Sara A. Hurvitz, MD, associate professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, anddirector, Breast Cancer Clinical Trials Program, UCLA, discusses sequencing therapeutic options for patients with HER2-positive breast cancer. 

The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) is a new standard-of-care approach in the second-line setting of HER2-positive breast cancer, Hurvitzsays. Trastuzumab deruxtecan improved patient outcomes compared with ado-trastuzumab emtansine (Kadcyla; T-DM1) and is utilized in patients who have progressed on trastuzumab (Herceptin) and taxane regimens, Hurvitz adds.

Moreover, the phase 2 HER2CLIMB (NCT02614794) trial demonstrated that tucatinib (Tukysa) plus capecitabine and trastuzumab showed activity in patients with brain metastases, Hurvitz emphasizes.

Ongoing efforts to expand HER2-targeted treatment options are ongoing, Hurvitz continues. Several novel HER2-targeted agents are currently in development, as well as additional targeted therapy combinations for this patient population, Hurvitz concludes.

Videos

Sara A. Hurvitz, MD, discusses sequencing therapeutic options for patients with HER2-positive breast cancer. 

Dr. Hurvitz on Sequencing Therapeutic Options in HER2+ Breast Cancer

Perhaps we will turn now to a case, and I'm going to pick your brain. How you would manage this particular scenario. So, we have a 57-year-old woman who was diagnosed with stage llA grade 3 triple negative breast cancer. She previously received neoadjuvant docetaxel cyclophosphamide and underwent a mastectomy followed by olaparib because she has a germline 

 mutation. Her tumor was tested and was PD-L1 negative. This treatment was given prior to the availability of neoadjuvant pembrolizumab, and I think that the PD-L1 testing in this setting was investigational, not something that is used to make treatment decisions. But at her 12-month follow-up, she developed a persistent cough and was complaining of right upper quadrant pain. She underwent CT imaging that revealed 2 lesions in the left lobe of the lung, 2 centimeters as well as a single 0.8-centimeter hepatic lesion that was suspicious. She had a biopsy and this confirmed metastatic triple-negative breast cancer. She underwent brain imaging and that was negative for brain metastasis. So, before I actually take us on this journey and talk about her treatment course, can you take me through how you would approach selection of treatment for this patient from a cytotoxic chemotherapy standpoint? What systemic therapy would you put this patient on?

 So, that's a very interesting case and as you said before, PD-L1 testing, at least earlier on, is really just investigational. For this patient, what we do know that accrued in the first-line setting is a PD-L1-based regiment, which is pembrolizumab with chemotherapy if PD-L1 positive, which I would k repeat in this patient on the metastatic lesion so we can have PD-L1 changes occurring from the primary to the metastatic. If not positive, then we do have chemotherapy options, including platinum or taxane. She had 12 months, I think, disease-free interval at least, so which made a taxane available for her. Interestingly, if she had early progression within the 12 months on a taxane- type chemotherapy, I would consider bringing up sacituzumab in that setting; I've done that in a few patients. But, overall, any type of chemotherapy is an option in the first line. GemCarbo [gemcitabine and carboplatin], for example, is another combination option for this patient depending on her tumor burden. Obviously, if you're looking for a response, you might consider doublet therapy versus single agent, but for most patients, single-agent chemotherapy is what would be expected unless they're PD-L1-positive, at which you would give them pembrolizumab. I like to do a molecular profile for my first-line patients, especially the triple negative, so we can recognize the 

 in a patient, for example. That patient should have been tested up in the earliest setting, even though she's triple negative. Oh, we did recognize that she's 

 positive. But she's already had olaparib, so I guess that's not an option for her at the first line because it progressed after that therapy.

Thank you very much for that great review. I completely agree with you and I want to highlight 1 thing that you brought up regarding PD-L1 testing. It is so interesting, when you look at data that was generated by Hope Rugo, [MD, FASCO, professor and director of Breast Oncology and Clinical Trials Education, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco] in the context of some clinical trials; she did show that PD-L1 expression levels differ not only from primary to metastatic lesions but also site of tissue. Liver lesions and liver biopsies tend to have the lowest PD-L1 expression, whereas lung and lymph node have really high expression, so I think it's a very salient point that you made to retest and make sure the patient is for sure PD-L1-negative before omitting pembrolizumab, given the significant benefits of pembrolizumab in that frontline setting. As it turns out, this particular patient did start on cisplatin. She received 3 cycles of therapy and experienced disease progression. One of her lung lesions increased to 2.7 centimeters and the liver lesion increased to 0.9 centimeters; therefore, it was a true progression. One thing I would highlight, as you mentioned, is she received olaparib in the adjuvant setting, and we don't have really good data about the efficacy of platinum drugs in 

 carriers after a PARP inhibitor. We know that a PARP inhibitor after progression on a platinum doesn't appear to work as well, but there does seem to be some level of cross resistance, so I can't say that this lack of response that we saw is something unusual. I think you mentioned that your next choice in the second line setting would be sacituzumab govitecan, so I wanted to get your input regarding sacituzumab govitecan and what type of responses you've seen in the metastatic setting and your patients whom you've treated with this agent.

