Advancing the Paradigm of Breast Cancer Therapies by Critically Gauging Success Across Histologies

Hurvitz is director of the Breast Cancer Clinical Research Program, co-director of the Santa Monica–UCLA Outpatient Hematology/Oncology Practice, and an associate professor of medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA in Santa Monica, California, as well as co-chair of the 20th Annual International Congress on the Future of Breast Cancer® West, hosted by Physicians’ Education Resource^®, LLC (PER^®).

In recent years, the field of breast cancer management–specifically tumors in the metastatic setting–has experienced numerous breakthroughs, with novel therapies on the horizon across histologies and treatment settings. Of late, substantial interest has been focused on the use of immunotherapies, which have finally emerged in the breast cancer setting after notable success in other tumor types such as lung cancer and melanoma. Despite apparent early promise, these therapies are being reconsidered by the FDA based on indeterminable benefits of therapy in patients without PD-L1–expressing tumors or those progressing past the first-line setting.

In addition, matching the success achieved in HER2-driven tumors across all histologies in breast cancer has been a challenge, with overall survival times holding steady in many settings. To address these concerns, ONCOLOGY® sat down with Sara A. Hurvitz, MD, director of the Breast Cancer Clinical Research Program, co-director of the Santa Monica–UCLA Outpatient Hematology/Oncology Practice, and associate professor of medicine in the Division of Hematology/Oncology at the David Geffen School of Medicine at UCLA in Santa Monica, California, to discuss issues of interest in the treatment of breast cancer.

Hurvitz is a program co-chair of the 20th Annual International Congress on the Future of Breast Cancer® West, hosted by Physicians’ Education Resource®, LLC (PER®), to be held July 30-31, 2021. The meeting will cover topics discussed by Hurvitz, with the hopes of demystifying some pressing questions in the field of oncology and facilitating thoughtful conversations about next steps in advancing care.

ONCOLOGY®: What are the most exciting studies involving targeted therapies you’re looking forward to seeing data from in the coming year?

Hurvitz: There are a number of therapies outside of the HER2-positive realm that are being tested in phase 1 through phase 3 trials right now. Just looking at the hormone receptor [HR]-positive subtype, I’m really excited to see data forthcoming related to one of the many oral SERDs, or [selective] estrogen receptor downregulators, that are being evaluated.

The furthest along is Elacestrant [RAD1901], which is being evaluated in a phase 3 randomized trial called EMERALD [NCT03778931]. That study should be reporting out in the next year or so, as the enrollment, I believe, completed this past year. So that’ll be interesting to see if we have an oral SERD available for patients. There are at least 7 or 8 other ones that are very promising being evaluated in neoadjuvant, adjuvant, and metastatic settings, so I’m excited to see those data come out.

There are some interesting studies looking at PI3K inhibitors—for example, alpelisib [Piqray]—and triple-negative, PI3K-activated breast cancers. I don’t know that we’ll have data in the next year, but I do know those studies are ongoing as well in the HER2-positive breast cancer setting. I’m also very excited to see data relating to sacituzumab govitecan [Trodelvy], the TROP-2 antibody-drug conjugate that was FDA-approved last year for triple-negative breast cancer.¹ It’s being looked at now in HR-positive breast cancer in the TROPICS-02 study [NCT03901339]. That is a study that also completed enrollment in HR-positive, metastatic disease. TROP-2 expression isn’t just limited to triple-negative breast cancer, so it makes sense to look at it in HR-positive breast cancer.

With T-DXd, or trastuzumab deruxtecan [Enhertu], which is FDA-approved for HER2-positive metastatic breast cancer, I’m excited to see data relating to the evaluation of this drug in HER2-low–expressing breast cancer, which comprises about two-thirds of HR-positive, HER2-negative breast cancer and about a third of triple-negative breast cancers. This is being evaluated in a randomized phase 3 trial called DESTINY-Breast04 [NCT03734029]. That study also completed enrollment this last year, so we should have data in the next year or so validating whether or not this agent really does look better than chemotherapy in HER2-low–expressing breast cancer that’s more heavily pretreated.

There are early studies looking at other antibody-drug conjugates. For example, there is ladiratuzumab vedotin, a targeted antibody-drug conjugate being looked at in triple-negative breast cancer. Phase 1 data are emerging relating to that. There are a lot of exciting, ongoing clinical trials that should have results in the next year or 2.

The FDA has been reconsidering the use of certain immune checkpoint inhibitors for many diseases, including atezolizumab (Tecentriq) for triple-negative breast cancer. What does that mean for its use in women with breast cancer?

Immunotherapy is very exciting for certain tumor types, but it’s not had the easiest path forward in breast cancer. Breast cancer was [one of] the last tumor histologies to show that it may be beneficial, and the benefits are restricted right now to those tumors that are PD-L1–positive in the metastatic setting. The benefits appear to be fairly restricted to the front-line setting rather than later-line settings. It hasn’t been the blockbuster that it was in other tumor histologies.

