Concurrent radiotherapy with capecitabine and pyrotinib in patients with HER2-positive breast cancer and brain metastases

Symptomatic brain metastases (BM) develop in approximately 30–40% of patients with human epidermal growth factor receptor type 2 (HER2) positive advanced breast cancer (1). The management of these patients depends on multiple factors, such as the number and volume of BM, extracranial disease, performance status, comorbidities, previous treatment, expected toxicity, and treatment availability.

According to international recommendations, preferred therapeutic options for active symptomatic BM are surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRT), and their combinations (2,3). Patients not requiring immediate local intervention and those with stable BM after local therapy may be managed with next-line systemic therapies, including anti-HER2 agents, whereas patients progressing solely in the brain may continue the same systemic treatment after local therapy until further progression (2,3).

Monoclonal antibodies, such as trastuzumab and pertuzumab, essential therapies for HER2-positive breast cancer, have limited activity in the brain due to their low blood-brain barrier permeability (4). However, this does not apply to anti-HER2 tyrosine kinase inhibitors (TKIs), which, due to lower molecular weight, penetrate effectively into the brain (5). The most commonly used anti-HER2 TKI are lapatinib (reversible HER1 and HER2 inhibitor), neratinib (irreversible HER1, HER2, and HER4 inhibitor), and tucatinib (reversible and selective HER2 inhibitor).

Another frequently used medication for patients with BM across all breast cancer phenotypes, thanks to its good penetration in the brain, clinical efficacy, ease of administration, and reasonable toxicity, is oral capecitabine (6). This compound has been typically combined with TKI; however, as used alone, it showed 18% brain overall response rate (ORR) and a median progression-free survival (PFS) of 5 months in HER2-breast cancer patients with BM (7).

Several clinical trials have demonstrated the intracranial efficacy of TKI alone or in combination with capecitabine in HER2-positive breast cancer patients. For example, in the phase 2 LANDSCAPE study, upfront systemic treatment with lapatinib and capecitabine for newly diagnosed BM without previous WBRT achieved a brain ORR of 66% and a median time to brain progression of 5.5 months (8). In the phase 3 NALA study, brain ORR with capecitabine plus neratinib or lapatinib were 33% and 27%, with a median response duration of 8.5 and 5.6 months, respectively (9). A spectacular example of TKI efficacy is the HER2CLIMB study, in which the addition of tucatinib to trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) doubled intracranial response, reduced risk of intracranial progression or death by two-thirds, and decreased risk of death by nearly half (10). Based on these results, the combination of tucatinib, capecitabine, and trastuzumab has been recommended in the second and subsequent treatment lines for patients with active BM not requiring local intervention or with stable intracranial disease (2,3). In the late-line scenario, reasonable approaches are lapatinib or neratinib plus capecitabine, lapatinib with trastuzumab, or margetuximab (a human/mouse chimeric and Fc-engineered monoclonal antibody directed to HER2) (2,3).

Another therapeutic option in HER2-positive breast cancer patients with BM is trastuzumab deruxtecan (T-DXd), a new antibody-drug conjugate (ADC) with a payload containing cytotoxic topoisomerase I inhibitor. This compound has notable clinical benefits, especially in second and subsequent-line settings. A pooled analysis from three trials (DESTINY-Breast -01, -02, and -03), including patients with asymptomatic, pretreated, and stable, or asymptomatic, untreated, and active BM, showed a robust intracranial response with T-DXd, without excessive toxicity (11). Of note, the interval between local brain therapy and initiation of T-DXd was at least 60 days in DESTINY-Breast -01 and 14 days in DESTINY-Breast -02, -03 trials (11). This is relevant in light of a recent study showing a higher grade 4–5 radiation necrosis occurrence with concurrent administration of SRT and ADC (trastuzumab emtansine, trastuzumab deruxtecan, or sacituzumab govitecan) compared to non-concurrent treatment (7.1% vs. 0.7%, respectively) (12).

It has been hypothesized that combining brain radiotherapy with systemic therapies may reduce intracranial progression risk. Recently, a retrospective study showed higher rates of brain complete response (35% vs. 11%, P=0.008) with the addition of lapatinib to SRT compared with SRT alone, suggesting a potential synergistic effect of both treatments (13). However, due to the concern about possible radiation necrosis, few studies have employed this strategy.

