Innovations in the Treatment of HER2+ Breast Cancer

Komal Jhaveri, MD, FACP

Major advances have been made in the HER2-positive breast cancer space in both the first-line and later-line settings.

First, in 2015, the results from the CLEOPATRA trial (NCT00567190) showed that adding pertuzumab (Perjeta) to trastuzumab (Herceptin) and docetaxel could significantly prolong overall survival (OS) compared with placebo. The median OS observed with the experimental combination in CLEOPATRA was 56.5 months. Another important survival end point in the HER2-positive breast cancer space is progression-free survival (PFS) which was shown to be significantly improved with the use of the irreversible pan-HER tyrosine kinase inhibitor neratinib (Nerlynx) in combination with capecitabine compared with lapatinib plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; stratified log-rank P = .0059) in the NALA study (NCT01808573). Notably, this result was seen among past with central nervous system (CNS) disease.

Another practice-changing clinical trial was HER2CLIMB (NCT02614794) which investigated tucatinib (Tukysa) versus placebo in combination with capecitabine and trastuzumab in patients with advanced disease. In the study, tucatinib was shown to improve both PFS and OS in the overall population as well as in patients with brain metastases compared with the control.

Kinase inhibitors such PI3K agents have also improved survival for many patients. Upcoming clinical trials may offer more insight into their uses in the earlier and later line settings.

In an interview with Targeted Oncology, Komal Jhaveri, MD, FACP, a medical oncologist at Memorial Sloan Kettering Cancer Center, discusses HER2-positive metastatic breast cancer innovations, treatments, and upcoming studies.

What is the first consideration that should be made when you meet a patient with metastatic HER2-positive breast cancer?

I think when you're meeting a patient with metastatic HER2-positive breast cancer, we're thinking about treatment in the first-line [setting] with a taxane in combination with trastuzumab and pertuzumab based on the unprecedented overall survival and progression-free survival benefit we've seen with a CLEOPATRA-like regimen, which is a taxane backbone with trastuzumab and pertuzumab. That's what we would do for our first-line patients when we go to meet them in clinic.

Do you outline a patient's expected treatment course in that initial visit? Or is it really just about that first-line therapy?

We first focus on the first-line therapy. It's very overwhelming for a patient who's newly diagnosed, including if it's de novo, metastatic, and even more so with a patient has already had early-stage disease and has now become recurrent. It's very devastating for them to hear that now, the actual goal for therapy is really additive and not necessarily curative. I think we focus predominantly on such a wonderful benefit that we've seen in the first-line [setting] with a taxane and so many patients stay on the therapy for such a long time. We usually try and keep the chemotherapy backbone until the maximum response, which is about 6 to 8 cycles, with docetaxel (Taxotere) for 6 months with weekly paclitaxel (Taxol) and then we continue maintenance. I think we predominantly focus on that, but we reassure them that there are multiple HER2 therapies that are now available in the therapeutic armamentarium for them and that this is not what it used to be a few years ago when we did not have these options for them.

Are there specific tests that can help structure a patient's treatment course? And if so, when are they typically implemented?

We focus predominantly still on a combination from the metastatic site at the time of metastatic diagnosis of estrogen receptor (ER), progesterone receptor (PR), and HER2. There are some data that we utilize from say next-generation sequencing (NGS), perhaps to guide our therapies if there were appropriate options. For example, currently, there is a new trial that is evaluating the role of maintenance, to PI3K inhibitor, even for our patient with HER2-positive metastatic breast cancer because the CLEOPATRA data set taught us this lesson that those patients in these trials that have PICK3CA mutations had a relatively poor prognosis compared to the others were PICK3CA negative. There is a trial looking at alpelisib (Piqray) approved in hormone receptor-positive metastatic disease, also in the first line [setting] maintaining setting in HER2-positive disease. For such a treatment options, we look at NGS. But short of that, for the majority of our patients, we're still relying on the biopsy confirmation and PR, ER, and HER2 to utilize that.

With the recognition that every patient is unique and requires an individual consideration, are there specific clinical trials that you're recommending for patients in this setting?