The data surrounding atezolizumab from the IMpassion130 trial [NCT02425891] are certainly very promising in terms of progression-free survival and possibly overall survival.² But it’s restricted to patients with PD-L1–positive tumor immune cells, as tested by [the VENTANA PD-L1 (SP142) assay]. The use of pembrolizumab [Keytruda] in the metastatic setting is restricted to those patients with a CPS [combined positive score] of 10 or greater, which is not the majority of triple-negative breast cancers.

We have some negative studies…and then we have very inconsistent data in the neoadjuvant setting where we’re seeing promising pathologic complete response rates by adding immune checkpoint inhibitors to chemotherapy, but it doesn’t appear to be restricted to PD-L1–positive cancers. It’s hard to sort through the different clinical trial designs, the different antibodies that we’re asked to use to test for PD-L1 expression, the different outcome results, and the lack of overall survival benefit thus far.

Although [these agents are] well-tolerated, there are severe, irreversible, and even life-threatening toxicities that can occur in patients receiving these drugs. Although this is more acceptable in the metastatic setting, where you are facing a life-threatening disease, it’s incurable. As we move these drugs forward into the curative setting, we have to take that toxicity seriously before endorsing the use of these agents with no long-term data suggesting long-term benefit.

Do you think the hope of immune checkpoint inhibitors exceeded the science and now we’re going back and doing some of the research that probably should have been done ahead of time?

There was a lot of hope surrounding these agents, especially since we are focusing the use of the drugs on triple-negative disease, where our therapies have been unsuccessful. For the most part, we haven’t budged the median overall survival [for this disease] in the past several decades. Patients just aren’t doing better with this disease. When we see an agent that may be well-tolerated and benefit patients, there’s a lot of excitement, especially when we see the enormous advances that immune checkpoint inhibitors have [achieved] in diseases like melanoma and lung cancer. I do think that there needs to be more work done to define biomarkers, subsets, and settings where this these agents are going to have the best therapeutic index, the highest efficacy, and the lowest chance of causing significant toxicity. Work needs to be done. I’m somebody who has been a little more skeptical along the way about immunotherapy, and I do think that these therapies, for the most part, still should belong in the research realm. We should be doing more clinical trials and more biomarker studies to define the role of these agents in this disease.

Why has treatment been so successful in the HER2-positive setting, but hasn’t translated to other breast cancers?

HER2-positive breast cancer is unique, and it’s relatively rare for a particular type of cancer to be defined by 1 genetic alteration that is driving the tumor biology. The tumor is addicted to its [HER2-expression]. That unique addiction of tumor cells in HER2-positive disease makes it simple relative to other tumor types where there’s a lot of things going on driving biology. It’s fairly homogeneous. The fact that this is the gene that is driving biology [allows you to] develop drugs to target that and go after it. The success of that is absolutely outstanding, but that type of story is not going to be possible in a number of other tumor subtypes.

For example, targeting CDK4/6 in HR-positive breast cancers has been incredibly successful both in terms of progression-free survival and overall survival benefits. But resistance to this pathway develops, and we haven’t demonstrated that the pathway remains important after the disease has become resistant to inhibitors of that pathway. In fact, it appears that once resistance develops to CDK4/6 inhibitors, its upregulation of other pathways, like PI3K, become the important drivers of tumor biology. [Therefore,] developing other inhibitors of CDK4/6 isn’t necessarily going to benefit patients whose disease is resistant to it. I think the heterogeneity of other tumor types and the number of other signaling pathways that are involved in the development of resistance makes it much more complicated.

I do think that we have made major strides in the treatment of HR-positive breast cancer. When CDK4/6 inhibitors were approved and available to patients, we start seeing median overall survival data come out for patients who were diagnosed with disease in 2018 through 2020. We will start to see that the length of median survival is improving for HR-positive breast cancer because of these agents, and my hope is that in the future we’re going to have better agents for triple-negative disease and that we’ll see an improvement in survival with that disease subtype as well.

Are there potential targets that you’re seeing that might be targets for therapeutics in the future, but aren’t quite there yet?

I think there are a lot of exciting targets being explored. I’m involved in a number of phase 1 clinical trials of agents that are targeting novel areas that relate to, for example, homologous recombination deficiencies—or different mechanisms of DNA repair—[trying to determine if] we can target that and prevent resistance to PARP inhibitors or if can we expand the use of agents beyond BRCA mutations. There are a lot of therapies that are looking at unique antigens expressed on tumor cells that can be targeted with antibody-drug conjugates. That is very promising. It’s a time for great hope with breast cancer, given the number of agents being evaluated now.

Is there one change you would make to the current treatment paradigm that would make the most difference for your patients?

I think if we knew that, what would stop us from doing it? Clinical trial enrollment is key to moving the science forward. If there was a way to augment the percentage of patients who enroll in at least 1 clinical trial in their lifetime, that would allow the advance of science (and in breast cancer) at a much faster pace. Getting more people involved in clinical trials and reaching a more diverse patient population is an unmet need. That’s something that we should be all charged with addressing.