 We know the data from ASCENT trial [NCT02574455] showed there is almost a doubling of progression—actually from 1.7 to 5.6—more than a doubling of progression free survival. It was overall survival benefit. In the real world, with my patients, I've had patients who've been on this drug for probably the longesgt 18 months I think and doing well. They have really good dip responses before having progression. Also, I've had some patients who have had really short intervals of benefit, but overall, most patients that I've given the drug do pretty well--At least get some response over time, somewhat in line with what we've seen in the trial. Right about maybe 5 to 6 months’ benefit.

Yes, I've noticed some really nice outcomes with my patients as well in terms of treatment with sacituzumab with very robust responses, even in patients with liver metastases. I've been very pleased with the type of activity that I've seen, and certainly, as you mentioned in the ASCENT study, it underscores the improvement and objective responses and clinical benefit rate. We have to keep in mind patients were really heavily pretreated in the ASCENT trial. So, perhaps by using it in a little earlier setting, in the second- or third-line setting, we might see even better activity.

After reviewing a patient scenario of relapsed/refractory metastatic TNBC, expert oncologists elucidate use of sacituzumab govitecan in this setting.

Clinical Scenario: mTNBC Treated With Chemotherapy Then Sacituzumab Govitecan

 Insights® program on treatment approaches in triple-negative breast cancer. I'm Dr Sara Hurvitz, a breast medical oncologist at the University of California, Los Angeles. I'm pleased to discuss how we approach a patient with triple-negative breast cancer with my colleague, Dr Gregory Vidal, a medical oncologist hematologist at West Cancer Center and Research Institute in Germantown, Tennessee. Welcome, Greg.

Let's get started. Triple-negative breast cancer actually comprises somewhere around 15% to 20% of all breast cancers diagnosed and typically is associated with a poor prognosis. There are multiple subtypes within triple-negative breast cancer itself. It is a heterogeneous entity, and it's not a very sophisticated definition that we use—calling something by what it is not. It is not hormone receptor-positive and it is not HER2-positive; thus the name is triple negative. The outcomes have been, however, described as being poorer in general. What is the general prognosis of patients diagnosed, Greg, with early-stage triple-negative breast cancer, stage for stage, compared with other subtypes? Can you give us some information on that?

 Certainly. Compared with the other types, mainly the estrogen positive and the HER2 positive, as a group, triple negative usually is noted in the metastatic setting, with an average median overall survival of 18 months, which is really poor compared with the other tumor types. So, there's a lot to do in that setting.

Absolutely, and we've seen treatment paradigms change, even recently. It wasn't so long ago that we really only had chemotherapy available to treat patients with any stage of triple-negative breast cancer. This subtype of breast cancer does appear to be very responsive to cytotoxic chemotherapy but paradoxically develops resistance quite quickly and can aggressively recur or progress. Can you tell us about some of the newer treatments available for our patients with triple-negative disease, maybe starting with the antibody-drug conjugates [ADCs] that we just had approved recently?

 Yes, we have had some newer therapies on the market for triple negative. We still, as I said, have a lot more to do to get in line with the other subtypes. But when we're talking about new drugs, for example, sacituzumab is an anti-TROP ADC with a topoisomerase inhibitor payload that has been recently approved in the second line or greater has shown both progression-free survival and overall survival benefit. We have PARP inhibitors for

 mutation, but we do have some phase 2 data that suggests that even in somatic 

 mutation, we may have some activity there. We do have other drugs like pembrolizumab, which—combined with chemotherapy for PD-L1 positive or MSI [microsatellite instability]-high cancer—can also be used. You could use immune checkpoint inhibitors for TNBC and for some of the 

 mutations to secondary breast cancer, which is not very common, but it's mainly a triple negative like those with a 95% 

fusion. Those drugs work very well in that context. So, we do have some new drugs on the market that are just not chemotherapy.

