Advances Improve Outcomes but Leave Space for Curative Strategies in Metastatic Breast Cancer

John T. Cole, MD

Data with antibody-drug conjugates (ADCs) and small molecule inhibitors like tucatinib (Tukysa) in HER2-positive breast cancer, CDK4/6 inhibitors in hormone receptor (HR)–positive breast cancer, and immunotherapy and sacituzumab govitecan-hziy (Trodelvy) in triple-negative breast cancer (TNBC) have pushed the paradigms toward improved outcomes, said John T. Cole, MD, who added that despite all of these advances, curative-intent therapies are needed for these populations.

“The theme [of breast cancer management] is that it is a dynamic field. It’s great for patients that so many things are happening, but we are still not curing a lot of patients. It is great to have improvements in progression-free survival and overall survival [OS], but cure is really what we are going for. We have a lot of work left to do to achieve that,” said Cole, in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

Cole, the chair of the IPC meeting, discussed how updates in HER2-positive breast cancer with fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib have affected sequencing strategies, how selections are made among CDK4/6 inhibitors in the adjuvant and metastatic settings of HR-positive breast cancer, and why additional therapies beyond pembrolizumab (Keytruda) and sacituzumab govitecan are needed in TNBC. Cole is chairman of Community Oncology Practices, South Shore of Ochsner Health, and clinical professor of medicine (gratis faculty), Section of Hematology and Oncology, Department of Medicine, School of Medicine, at Louisiana State University Health Shreveport.

OncLive^®: With novel HER2-directed agents, small molecule inhibitors, and ADCs, how are you navigating treatment sequencing for patients with metastatic HER2-positive breast cancer?

Cole: The recent data have clarified some things but also muddied the waters in that the prior paradigm of chemotherapy plus dual-antibody therapy followed by ado-trastuzumab emtansine [T-DM1; Kadcyla] was blown out by the results from the DESTINY-Breast03 trial [NCT03529110]. It became clear then that trastuzumab deruxtecan [should be] a second-line therapy, which put T-DM1 in no man’s land because data haven’t looked at the effectiveness of T-DM1 after trastuzumab deruxtecan. The converse was true wherein patients who had T-DM1 could [derive] a lot of benefit from trastuzumab deruxtecan. Since we don’t have [data evaluating T-DM1 after trastuzumab deruxtecan], third-line therapy in my practice has gone to tucatinib-based treatment.

What happens after that is murky. What role do other TKIs have? Do we go back to antibody therapy with other chemotherapy partners? Margetuximab-cmkb [Margenza] is an antibody that has some data in previously treated patients and showed some benefit in some subgroups vs trastuzumab [Herceptin]. Yet there aren’t a lot of data for [margetuximab] in the fourth-line setting for heavily pretreated patients.

We have to look at what patients have had in terms of toxicities and how well they have tolerated [agents] and their performance status when they get to [fourth-line therapy]. Fortunately, many patients will have [remained in remission] for years after starting HER2-directed therapies. To me, the right answer after third-line therapy is a clinical trial if we have one.

The role of mutational status with liquid biopsies or [tissue] biopsies of the primary metastatic sites also has a lot of potential for helping us direct therapies, especially if we are looking for clinical trials of newer agents that might be directed at a specific mutation or target.

Following the updated OS data seen with tucatinib, what do you anticipate is next for that agent?

There is the [CompassHER2 RD] trial [NCT04457596] that completed accrual, which is looking at adding [tucatinib] to T-DM1 [vs T-DM1 plus placebo] and [asking whether] a combination of HER2-directed therapy is superior in that setting. That is a second-line therapy trial, so we won’t know what to do with [those findings in light of the] DESTINY-Breast03 data [if they are equally positive]. Tucatinib is still a young drug; it has only been a couple of years since the first results were published. A lot of investigation needs to be done. Whether combinations of these drugs will be more effective [is unknown], but it also becomes [a matter of] whether the toxicity of the combination is acceptable and superior to sequential therapy.

The other things that we haven’t used in our treatment decisions is whether HER2-rich tumors should be treated differently than other subtypes of HER2-positive disease. We’ve also got the estrogen receptor [ER]–positive subgroup of patients and investigations are ongoing for those patients as to whether CDK4/6 inhibitors will provide additional benefit to endocrine therapy. 