Beyond the first- and second-line setting, when a patient starts off in the first-line, we're giving them THP [docetaxel, trastuzumab and pertuzumab]. Then in the second-line setting we’re still recommending trastuzumab emtansine (Kadcyla) and based on the EMILIA trial (NCT00829166) that got approved compared to capecitabine (Xeloda). While that trial does not have patients with who progress after trastuzumab, in clinic, this is what we're going to be following as a second-line therapy. After a second-line option, given we have 3 additional drugs that were approved, which is great for our patients, including trastuzumab deruxtecan (Enhertu), and other next-generation novel antibody drug conjugates. We have to tucatinib with capecitabine and trastuzumab that was approved. And then we also have approval for ripretinib (Qinlock) plus capecitabine based on the phase three NOVA trial (NCT01847274) this year. So, we have multiple options.

Given that the data from the HER2CLIMB study, which evaluated tucatinib plus trastuzumab plus capecitabine shows not only a PFS and OS benefit for the entire intent to treat population, but have very Impressive benefits, including survival in those subgroup of patients who were enrolled with active brain metastases in this trial. I do favor that regimen specifically if I am dealing with a patient in clinic with active brain metastases. For patients with stable brain metastases, meaning they have been treated in the past with local therapies, and at the time of the progression in the systemic areas, the brain metastases are still stable, you can think about both tucatinib, capecitabine and trastuzumab. Or I think because the body is really progressing, or the system if metastases are really progressing, you really also have an option, which is wonderful with trastuzumab deruxtecan. We saw very impressive efficacy data, including a PFS of about 16 months, and we don't have the OS, but the disease control rate was about 98%. And the duration of response was about 15 months. So, it was very impressive. I do utilize that a whole lot and discuss that as a recommendation with the patient in front of me.

I think what we're struggling with is the utility of lapatinib (Tykerb) with capecitabine, which was our original second-line option. It was replaced by trastuzumab emtansine and now we have tucatinib and capecitabine and trastuzumab which is much better tolerated and a preferred regimen as well, compared to other TKIs. So, we are trying to figure out how do we sequence the partner capecitabine which is being pushed down even further. Then neratinib with capecitabine from the NALA trial, especially if you have already utilized tucatinib and capecitabine/trastuzumab. I think these are still options and can be utilized. But I think their position in terms of our treatment clinical pathway is getting lower and lower, below utilization trastuzumab deruxtecan and tucatinib.

The time is very exciting. I think we really have so many great options for these patients and have made a big difference. Yet, I think we haven't achieved what we really want to achieve for every patient, which is cure. We're striving to figure out what more can we do and how better we learn to further improve the outcomes for these agents. So, we're trying to figure it out what are newer ways of trying to target this pathway such that we can continue to make these advances that we've got.

What would you say are the next steps for CDK4/6 combination therapy based on what’s been observed in patients with HER-negative disease?

I think there are many important questions that we're still now trying to understand in clinic and these research efforts are underway, including, do we have a role for continuing CDK4/6 beyond progression? So, the paradigm that we use in HER2-positive metastatic breast cancer is that targeting the HER2 pathway remains important. And we continue to implement HER2 therapy on progression. The same is not yet clear for the utilization of CDK4/6 inhibitors beyond CDK4/6 [progression] and that is something that we're actively evaluating in trials, including randomized trials, such as the FACE trial (NCT00248170), MAINTAIN trial (NCT02632045), and others.

The second thing is that we're trying to understand is how do we appropriately treat our patients and what's the next line of therapy that one should offer for a patient who progresses on CDK4/6 inhibitors? Are there certain biomarkers that can guide us in how this patient should get chemotherapy versus targeted therapy? And if it's targeted therapy, which targeted therapy would be preferred? Because of that we're trying to understand the genomic alterations and the NGS data, both from tissue and plasma to better address that question and overcome this issue.

Lastly, and most importantly, we're now seeing early readouts from the monarchE trial which shows that when utilized for a high-risk patient population in the early-stage setting, abemaciclib led to a 3.5%, absolute improvement in invasive disease-free survival compared to endocrine therapy alone. And so, the question that we'll face will be, what would be the impact of these classes, agents in the first-line, metastatic setting when and if patients progress on or after CDK4/6 inhibitors in the early-stage setting? So, I think we're trying to understand a lot of questions. And we will continue to strive to address these so that we can continue to improve outcomes with these patients.

And going back to some of the earlier combinations you mentioned including those with selective estrogen receptor downregulators (SERDS) and PI3K inhibitors, what is the rationale for these combinations?

