Targeted therapy: An integral component of HER2-positive breast cancer care
Click Here to Manage Email Alerts
Targeted therapies in HER2-positive breast cancer are integral to the success of treatment outcomes in this patient population.
Trastuzumab (Herceptin, Genentech) is the backbone treatment in the HER2 setting, with certain low-risk patients receiving this treatment alone, whereas those with metastatic disease are treated with trastuzumab alone or in combination with other therapies.
“More often than not, patients receive multiple HER2-targeted therapies together,” Arielle Heeke, MD, oncologist at Atrium Health, said during an interview with Healio. “We are very lucky in breast cancer to have three receptors that we can identify through biopsy of breast cancer cells — the estrogen receptor, progesterone receptor and the HER2 receptor — and we have the opportunity to use targeted therapies against these three receptors. Essentially, there is not a situation where we would not use these targeted therapies, except for a patient with very low-risk disease in which the risks of systemic treatment outweigh the potential benefits.”
Early-stage disease
In the early-stage disease setting, it is common practice to prescribe a dual agent blockade with trastuzumab plus the monoclonal antibody pertuzumab (Perjeta, Genentech).
“We initially saw improvements with this dual blockade in the neoadjuvant space, which is why patients who received treatment before surgery more often than not received dual HER2-targeted therapy with this combination,” Heeke said.
Benefit with this combination has also been observed in the adjuvant space.
In the phase 3 APHINITY trial , the addition of pertuzumab to adjuvant trastuzumab led to a significant improvement in invasive DFS among women with HER2-positive breast cancer.
Researchers assigned 4,805 women to either standard adjuvant chemotherapy plus 1 year of trastuzumab plus pertuzumab (n = 2,400) or placebo (n = 2,405). All patients had undergone lumpectomy or mastectomy.
Results showed invasive DFS events occurred in 171 women assigned pertuzumab compared with 210 women assigned placebo (7.1% vs. 8.7%; HR = 0.81; 95% CI, 0.68-1). Moreover, 3-year invasive DFS rates were 94.1% in the pertuzumab group vs. 93.2% in the placebo group. In addition, the 3-year invasive DFS rate was 92% with pertuzumab and 90.2% with placebo among women with lymph node-positive disease (HR = 0.77; 95% CI, 0.62-0.96).
“The APHINITY trial showed some benefit — although not as great as we had initially thought — with the combination that particularly benefited lymph node-positive patients as well as HR-negative patients,” Heeke said.
Yet another approved treatment in the adjuvant therapy space is the oral anti-HER2 agent, neratinib (Nerlynx, Puma Biotechnology).
“Neratinib is sometimes prescribed after completion of a trastuzumab-based neoadjuvant treatment plan that is completed during the course of 1 year — neratinib does not get introduced into the treatment plan until much later,” Heeke said. “Neratinib is another attempt against HER2. The downside of this therapy is having to ask a patient who has already gone through a year of treatment to start another treatment for another year. This is sometimes difficult.”
Neratinib is also used in the adjuvant setting.
“There are data suggesting that this therapy may penetrate the blood-brain barrier better than trastuzumab,” Heeke said. “For example, neratinib may be used in a high-risk patient with CNS metastases, which we know is possible in HER2 disease, and we are trying to prevent recurrence because that does happen, too. Neratinib is what comes to my mind when trying to prevent CNS relapse.”
Metastatic ‘toolbox’
In the metastatic setting, trastuzumab, pertuzumab, neratinib and the oral tyrosine kinase inhibitor lapatinib (Tykerb, Novartis) are used as well as tucatinib (Tukysa, Seagen), an oral TKI that is known to be highly selective for HER2.
Results of the global, double blind, randomized, phase 3 HER2CLIMB trial showed tucatinib plus trastuzumab and capecitabine extended OS among patients with brain metastases from HER2-positive breast cancer.
The triplet combination conferred a 68% decrease in risk for CNS progression compared with placebo plus trastuzumab and capecitabine (median CNS PFS, 9.9 months vs. 4.2 months; HR = 0.32; 95% CI, 0.22-0.48). Moreover, the triplet therapy demonstrated a higher intracranial-confirmed objective response rate (47% vs. 20%) and a longer median intracranial duration of response compared with placebo (6.8 months vs. 3 months).
“HER2CLIMB showed an impressive intracranial response in previously untreated brain metastases. The researchers were able to document responses to these brain metastases that were either progressing or newly identified at the time of trial enrollment,” Heeke said. “This has definitely given us a lot of hope for our HER2-positive patients who have CNS recurrence. It is, however, a bit of a ‘mixed bag’ in practice with some patients having a significant response to this treatment and others not having a significant response. Nonetheless, it is nice to have another option to treat brain metastases without having to rely only on radiation.”
Trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) is another therapy used in the HER2 metastatic setting.