There are a lot of questions that have yet to be answered. We almost have an embarrassment of riches because we have so many different drugs and different ways we can take a look at them. We have to remind ourselves that probably half of patients who are HER2 positive are also ER positive. That is good for patients because we have a lot of endocrine therapies.

The waters are muddy, and we are going to have to navigate our way through by clinical trials. We try to be smart about how to [do clinical trials] because a patient population is not endless. What makes sense from the pharmaceutical perspective? What is worth investing in in terms of a clinical trial which, if successful, will make it appropriate to bring that drug to market with a different indication.

How could some of these newer agents change the paradigm for patients with brain metastases?

It’s such a dynamic area right now. There are lots of agents to choose from. The global outlook for these patients is getting better because of the efficacy we have [with the agents we now have].

At the 2021 San Antonio Breast Cancer Symposium, something that was brought up was that there is brain activity with trastuzumab deruxtecan. That is exciting because brain metastases are so common in this subgroup of patients. Having more than the small molecule inhibitors that seem to have CNS [central nervous system] activity is also going to be important, especially for patients with low-volume brain metastases. When [those patients] go to second-line therapy, previously I would have automatically gone to tucatinib in that setting if they weren’t treated. Now, we can make an argument that we could go to trastuzumab deruxtecan in patients with untreated low-volume brain metastases or certainly those with treated brain metastases.

During the IPC meeting, Melanie A. Sheen, MD, of Ochsner Health, discussed early-stage HER2-positive breast cancer. What has become the focus of treatment in the early-stage setting?

The big story there is really de-escalation. When should we apply neoadjuvant therapy? How do we give the least amount of cytotoxic therapy possible to achieve the same benefit [as with the full dose]? Certainly, Sara M. Tolaney, MD, of Dana-Farber Cancer Institute, led that charge with her work looking at weekly paclitaxel plus trastuzumab in lower-risk patients with HER2-positive disease in the adjuvant setting. The WSG ADAPT-TP trial [NCT01779206] from Nadia Harbeck, MD, PhD, of the University of Munich, demonstrated outstanding results with limited chemotherapy in the neoadjuvant setting.

Several studies have now shown that dual-antibody therapy by itself [yields] a significant response rate. If we can pick out patients who might be able to get away with no chemotherapy at all, that would be a good thing. In the ADAPT trial, there were also patients who had antibody therapy alone who [derived] a pathologic complete response [pCR] who never got chemotherapy. That is amazing that we could potentially [offer] chemotherapy-free treatment.

In the neoadjuvant studies with lapatinib [Tykerb] and trastuzumab, patients also had pCRs with dual-HER2 inhibition as well.

In the early-stage and the advanced settings, one of the big unanswered questions is: Can we subgroup patients with HER2-positive disease above and beyond whether they are ER positive or negative? [Can they be split] into other groups that might help us tailor therapy more specifically? There is a lot of interest in that, so we will be seeing some trials trying to get a handle on that soon.

Rabia Cattie, MD, of Ochsner Health, spoke to the utility of CDK4/6 inhibitors in HR-positive, HER2-negative breast cancer. What stands out to you regarding the data with these agents in the adjuvant setting?

I have been most [surprised] with the lack of uniformity of the data in that setting. The positive results with abemaciclib [Verzenio], albeit clearly in a higher-risk subgroup of patients, [are contextualized by] the negative results of the PALLAS study [NCT02513394]. Even in the subgroup analysis of PALLAS, the higher-risk subgroup didn’t seem to benefit from [palbociclib (Ibrance)]. That certainly speaks to a potential difference in those 2 drugs. We are waiting for the results of the NATALEE trial [(NCT03701334), which is evaluating] ribociclib [Kisqali], which will go a long way toward telling us whether there is a group effect or not. If [NATALEE] is a positive trial, the people at Pfizer will be scratching their heads about why [PALLAS] didn’t succeed.

It’s great to have other drugs in the high-risk subgroup of patients. We treat a lot of patients neoadjuvantly with aggressive ER-positive tumors that are probably luminal B if we look at them from a genomic perspective. [These patients have] higher Ki-67. They are often ER-positive and progesterone receptor negative. They often have significant residual tumor burden at the time of surgery. Being able to offer them more than just single-agent endocrine therapy is a big plus. We have certainly been doing that routinely in our practice. In the adjuvant setting, that is important.

