ongoing clinical trials may have the biggest effect on the HER2-positive treatment landscape?

The 1 that most of us will wait for with the most anticipation is the [phase 3] DESTINY-Breast09 trial [NCT04784715], because that’s a first-line trial. Currently, trastuzumab plus pertuzumab [Perjeta] and a taxane [THP], the [phase 3] CLEOPATRA trial [NCT00567190] regimen, has been our standard in the first line for many years and remains our standard there, even as we make changes in the later lines. DESTINY-Breast09 is evaluating trastuzumab deruxtecan plus or minus pertuzumab compared with THP in the first-line setting.

That will be totally paradigm shifting if it reads out and shows that trastuzumab deruxtecan with or without pertuzumab is the winner compared with THP, because that would supplant our current first-line therapy. [Importantly], that trial is still enrolling, and these patients stay on these regimens for a long time, so we’re probably several years away from knowing whether that will change our practice. However, it will be important when it [reads out].

Another [important factor] will be tolerability. Alongside the efficacy results we see from that trial, it will be important to see how patients tolerate potentially long-term use of a drug like trastuzumab deruxtecan in the first line. Right now, we tell patients they will receive approximately 6 cycles of taxane chemotherapy and then get onto a nice antibody maintenance phase, which I think patients appreciate because there’s not as much long-term toxicity. Understanding how an agent like trastuzumab deruxtecan might fit into that landscape long-term and change that landscape regarding the adverse effect burden for patients will be interesting and important. That’ll be exciting but is many years away.

References

1. Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(6):763-775. doi:10.1016/S1470-2045(20)30112-1
2. A study of tucatinib vs. placebo in combination with ado-trastuzumab emtansine (T-DM1) for patients with advanced or metastatic HER2+ breast cancer. ClinicalTrials.gov. Updated July 18, 2023. Accessed July 18, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT03975647