Until recently, few options existed for patients with HER2-positive breast cancer who progressed on earlier lines of therapy. Recent approvals of 3 drug combinations offer new tools that may prolong life and control brain metastases across lines of therapy.
Until recently, few options existed for patients with HER2-positive breast cancer who progressed on earlier lines of therapy. “We had a first-line and second-line therapy; and then, third line and beyond, there wasn’t what we would consider a standard regimen,” Rashmi K. Murthy, MD, MBE, assistant professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology.
Progression-free survival (PFS) was often short, typically less than 5 months. Brain metastases, which occur in approximately 40% to 50% of patients with HER2-positive breast cancer, affected the quality of life of many who survived.
Recent approvals of 3 drug combinations—neratinib (Nerlynx) in combination with capecitabine1; tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine2; and Phesgo, a subcutaneous formulation containing trastuzumab, pertuzumab (Perjeta), and hyaluronidase-zzxf for injection under the skin3—offer new tools that may prolong life and control brain metastases across lines of therapy. In addition, promising research has demonstrated the potential for the second- generation antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) to treat patients who have received 2 or more lines of prior therapy.4
Recent data have indicated that HER2-targeted tyrosine kinase inhibitors (TKIs) are reasonable options for therapy of patients with metastatic breast cancer in the second-line setting and beyond.
In February 2020, the FDA approved neratinib (an irreversible pan-HER TKI) in combination with capecitabine for adults with advanced or metastatic HER2- positive breast cancer who have already received 2 or more anti-HER2–based regimens.1 Approval for this indication was based on the NALA trial (NCT01808573), which compared the effectiveness of capecitabine plus neratinib versus capecitabine plus lapatinib (Tykerb), a reversible TKI targeting both EGFR and HER2. The trial demonstrated that neratinib resulted in a superior 12-month PFS rate of 28.8% versus 14.8% for the lapatinib arm. The corresponding mean PFS values were 8.8 months and 6.6 months (HR, 0.76; 95% CI, 0.630.93; P = .0059). Median overall survival (OS) improved numerically for the neratinib group, at 21.0 months compared with 18.7 months for the lapatinib group, but the difference was not statistically significant (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). Median response duration was also longer for the neratinib group, at 8.5 months versus 5.6 months with lapatinib (HR, 0.50; 95% CI, 0.33-0.74; P = .004).5
“The NALA trial showed a modest progression-free survival benefit, but it has not yet shown a [significant] overall survival benefit,” Murthy said. Of note were results regarding the development of metastatic central nervous system (CNS) disease. There were fewer interventions for CNS disease in patients treated with neratinib (22.8%) compared with lapatinib (29.2%; P = .043), and time to intervention for CNS disease also improved in the neratinib arm. These results led investigators to suggest that the neratinib combination may have helped prevent or at least delayed the development of CNS disease.5
Importantly, although neratinib has shown some efficacy in patients with brain metastases, the NALA trial did not include any patients with active, symptomatic brain metastases. The phase 2 TBCRC 022 trial (NCT01494662) evaluated the neratinib/capecitabine combination in 49 patients with measurable, progressive HER2-positive brain metastases. In patients without prior lapatinib therapy (n = 37), the CNS objective response rate (ORR) was 49%, with 19% of patients having stable disease (SD) for 6 or more cycles; only 3% of patients experienced progressive CNS disease only. Among those who had previously received lapatinib (n = 12), the CNS ORR was 33%, with 25% of patients having SD for 6 or more cycles; only 8% of patients experienced progressive disease in the CNS only.6
In the lapatinib-naïve group, the median PFS was 5.5 months and the median OS was 13.3 months. Corresponding rates in the lapatinib group were 3.1 months and 15.1 months. These results led investigators to conclude that the combination is active against refractory, HER2-positive breast cancer brain metastases.
Diarrhea is the primary toxicity associated with neratinib, and it was the most common AE in both the NALA and TBCRC 022 trials. The investigators recommended strategies for diarrhea prevention and management to limit the dose reductions and study discontinuation associated with this AE (TABLE5,6 on page 22).