“In clinical practice and in clinical trials, trastuzumab deruxtecan has shown response in patients who had previously progressed on trastuzumab and pertuzumab and the partial responses observed are deep, despite disease progression,” Heeke said. “There has been some concern about lung toxicity with this therapy observed in clinical trials, but we have been pleased that it has not been a major concern in clinical practice.”
One “question mark” in the metastatic setting is learning how to sequence some of the newer HER2-targeted therapies, according to Heeke.
“It depends on where the patient is with brain metastases vs. how active their intracranial disease is,” she said. “We do not have evidence that trastuzumab deruxtecan will impact CNS lesions, so as it stands right now in the third-line, if I have a patient with large volume intracranial disease, I treat them with trastuzumab deruxtecan, but if the patient has CNS disease that is maybe difficult to treat in the absence of whole brain radiation, then a tucatinib-based regimen may be favored in the third-line setting.”
The antibody drug conjugate ado-trastuzumab emtansine (Kadcyla, Genentech) is yet another treatment that can be used in the second-line metastatic disease setting and in the patient with early-stage disease who has undergone neoadjuvant therapy and has residual disease after surgery.
“There are wonderful data suggesting a 50% reduction in breast cancer recurrence if the patient transitions to ado-trastuzumab emtansine,” Heeke said.
In the randomized, phase 3 KATHERINE trial , investigators sought to assess whether adjuvant ado-trastuzumab emtansine for invasive residual breast cancer would outperform standard trastuzumab in reducing recurrence risk without increasing toxicity.
According to the study results, ado-trastuzumab emtansine reduced the risk for invasive recurrence or death by half (HR = 0.5; 95% CI, 0.39-0.64). In addition, 3-year DFS rates were 88.3% in the ado-trastuzumab emtansine group compared with 77% in the trastuzumab group.
“When this study came out in 2018, we switched our patients to ado-trastuzumab emtansine because even with the smallest bits of residual disease, there was a benefit there,” Heeke said. “Yet, ado-trastuzumab emtansine is a bit harder to tolerate. We sometimes run into issues with blood count, whether it be elevation in liver enzymes or decreases in platelet counts. These potential problems are real and may be long-term for these patients. There is also quite a bit of neuropathy, fatigue and muscle aches with this combination.”
While the KATHERINE study was exciting and there are certain populations who will benefit greatly from this therapy, there are patients with smaller-volume residual disease or a strong component of a hormone-driver cell, for whom many physicians are “gun shy” about automatically switching to ado-trastuzumab emtansine, Heeke added.
Toxicity
Despite the benefit, HER2-targeted agents are accompanied by toxicities.
“Trastuzumab is the standard therapy for this patient population and many of the toxicities of that therapy are accepted,” Heeke said. “Neratinib, however, can be accompanied by diarrhea, which can impact quality of life. The company that developed this therapy has done a very nice job assessing that side effect and figuring out how to best manage it. There are also some nice data looking at a ramped-up strategy for dosing with an anti-diarrheal, such as loperamide (Imodium). With that approach, patients do seem to tolerate neratinib better, but even so, it is still a lot of work on the patient’s part to communicate with their clinical team about symptoms and they must come back to the clinic more frequently to assess for symptoms and undergo lab work. There is a huge burden placed on the patient.”
Other serious side effects associated with these agents include cardiotoxicities.
“If a patient is fortunate enough to have a cardio-oncologist, which not everyone has, then that is wonderful. For those who do not have that opportunity, depending on the risk profile, if the patient has several cardiac diagnoses, then any cardiologist should be able to partner in their care and monitor in documenting their medications,” Heeke said.
Levine Cancer Institute at Atrium Health, Heeke’s institution, has a cardio-oncology program that allows for monitoring of evidence of cardiac toxicity from chemotherapy, Heeke added.
“Depending on the severity of the ejection fraction drop, we may hold treatment for a cycle or two, but fortunately and typically the ejection fraction will improve or even normalize where we can continue with treatment,” Heeke said. “For these patients, we do not typically use iron chelating agents, although in a very severe case that could be pursued, but usually it is the typical monitoring of every 3 months with echocardiograms. If there is a concerning patient upfront, then a cardiologist can help give advice on whether or not to treat the patient with the cancer therapy. There is usually a path forward; it is just a matter of how frequently the patient should be monitored with an echocardiogram, how frequently do we perform cardiac MRIs and should we push ACE inhibitors and beta blockers if they are not already on them.”
Concerns about resistance
There are also concerns about treatment resistance with HER2-targeted therapies.
“However, this is not just HER2-specific and is true for any targeted therapy in general,” Heeke said. “Unfortunately, cancers are super smart and what happens when a cancer cell is born is that it is made to be very adaptable. Cancer responds to pressures. If there is a road that is blocked, it finds another road. We see this with HER2 therapies as well as with endocrine therapies and chemotherapy.”