How do you get more patients from minority populations to participate in clinical trials?

There are a number of factors that lead to this. A lot of it has to do with access to centers that have clinical trials and the type of insurance that patients have. Clinical trials don’t cover 100% of care; when a patient is on a clinical trial, you need to have insurance that’s going to be able to cover the standard of care, exams, imaging, and therapies that are involved in the clinical trial. It’s not as though if you go on a clinical trial, 100% of your care is covered. If you have somebody who has a very limited insurance plan, their access to clinical trials is going to be limited. Moreover, a lot of our centers that do clinical trials—phase 1, 2, and 3—are placed in more economically wealthy areas, so I think the NCI [National Cancer Institute] is asking Comprehensive Cancer Centers to demonstrate that they’re enrolling a diverse patient population. [Thereby,] in order to get NCI backing and be a part of the NCCN [National Comprehensive Cancer Network], you have to open centers or collaborate with centers that are in low-income areas, county facilities, and the like. That motivation helps access for these patients.

Then you’ve got the other side of it—the patient side. Science has not been completely ethical in the past century if you look at how there have been some wrongs done to vulnerable patient populations, including African Americans. There are some real injustices that occurred, so gaining trust about going on a clinical trial is something that is a challenge that needs to be addressed. Engaging with advocates who have access to communities is useful as well.

I think you have to address it from financial aspects by motivating the centers to put resources and funding into it, motivating [the pharmaceutical industry] to put resources and funding into it, and then providing a level of reassurance on the patient side where trust is earned and deserved

It appears as though cancer care has moved away from multimodality therapy and has moved toward combining agents and sequencing. Are we heading that way?

In the metastatic setting, that is certainly the case. In the early-stage setting, it remains multimodality. You approach cancer with your surgery or radiation and your systemic therapy. But in the metastatic setting, the results from the ECOG-ACRIN [2108 (NCT01242800)] trial, looking at whether removal of the primary tumor in a person with de novo metastatic breast cancer improves survival, were negative; it did not demonstrate an improvement in overall survival.³ It’s data like that that indicate, when you have systemic disease throughout the body, even if you can only see it in 1 or 2 spots on scan, the best way of addressing it is with systemic therapy that goes everywhere. “Cherry picking” by using surgery here and radiation there and ablation there, how much is that going to add to a patient’s survival and quality of life compared with just getting systemic therapy and focusing on the safety and efficacy of that? We still utilize radio-ablation and radiation and surgery for palliation, but the goal is on survival. I personally want to see that adding those therapies to effective systemic therapy improves survival for a patient compared with just doing systemic therapy, because you can only use locoregional therapies so many times.

Is there a study that you would like to conduct or you’d like to lead that you haven’t? Or a topic you’d like to study that you haven’t been able to get into yet?

I think there are so many, it’s hard to focus. I would love to see a clinical trial dovetailing off the topic of looking at a molecularly defined patient population—meaning triple-negative, HR-positive, or HER2-positive—[instead of] an all-comer population, which all of these multimodality studies do. They take all tumor subtypes, and then you have to do your subset analyses retrospectively and see whether we benefit patients by radiating oligometastatic disease or removing the tumor at the time of surgery.

My suspicion is that doing all of that extra locoregional therapy and spot radiation is not improving survival in a disease that already has such good survival as HER2-positive breast cancer. There are a lot of unanswered questions out there. One of the big ones that came out from the 2020 San Antonio Breast Cancer Symposium that’s generated a lot of discussion is relating to early-stage HR-positive breast cancer with a few lymph nodes involved from the RxPONDER study [NCT01272037]. In that study, they showed that, you know, if your OncotypeDx [Recurrence Score] is less than 26, you don’t need chemotherapy if you have 1 to 3 positive nodes, and that’s with HR-positive, HER2-negative breast cancer.⁴ But premenopausal women do appear to benefit from chemotherapy, regardless of how low the score is. The question that has been asked from that trial that everybody wants to see [answered] is if chemotherapy is really necessary.

I think we all suspect that chemotherapy probably isn’t benefiting these patients with 1 to 3 nodes with [high] OncotypeDx Recurrence Scores as long as you suppress the ovaries. That’s one of those huge questions, I would love to see that [studied].

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References

1. FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. News release. FDA. April 22, 2020. Accessed March 24, 2021. https://bit.ly/3vVI6CM

2. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi:10.1056/NEJMoa1809615

3. Khan SA, Zhao F, Solin LJ, et al. A randomized phase III trial of systemic therapy plus early local therapy versus systemic therapy alone in women with de novo stage IV breast cancer: a trial of the ECOG-ACRIN Research Group (E2108). J Clin Oncol. 2020;38(suppl 18):LBA2. doi:10.1200/JCO.2020.38.18_suppl.LBA2

4. Kalinsky K, Barlow WE, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; Virtual. Abstract GS3-00. doi: 10.1158/1538-7445.SABCS20-GS3-00