Pyrotinib is a relatively new oral, small-molecule irreversible inhibitor of HER1 and HER2 TKI. The drug has been developed by Shanghai Hengrui Pharmaceutical (a subsidiary of Jiangsu Hengrui Medicine) to treat HER2-positive breast cancer (14). In August 2018, China’s State Drug Administration conditionally approved pyrotinib (400 mg orally, once daily) in combination with capecitabine (1,000 mg/m² orally, twice daily, on days 1–14 of each 21-day cycle) in advanced HER2-positive breast cancer previously treated with anthracycline or taxane. Subsequent phase 2 and 3 studies have established pyrotinib plus capecitabine as an effective second-line treatment in patients who failed to trastuzumab, taxanes, and anthracycline combinations (15-17). In the phase 2 PERMEATE trial in patients with unlimited prior lines of BM treatment, the intracranial ORR with pyrotinib and capecitabine in patients with and without previous radiotherapy was 42% and 75%, and response duration of 5.6 and 11.3 months, respectively (18).

The data on the combinations of radiotherapy and pyrotinib-based regimens have been scarce and inconsistent (Table 1) (19-25). A recent phase 1b/2 BROPTIMA study investigated the combination of pyrotinib plus capecitabine and radiotherapy in HER2-positive metastatic breast cancer with BM (26). The primary endpoint was central nervous system (CNS) PFS rate at 12 months per, which was assessed according to the Response Assessment in Neuro-Oncology (RANO-BM) criteria. The secondary endpoints included PFS, CNS ORR, overall survival, radiation and drug safety, and neurocognitive functions. The type of radiotherapy (WBRT or SRT) was chosen based on the size and number of BM and the site of parenchymal brain lesions. SRT with a total dose of 24 to 40 Gy in 3 to 5 fractions (8 Gy per fraction) was used for one to four lesions. Patients with five to ten lesions received SRT or WBRT (30 Gy/10 fx), and patients with more than ten lesions were managed with WBRT. The study included 40 patients, 19 (48%) and 10 (25%) with no previous or only one systemic therapy in the metastatic setting, respectively. Twenty-two patients (55%) had extracranial metastases, 30 patients (75%) had neurological symptoms at baseline, and 5 (12.5%) previously received brain therapy. Twenty-nine patients (73%) received SRT and 11 (27%) WBRT. All 40 patients completed radiotherapy, and 39 received at least one cycle of pyrotinib plus capecitabine. Only 6 patients (15%) stopped therapy due to adverse effects.

The 1-year brain PFS rate was 75%, and the median brain PFS was 18.0 months. Thirty-four patients (85%) achieved an intracranial response, including 17 (43%) with a confirmed complete response. The brain progression occurred in 21 patients, including six with concurrent extracranial progression. The new brain lesions appeared in 7 of 12 patients (58%) after SRT and in 6 of 9 patients (67%) after WBRT. Notably, the radiation necrosis in the SRT group occurred in only 4 of 29 patients (4 of 67 brain lesions; 6%), with a median time to arise of 17.4 months and a good response after symptomatic treatment.

Unlike other studies using capecitabine and TKI with or without trastuzumab in patients with BM (8-10), the majority of patients in the BROPTIMA study were symptomatic, and as many as 25% of them, due to severe neurological symptoms, could not complete the baseline Mini-Mental State Examination form. This limitation means that study findings need to be interpreted cautiously. Such patients, apart from treatment side effects, may experience worsening of already existing neurological symptoms (e.g., nausea or vomiting); thus, concurrent radiotherapy and systemic treatment may be challenging. On the other hand, potential withholding or delaying systemic treatment during radiotherapy may lead to extracranial progression.