So, our treatment regiments have become a little more sophisticated in terms of patient selection, as you mentioned. I feel like we still have a long way to go, but in the frontline setting, a patient whose tumor is PD-L1 positive by the combined positive score using the 22C3 antibody is a candidate for the use of pembrolizumab in combination with chemotherapy. Then, as you mentioned in the second line setting, sacituzumab govitecan for all patients with triple-negative breast cancer, which is better than single agent chemotherapy. I am excited to see results from ongoing clinical trials looking at other strategies, other antibody-drug conjugates, PI3-kinase pathway inhibitors for those with a 

mutation, and I think we even saw some really exciting data from the DESTINY-Breast04 study [NCT03734029] at ASCO [American Society of Clinical Oncology] 2022 that showed a small subset of patients with triple-negative breast cancer that was low-expressing for HER-2 benefited greatly from T-DXd [trastuzumab deruxtecan], so it's going to be interesting to see more data relating to that.

Expert oncologists share insight on the prognosis of triple-negative breast cancer (TNBC) and broadly review current treatment options for patients.

Perspectives on the Current Treatment Landscape of TNBC

Sara A. Hurvitz, MD, associate professor, the David Geffen School of Medicine, the University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, director, Breast Cancer Clinical Trials Program, UCLA, discusses the clinical implications of the phase 3 DESTINY-Breast03 trial (NCT03529110) in HER2-positive breast cancer.

DESTINY-Breast03 produced some of the most riveting data in the HER2-positive breast cancer space in 2021, Hurvitz says. In this trial, randomized patients received either fam-trastuzumab deruxtecan-nxki (Enhertu) or ado-trastuzumab emtansine (T-DM1; Kadcyla) after prior treatment with trastuzumab (Herceptin) and a taxane, Hurvitz explains.

This phase 3 trial demonstrated a substantial improvement in progression-free survival with the use of trastuzumab deruxtecan vs T-DM1. Notably, trastuzumab deruxtecan benefited patients who had a history of brain metastases at baseline, Hurvitz concludes.

Sara A. Hurvitz, MD, discusses the clinical implications of the phase 3 DESTINY-Breast03 trial in HER2-positive breast cancer.

Dr. Hurvitz on the Clinical Implications of the DESTINY-Breast03  Trial in HER2+ Breast Cancer

Sara A. Hurvitz, MD, associate professor, the David Geffen School of Medicine, the University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, director, Breast Cancer Clinical Trials Program, UCLA, discusses utilizing CDK4/6 inhibitors in hormone receptor (HR)-positive breast cancer.

When disease progression occurs in a patient with HR-positive disease following treatment with a CDK4/6 inhibitor, multiple therapies are available to this patient, Hurvitz says. However, optimal sequencing strategies for these treatments in this setting are not well known, Hurvitz explains.

Some studies have investigated the inhibition of the PI3K pathway, including the use of agents such as alpelisib (Piqray) in patients whose disease has been previously treated with a CDK4/6 inhibitor, Hurvitz continues. Another agent, apitolisib (GDC-098), has highlighted some of encouraging data regarding PI3K pathway inhibitors, Hurvitz concludes.

Sara A. Hurvitz, MD, discusses utilizing CDK4/6 inhibitors in hormone receptor-positive breast cancer.


Dr. Hurvitz on Utilizing CDK4/6 Inhibitors in HR+ Breast Cancer

Sara A. Hurvitz, MD, associate professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, director, Breast Cancer Clinical Trials Program, UCLA, discusses progress made in 2021 with antibody-drug conjugates (ADCs) in HER2-positive breast cancer.

During the 2021 ESMO Congress, interim findings from the phase 3 DESTINY-Breast03 trial (NCT03529110) were presented. The results showed that fam-trastuzumab deruxtecan-nxki (Enhertu) improved progression-free survival (PFS) compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with metastatic HER2-positive breast cancer. Notably, these results were practice changing because they supported the use of trastuzumab deruxtecan vs T-DM1 in the second-line setting for this patient population. 

Additionally, findings from the phase 3 TULIP trial (NCT03262935), which were also presented during the 2021 ESMO Congress, demonstrated an improvement in PFS with vic-trastuzumab duocarmazine (SYD985) vs physician’s choice of treatment in patients with metastatic HER2-positive breast cancer who received 2 prior regimens or T-DM1 in the metastatic setting.

Regarding safety with trastuzumab duocarmazine, ocular toxicities were observed as the most prevalent safety event, Hurvitz explains. As such, further research is needed to determine the severity of the ocular toxicities and how to best manage these events in this clinic, Hurvitz says.