We have not yet brought genomics into the equation in terms of [determining] whether there are patients who have higher-risk genomic scores who would benefit from not just chemotherapy but CDK4/6 inhibitors in the adjuvant setting. I don’t know the answer to that question.

There is additional work that could be done in that setting. If we can extrapolate from the patients who have larger disease burden and presentation than patients who have early-stage disease, it would make sense that that subgroup of patients might be amenable [to CDK4/6 inhibitors]. However, in none of the studies I’m aware of has that been looked at in terms of breaking those subgroups out to see any differences. I’m sure [investigators] could do that, but most of the trials have looked for patients who had some marker for increased risk. Whether there is enough of those patients to warrant that subgroup analysis, I don’t know. 

In the metastatic HR-positive, HER2-negative setting, do the survival data observed with ribociclib have any influence on treatment selection with CDK4/6 inhibitors?

If we look at the data, they show that all [the CDK4/6 inhibitors] have similar effectiveness, at least if we look at the hazard ratios and survival benefit. Obviously, we don’t have head-to-head comparisons. In the community, palbociclib is still the treatment of choice for most people. Part of that is related to the ease of use because there is a necessity to check QT intervals when we initiate ribociclib. That is still a barrier for many practicing clinicians. Although that doesn’t seem like a lot of effort, it is something else that very busy clinicians have to do.

At least in talking to colleagues across the country, many people choose not to use [ribociclib] because there is no clear head-to-head comparison that says [ribociclib] is better than [the other CDK4/6 inhibitors]. Clearly, the data for ribociclib in terms of survival are very robust and that is one of the reasons I choose to use it in some patients and deal with the ancillary things that have to get done for patients on that treatment. I don’t think that [mindset has] swept [through] the country; people will still need to be convinced that there is a difference between the agents [before they start to favor ribociclib]. 

Finally, Zoe Larned, MD, of Ochsner Health, discussed TNBC, which during the meeting you highlighted is the most difficult patient population to treat in breast cancer. What advances have been made for this patient population and where is the field headed to overcome some of the remaining challenges?

The immunotherapy trials have altered how we approach these patients, but we must remember that at least in the United States, pembrolizumab is the only approved agent and it is only for those patients who have evidence of PD-L1 expression with a [combined positive score] of at least 10. [Pembrolizumab] is not for everybody and all patients will not be eligible for or likely to benefit from it. Even those patients who get [pembrolizumab] aren’t going to be cured, so it is not the panacea for all those patients.

Sacituzumab govitecan is going to be evaluated in earlier-stage treatment; it makes a lot of sense [to do so]. Clinical trials are moving forward in that vein. That is an innovative approach.

The other aspect of TNBC is the fact that this is a heterogenous group of patients. Looking at molecular subtyping makes a lot of sense because there are clearly some patients who may not benefit at all from chemotherapy. [Chemotherapy] is our mainstay, and we plan to give chemotherapy to every patient with TNBC. If we are wasting our time [giving chemotherapy] to certain molecular subgroups, we need to think about alternative treatments.

I am thinking about the androgen receptor–positive subgroup of patients where there might be other therapies that make sense, but that hasn’t made it to the clinic yet. We are all aware of it and capable of discussing it, but in terms of acting on it or operationalizing it, we haven’t done that yet. That is an important field for TNBC to help us tailor therapy more successfully than we have been.

For the immunotherapies, at least we have a biomarker we can use to try to predict benefit [from treatment]. We need to expand that to other groups of patients and look for biomarkers that might predict whether a particular therapy would be beneficial, especially if we are giving toxic and [potentially] ineffective therapies. [In those situations], we need to stop [blindly recommending treatment] and move to something that is more rational.

There is a lot of research left to be done in TNBC, where we consistently, unfortunately, see a lot of younger African American women diagnosed. It’s often tremendously challenging to try to get patients in a situation we want them to be in. It’s frustrating and a lot of times patients don’t respond the way we hope they would. We have limited tools in the toolbox right now for these patients. Looking at newer agents and especially trying to find new targets for this relatively untargetable disease characterized by its lack of targets [will be important].