Nevertheless, the results of this study suggest that radiotherapy combined with pyrotinib and capecitabine is relatively safe and may provide a durable intracranial survival benefit in HER2-positive breast cancer patients with BM. Further research is warranted to compare sequential vs. concomitant drug-radiotherapy combinations, considering treatment efficacy, safety, neurological symptoms control, and quality of life.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-39/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-39/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hurvitz SA, O’Shaughnessy J, Mason G, et al. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res 2019;25:2433-41. [Crossref] [PubMed]
2. Curigliano L, Castelo-Branco L, Gennari A, et al. ESMO Metastatic Breast Cancer Living Guidelines, v1.1 May 2023. [Accessed 2024-06-06]. Available online: https://www.esmo.org/living-guidelines/esmo-metastatic-breast-cancer-living-guideline
3. National Comprehensive Cancer Network. Breast Cancer (Version 4. 2024). [Accessed 2024-06-06]. Available online: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf
4. Stemmler HJ, Schmitt M, Willems A, et al. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs 2007;18:23-8. [Crossref] [PubMed]
5. Duchnowska R, Loibl S, Jassem J. Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer. Cancer Treat Rev 2018;67:71-7. [Crossref] [PubMed]
6. Morikawa A, Peereboom DM, Thorsheim HR, et al. Capecitabine and lapatinib uptake in surgically resected brain metastases from metastatic breast cancer patients: a prospective study. Neuro Oncol 2015;17:289-95. [Crossref] [PubMed]
7. Gouveia MC, Hidalgo Filho CM, Moreno RA, et al. Activity of capecitabine for central nervous system metastases from breast cancer. Ecancermedicalscience 2023;17:1638. [PubMed]
8. Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013;14:64-71. [Crossref] [PubMed]
9. Saura C, Oliveira M, Feng YH, et al. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol 2020;38:3138-49. [Crossref] [PubMed]
10. Lin NU, Borges V, Anders C, et al. Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial. J Clin Oncol 2020;38:2610-9. [Crossref] [PubMed]
11. Hurvitz SA, Modi S, Li W, et al. A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINYBreast (DB) -01, -02, and -03. Ann Oncol 2023;34:S335-6. [Crossref]
12. Lebow ES, Pike LRG, Seidman AD, et al. Symptomatic Necrosis With Antibody-Drug Conjugates and Concurrent Stereotactic Radiotherapy for Brain Metastases. JAMA Oncol 2023;9:1729-33. [Crossref] [PubMed]
13. Kim JM, Miller JA, Kotecha R, et al. Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis. Neuro Oncol 2019;21:659-68. [Crossref] [PubMed]
14. Li X, Yang C, Wan H, et al. Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci 2017;110:51-61. [Crossref] [PubMed]
15. Yan M, Bian L, Hu X, et al. Pyrotinib plus capecitabine for human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab and taxanes (PHENIX): a randomized, double-blind, placebo- controlled phase 3 study. Transl Breast Cancer Res 2020;1:13. [Crossref]
16. Ma F, Ouyang Q, Li W, et al. Pyrotinib or Lapatinib Combined With Capecitabine in HER2-Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study. J Clin Oncol 2019;37:2610-9. [Crossref] [PubMed]
17. Xu B, Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:351-60. [Crossref] [PubMed]
18. Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial. Lancet Oncol 2022;23:353-61. [Crossref] [PubMed]
19. Anwar M, Chen Q, Ouyang D, et al. Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data. Clin Cancer Res 2021;27:4634-41. [Crossref] [PubMed]
20. Lin Y, Lin M, Zhang J, et al. Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis. Cancer Res Treat 2020;52:1059-66. [Crossref] [PubMed]
21. Ma X, Li Y, Zhao Z, et al. Pyrotinib combining with radiotherapy on breast cancer with brain metastasis. Exp Biol Med (Maywood) 2023;248:106-16. [Crossref] [PubMed]
22. Gao M, Fu C, Li S, et al. The efficacy and safety of pyrotinib in treating HER2-positive breast cancer patients with brain metastasis: A multicenter study. Cancer Med 2022;11:735-42. [Crossref] [PubMed]
23. Liang X, Gui X, Yan Y, et al. Long-term Outcome Analysis of Pyrotinib in Patients With HER2-Positive Metastatic Breast Cancer and Brain Metastasis: A Real-World Study. Oncologist 2024;29:e198-205. [Crossref] [PubMed]
24. Tian W, Hao S, Wang L, et al. Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients. Anticancer Drugs 2022;33:e622-7. [Crossref] [PubMed]
25. Huang J, Zhu W, Duan Q, et al. Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases. Breast Cancer (Dove Med Press) 2023;15:841-53. [Crossref] [PubMed]
26. Yang Z, Meng J, Mei X, et al. Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases: A Nonrandomized Phase 2 Trial. JAMA Oncol 2024;10:335-41. [Crossref] [PubMed]