Approval for tucatinib in combination with trastuzumab and capecitabine in patients with advanced, unresectable or metastatic HER2-positive breast cancer following 1 or more prior anti-HER2–based regimens was based on the HER2CLIMB study (NCT02614794).2 The phase 2 trial compared the triplet regimen against placebo plus trastuzumab and capecitabine and included patients with active brain metastases. All patients had previously received trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting.7
“To date, there had not been a randomized study for metastatic HER2-positive breast cancer that included patients with brain metastases,” Murthy said. The inclusion of these high-risk patients was a deliberate decision based on “preclinical data that suggested [tucatinib] would have efficacy across the blood-brain barrier,” she said. “There are also preclinical data showing that mice that had intracranial disease and were treated with tucatinib lived longer than mice that had been treated with lapatinib or neratinib.”
As expected, data from the trial showed significant benefits for patients treated with the tucatinib combination, with 1-year PFS rates of 33.1% versus 12.3% for the placebo group (HR, 0.54; 95% CI, 0.42-0.71; P < .001). Among patients with brain metastases, the 1-year PFS rates were 24.9% for the tucatinib group and 0% for the placebo group. In the overall cohort, 2-year OS rates were 44.9% in the tucatinib group and 26.6% in the placebo group (HR, 0.66; 95% CI, 0.50-0.88; P = .005).7
“HER2CLIMB showed a survival advantage for patients with [previously] treated brain metastases, an effect that had not been seen before with such large numbers of patients in a controlled clinical trial,” said William J. Gradishar, MD, professor of medicine (hematology and oncology) and chief of hematology and oncology in the Department of Medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois. “This is probably the most compelling data set for a specific therapy that affects survival of patients who have brain metastases.”
According to an exploratory analysis of patients with CNS disease treated on HER2CLIMB, 47.3% of those with active, measurable brain lesions treated with the tucatinib triplet regimen experienced intracranial ORR compared with only 20.0% of those who were treated with the placebo regimen (P = .03). In all patients with brain metastases, CNS PFS (time to disease progression in the brain or death) improved significantly (HR, 0.32; 95% CI, 0.22-0.48; P < .00001), as did OS (HR, 0.58; 95% CI, 0.400.85; P = .005), and these benefits were further validated in subgroups of patients whose brain metastases were classified as either active or stable.8
“It’s not just that patients with brain metastases were staying alive longer but also that they saw objective shrinkage of the tumors in the brain,” said Ian E. Krop, MD, PhD, associate chief of the Division of Breast Oncology of the Susan F. Smith Center for Women’s Cancers and clinical research director of the Breast Oncology Center, both at Dana-Farber Cancer Institute in Boston, Massachusetts.
In the overall cohort, adverse effects (AEs), particularly diarrhea and elevated aminotransferase levels, occurred more frequently in the tucatinib group.7 “There was about a 13% incidence of grade 3 or higher diarrhea on tucatinib versus 9% on the placebo arm, but the diarrhea was quite manageable with short courses of antidiarrheals and wasn’t a significant problem,” said Murthy, who treated patients participating in HER2CLIMB and was the first study author. “We know that capecitabine, in and of itself, can cause diarrhea. For me, based on the adverse effect profile, it was hard to tell which patients were on tucatinib and which were on placebo.”
Most patients in the tucatinib group experienced AEs, but less than 6% discontinued treatment with tucatinib because of them.
Based on the results of both the NALA and HER2CLIMB trials, Krop said, “I think it makes more sense to use the HER2CLIMB regimen with tucatinib than it does to use neratinib” when treating women with metastatic HER2-positive breast cancer. “To me, the question is: Does neratinib work in a patient whose cancer has progressed on tucatinib?” he said. “Neratinib is a very potent and powerful agent in the laboratory setting; it’s an irreversible inhibitor, as opposed to tucatinib, which is reversible. Based on that, it may be that even when a cancer becomes resistant to tucatinib, it could still be sensitive to neratinib. I think that’s a question that needs to be addressed.”