In addition to these data regarding ADCs, data from phase 1 studies evaluating novel ADCs are also coming to light, so this will be a continually evolving field in 2022, Hurvitz concludes.

Sara A. Hurvitz, MD, discusses progress made in 2021 with antibody-drug conjugates in HER2-positive breast cancer.  



Dr. Hurvitz on Progress Made With Antibody-Drug Conjugates in HER2+ Breast Cancer 

Sara A. Hurvitz, MD, associate professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, director, Breast Cancer Clinical Trials Program, UCLA, discusses the clinical implications of the ongoing phase 2 SUMMIT trial (NCT01953926) in 

Updated results from the SUMMIT trial, which were presented during the 2021 San Antonio Breast Cancer Symposium, demonstrated that the combination of neratinib (Nerlynx), fulvestrant (Faslodex), and trastuzumab (Herceptin) elicited encouraging clinical activity in patients with heavily pretreated hormone receptor (HR)–positive, HER2-mutated metastatic breast cancer who received prior CDK4/6 inhibitors. The overall objective response rate (ORR) was 42.4% and the median progression-free survival (PFS) was 7 months. Additionally, the combination demonstrated promising clinical activity in patients with 

-mutated triple-negative breast cancer (TNBC). Here, the ORR was 33.3% and the median PFS was 6.2 months.

Additional research with a larger study is needed to further evaluate the utility of neratinib in patients with 

-mutated breast cancer. Many patients have 

 amplification, so this regimen provides another therapeutic option for patients with HR-positive breast cancer or TNBC that harbor 

Sara A. Hurvitz, MD, discusses the clinical implications of the ongoing phase 2 SUMMIT trial in HER2-mutated breast cancer.  



Dr. Hurvitz on the Clinical Implications of the SUMMIT Trial in HER2-Mutated Breast Cancer 

Sara A. Hurvitz, MD, associate professor, David Geffen School of Medicine, University of California, Los Angeles (UCLA), medical oncologist, medical director, Jonsson Comprehensive Cancer Center Clinical Research Unit, co-director, Santa Monica-UCLA Outpatient Oncology Practices, director, Breast Cancer Clinical Trials Program, UCLA, discusses the results of subgroup analyses from the phase 3 DESTINY-Breast03 trial (NCT03529110) in patients with HER2-positive metastatic breast cancer.

The DESTINY-Breast03 trial randomized patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab (Herceptin) and a taxane to fam-trastuzumab deruxtecan-nxki (Enhertu) vs ado-trastuzumab emtansine (T-DM1; Kadcyla). Initial results demonstrated a clinically meaningful progression-free survival (PFS) benefit with trastuzumab deruxtecan vs T-DM1 in this patient population.

During the 2021 San Antonio Breast Cancer Symposium, updated results from exploratory subgroup analyses of the study were presented. The findings showed that trastuzumab deruxtecan induced PFS and overall response rate (ORR) improvements vs T-DM1 across patients irrespective of hormone receptor status, prior pertuzumab (Perjeta), number of prior lines of therapy, and presence or absence of visceral disease.

Notably, patients with baseline brain metastases also derived a PFS and ORR benefit with trastuzumab deruxtecan vs T-DM1. In patients with stable brain metastases at baseline, the median PFS was 15 months with trastuzumab deruxtecan vs 3 months with T-DM1. The ORRs were 67.4% vs 20.5%, respectively.

Sara A. Hurvitz, MD, discusses the results of subgroup analyses from the phase 3 DESTINY-Breast03 trial in patients with HER2-positive metastatic breast cancer.  



Sara A. Hurvitz, MD, University of California, Los Angeles

Articles

Dr. Hurvitz on Sequencing Therapeutic Options in HER2+ Breast Cancer

Clinical Scenario: mTNBC Treated With Chemotherapy Then Sacituzumab Govitecan

Perspectives on the Current Treatment Landscape of TNBC

Dr. Hurvitz on the Clinical Implications of the DESTINY-Breast03 Trial in HER2+ Breast Cancer

Dr. Hurvitz on Utilizing CDK4/6 Inhibitors in HR+ Breast Cancer

Dr. Hurvitz on Progress Made With Antibody-Drug Conjugates in HER2+ Breast Cancer

Dr. Hurvitz on the Clinical Implications of the SUMMIT Trial in HER2-Mutated Breast Cancer

Dr. Hurvitz on the Results of Subgroup Analyses From DESTINY-Breast03 in HER2+ Breast Cancer

Rapid Readouts: Updated Results From DESTINY-Breast01