With HER2-targeted therapies, there is an interplay between the HER2 receptor and the estrogen receptor that leads to resistance, according to Heeke.
“For the patient with HER2-positive and ER-positive disease, we want to make sure that we are targeting both of those receptors because if we block one but do not block the other, then it will upregulate the other,” Heeke said. “In general, there is definitely resistance to trastuzumab and that is why the addition of pertuzumab is so helpful. Rather than putting all the work on trastuzumab, we add pertuzumab to the mix so that if a cancer cell is trying to overcome the block from trastuzumab alone then we have pertuzumab on board fighting the fight so that the resistance is delayed. There are always concerns about resistance, but we cannot throw all the therapies at a patient at once. We also know that just one therapy on its own is not going to be enough because of resistance. In a perfect world, we would biopsy every time a patient has progression, but we are not going to do that to our patients. Instead, if we can figure out how to best sequence therapies to provide the patient with durable response, then that would be amazing.”
In an updated analysis of the phase 2 DESTINY-Breast01 study , Modi and colleagues found that trastuzumab deruxtecan provided benefit among women with heavily pretreated HER2-positive metastatic breast cancer.
In addition, 74% of women remained alive at 18 months and a low number of women discontinued treatment due to treatment-associated adverse events, researchers noted.
“[Trastuzumab deruxtecan] continued to demonstrate clinically meaningful and durable efficacy, with an unprecedented median duration of response,” Modi and colleagues wrote. “Treatment resulted in a robust survival outcome...[and the therapy] showed a generally tolerable safety profile.”
Pipeline
Looking ahead, much of the work in the HER2 breast cancer space is being done in HER2-low populations, according to Heeke.
“This is exciting for these patients because they have not benefited recently from these newer drug developments,” Heeke said. “There is also an increasing understanding that pathways beyond the HER2 receptor can be upregulated in response to treatment pressure. This is where the CD4K6 inhibitors come into play to block some of those down-stream proliferation pathways that may get stimulated to bypass the attempted blockade of the HER2 pathway.”
Research looking into combining newer agents with older HER2-targeted therapies is also ongoing.
“There are tons of studies looking at immunotherapy combined with HER2-targeted therapy in a variety of different settings, including metastatic and even early-stage disease,” Heeke said. “Also, PI3K pathways, CD4K6 and others may not be ‘game changers,’ so to speak, but with ongoing efforts for more personalized care for our patients with increasing molecular profiling, we may be able to identify certain molecular features and genetic signatures for combination therapies that may be able to benefit patients more than the standard approach. This could be coming soon.”
Antibody drug conjugates that are even more potent than ado-trastuzumab emtansine and trastuzumab deruxtecan are also in development, Heeke added.
“These antibody drug conjugates can potentially be developed to do other things such as a side function that independently stimulates the immune system,” she said. “Trastuzumab itself is immune-modulating and then there is an antibody drug conjugate that independently stimulates our immune system, which together could be more effective or could set up an environment that is more susceptible to immunotherapy when combined.”
Developing TKIs that are smaller and more selective is also an active area of research.
“The push for smaller is to penetrate the CNS better and we have already seen this success with tucatinib,” Heeke said. “The aim of making them more selective is to help with all of the toxicities, such as diarrhea and rash, and that work is ongoing.”
Investigators are also working to repurpose current agents.
“We are definitely looking forward to data coming out on trastuzumab deruxtecan and tucatinib in the earlier-line setting — using these therapies potentially in the adjuvant setting or in the neoadjuvant setting rather than having to wait to use them in the metastatic scenario,” Heeke said. “The most exciting for me is figuring out how to use tucatinib in the adjuvant setting because we do have a selection of patients who develop CNS recurrence with no extracranial disease, which is a difficult scenario to be in. If we can use tucatinib to capture those patients and treat the brain so that they do not experience recurrence, then that would be wonderful. It is an area of unmet need.”
It will be difficult to identify the appropriate patients for that approach because not everyone will need tucatinib as the rates of CNS recurrence are relatively low, Heeke added.
“Still, it is tragic when it does happen, so this will be another area to investigate during the next few years: how to best select the right patients for these treatments,” Heeke said.
References:
Geyer JR CE, et al. Abstract GS1-10. Presented at: San Antonio Breast Cancer Symposium; Dec. 4-8, 2018; San Antonio.
Lin NU, et al. Abstract 1005. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Modi S, et al. Abstract PD3-06. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
von Minckwitz G, et al. Abstract LBA500. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
For more information:
Arielle Heeke, MD, can be reached at Atrium Health, 1021 Morehead Medical Dr. #6200, Charlotte, NC 28204.
Collapse
Healio Interview
Click Here to Manage Email Alerts