T-DM1 and T-DXd are HER2-directed antibody-drug conjugates. Both agents have data supporting their use in patients with HER2-positive breast cancer, with FDA-approved indications in the relapsed setting.9,10
In the prospective phase 3b KAMILLA trial (NCT01702571), which involved T-DM1, almost 43% of patients with measurable brain metastases and HER2-positive locally advanced or metastatic breast cancer derived clinical benefit from treatment.11 Three of the 126 patients with measurable brain metastases experienced a complete response. Twenty-four had a partial response, and 27 experienced SD lasting 6 months or more. Almost half of patients (49.3%) who had not received prior radiotherapy for brain metastases experienced metastasis shrinkage of 30% or more. The median PFS and OS in these patients was 5.5 months and 18.9 months, respectively.
Patients with brain metastases experienced more nervous system toxicities from treatment, including epilepsy, seizure, and brain edema, than did those without brain involvement. Grade 5 AEs occurred in 3.5% of patients with baseline brain metastases and 1.9% of patients without brain metastases.
These data led investigators to conclude that T-DM1 is active and generally well tolerated, and patients who develop brain lesions during treatment with the agent may benefit from continued T-DM1 treatment after local therapy.
Krop detailed how T-DXd stands apart from other available agents with a similar mechanism of action. “The antibody part is essentially the same, but the payload—the chemotherapy part—is a different class of chemotherapy,” he said. “It’s from a class that’s not typically used in the treatment of breast cancer, so there’s less of a chance the cancer would have developed resistance.”
Additionally, Krop said, “once the conjugate delivers the payload to a HER2-positive cancer cell, some of the chemotherapy molecules can diffuse out of the cell and kill neighboring tumor cells.” That is important because research has shown that heterogeneous HER2 expression can decrease the effectiveness of drugs like T-DM1. “If you have a tumor that’s a mixture of cells, some with a lot of HER2 [expression] and others without, the concern is that you’ll kill the high-HER2 cancer cells but leave some behind,” he said.
The DESTINY-Breast01 trial (NCT03248492) examined the effects of T-DXd in patients with heavily pretreated HER2-positive metastatic breast cancer. All patients had previously been treated with T-DM1; most had received multiple other therapies as well. Nearly 61% of patients experienced a response to therapy. Median response duration was 14.8 months, and median PFS was 16.4 months.4
“To see a 61% response rate in a very heavily pretreated population is unprecedented,” Krop said. “The response rates and duration of disease control are much better than [what] we’ve seen with any other drug in this setting.” The most common grade 3 or higher AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Patients developed interstitial lung disease at a rate of 13.6%.
“The downside to trastuzumab deruxtecan is that a fraction of patients can experience interstitial lung disease. A few on the trial died,” Gradishar said. “But for the most part, the drug is well tolerated.” Given the risk of serious lung involvement, he said that clinicians should carefully question patients about their breathing and lung health and “have a low threshold” for determining which complaints should receive more in-depth attention.
Of the 184 patients treated on the trial, 48 experienced disease progression; among them, the CNS (brain) was the site of progression in only 4 patients. Two of these patients had CNS metastases at baseline and experienced CNS progression at 78 and 85 days. Brain metastases were noted at 323 and 498 days in the other 2 patients, who had no prior history of CNS disease. Additionally, a patient experienced 55% regression of a metastatic brain lesion after 12 weeks of treatment; she had undergone 16 prior lines of treatment, wholebrain radiotherapy, and stereotactic radiosurgery.
Median PFS values were similar for patients with and without brain involvement.
Despite these promising findings, additional research is needed to expand the examination of T-DXd’s impact beyond stable, asymptomatic brain metastases. As Murthy noted, the DESTINY-Breast01 trial “did not include patients with active brain metastases.”
According to Krop, investigators are currently conducting studies to determine whether administering T-DXd sooner might ultimately extend survival and disease-free progression. Trials are currently comparing the effectiveness of T-DM1 and T-DXd in the second-line setting.