I think certainly, these combinations are based on the rationale that we find these alterations as potential mechanisms of resistance. For example, there are some applications from the PALOMA-3 (NCT01942135) analyses and from the MONALEESA-2 trial (NCT01958021), that perhaps and other preclinical data actually that supports that, that perhaps FGFR-1 amplification is the mechanism of resistance. That would lead to a benefit if one were to potentially target it with an FGFR inhibitor. Data from Carlos Arteaga, MD, and the University of Texas Southwestern Medical Center's lab, has shown that perhaps it might be a role for a triplet strategy of utilizing FGFR integration in combination with adequate therapy and CDK4/6 and that is what is being evaluated in an ongoing clinical trial with lapatinib in combination with fulvestrant (Faslodex) and palbociclib (Ibrance). That's one example. When it comes to oral SERDs, I think that there's a lot of emerging data from our group at Memorial Sloan Kettering Cancer Center, and others, that these are mutations that occur at the ER gene and then are acquired in the metastatic setting, after aromatase inhibitor use. So, targeting this mutation with a SERD that might be orally bioavailable, perhaps might be able to achieve higher exposures and have better clinical activity has been an active area of research, and has led to multiple oral SERDs in clinic, including many that have now entered phase 3 trials. The prevalence of these remains high. From the plasma, the prevalence of ESR mutations are about 30%. So, this is a significant prevalence for us to figure out if oral SERDs might be the most optimal way of approaching things, whether it's a single agent or in combination with other targeted therapies.

You mentioned the triplet with erdafitinib. Without generalizing here, would you say that the field is moving towards triplet therapy?

It totally depends on the context, and what kind of preclinical data and our understanding of that pathway is. For example, I also mentioned another triplet with a PI3K inhibitor. We realized from preclinical data that perhaps dual vertical inhibition of the pathway, because CDK4/6 is downstream of the PI3K pathway. So, 1 regimen to consider is dually, vertically integrating these pathways together. We might be able to see better synergistic activity. And that is the premise that we're using for the studying the triplet strategy of PI3K, with CDK, and endocrine therapy. In the phase 1 trial, we did show that is safe, and that could be efficacious. We're trying to understand, basically, what is it about post CDK4/6 inhabitation of the tumors, what are the mechanisms of resistance? And what do we understand preclinically, and then bring them to clinic. As to how do we target these mechanisms of resistance efficiently to improve the outcomes for these patients.

Can you talk about the LSC102 trial?

Data for the LSC102 trial was presented at the ESMO Breast Cancer Meeting 2020. That was the first study that evaluated and presented the results for an oral SERD in combination with both the CDK4/6 inhibitor and also a combination with alpelisib, the alpha specific PI3K inhibitor. So, that's a different distinct trial. But there are many oral SERDs that are currently in clinic.

We've talked about a bunch of pending trials. But if you were to give me your top 3 that you're looking forward to, what would you say they are?

I'm certainly looking forward to the role of antibody drug conjugates in this post CD4/6 phase. So, we're looking forward to results from the DESTINY-04 (NCT03734029) study that is evaluating trastuzumab deruxtecan versus physician choice chemotherapy, for HER2-low expressing tumors. We have seen impressive overall response rates (ORR) of 37% in the initial presentation from the phase 1/2 trial that was published in the JCU. We're also looking forward to the results from the TROPICS-02 (NCT03901339), which is evaluating sacituzumab govitecan (Trodelvy) compared to physician choice chemotherapy in HR-positive/HER2-negative tumors, who have progressed on the CDK4/6 and up to two lines of chemotherapy. And Initial reports from this was presented and published in Annals of Oncology showed an overall response rate (ORR) of 31%. Again, promising data. So, I'm certainly looking forward to seeing how we can utilize these antibody drug conjugates that are already approved in triple-negative and HER2-positive disease, and how do we bring them to our patients with hormone receptor-positive [disease] as well. I'm also really looking forward to seeing how we would be utilizing these group of endocrine therapy agents, both for our ESR1 wild type, but also for our ESR1-mutant patient population.

_References:

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_{2.Saura C, Oliviera M, Fen YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Phase III NALA trial. J Clin Oncol. 2020;38(27): 3138-3149. doi: 10.1200/JCO.20.00147}