On June 29, 2020, the FDA approved Phesgo, a fixed-dose combination of trastuzumab and pertuzumab, along with hyaluronidase-zzxf, for subcutaneous administration in combination with intravenous chemotherapy to treat adults with metastatic HER2-positive disease.3 This new formulation, which can also be used in patients with recurrent disease, combines 2 monoclonal antibodies to be administered as a single subcutaneous injection.13
This approval has the potential to dramatically alter the treatment experience for patients with HER2-positive breast cancer, as the combination of trastuzumab, pertuzumab, and taxane chemotherapy, administered intravenously, is currently listed as a preferred regimen for patients with HER2-positive recurrent or metastatic breast cancer in the National Comprehensive Cancer Network Clinical Practice Guidelines.14 Intravenous infusion of trastuzumab and pertuzumab typically takes 1.0 to 2.5 hours, whereas subcutaneous injection of Phesgo takes approximately 5 to 8 minutes.13
Results of the phase 2 PHranceSCa study (NCT03674112) showed that 85% of patients receiving treatment for HER2-positive breast cancer preferred subcutaneous treatment because it was more comfortable and required less time in the clinic. The results of the phase 3 FeDeriCa study (NCT03493854), which supported the Phesgo approval, demonstrated noninferiority of the subcutaneous option compared with standard intravenous delivery. Specifically, blood concentrations of trastuzumab and pertuzumab after subcutaneous treatment confirmed delivery of sufficient drug doses.
Based on these data, Krop said new options represent an opportunity to tailor treatment across lines of therapy depending on the patients’ needs. “I don’t think we can use a one-size-fitsall approach anymore,” he said. “You have to pay attention to the specifics of the particular patient in front of you. If you have a patient who has progressive brain metastases, then I think it clearly makes sense to use the tucatinib triplet regimen. In contrast, if you have a patient who’s never had brain metastases or had a metastasis long ago that was treated and hasn’t recurred, I think treating with T-DXd gives you a high chance of a good and durable response.”
“I think the real comparison now is between trastuzumab deruxtecan and tucatinib. Trastuzumab deruxtecan has an advantage in that it was first out and it’s a single drug, not a 3-drug regimen,” Gradishar said. “Where it’s lacking at this point is that there are more data regarding brain metastases with tucatinib than with trastuzumab deruxtecan.”
Moving forward, novel drug combinations may further expand treatment alternatives. “We saw excellent results with trastuzumab deruxtecan,” Murthy said. “We’ve seen excellent results with tucatinib. What about combining those 2 drugs and seeing [whether] we can improve outcomes even further?
1. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed August 31, 2020. https://bit.ly/3jACK8P
2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed August 31, 2020. https://bit.ly/3gPhryO
3. FDA approves breast cancer treatment that can be administered at home by health care professional. FDA. June 29, 2020. Accessed August 27, 2020. https://bit.ly/3cnaPqA
4. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
5. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: phase III NALA trial. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147.
6. Feldman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2–positive breast cancer and brain metastases. J Clin Oncol. 2019;37(13):1081-1089. doi:10.1200/JCO.18.01511
7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
8. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi: 10.1200/JCO.2020.38.15_suppl.1005
9. Kadcyla. Prescribing information. Genentech Inc; 2013. Accessed September 1, 2020. https://bit.ly/2ELtDnc
10. Enhertu. Prescribing information. Daiichi Sankyo Inc; 2019. Accessed September 1, 2020. https://bit.ly/3lCqG99
11. Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Published online July 5, 2020. Ann Oncol. doi:10.1016/j.annonc.2020.06.020
12. Jerusalem G, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(suppl 2):S63-S64. doi:10.1016/j.annonc.2020.03.239
13. FDA approves Roche’s Phesgo (fixed-dose combination of Perjeta and Herceptin for subcutaneous injection) for HER2-positive breast cancer. News release. June 29, 2020. Accessed August 31, 2020. https://bit.ly/34RrHV0
14. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2020. Accessed August 31, 2020. https://bit.ly/3bfyAjL