Treatment Strategies for Metastatic Breast Cancer: 2023 ASCO Annual Meeting

From June 2 to June 6, 2023, the annual meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, brought together oncologists, researchers, and members of the cancer care community to discuss innovative treatment strategies in the field of oncology, including immunotherapy, radiation therapy, neoadjuvant therapy, and chemotherapy. Many discussions focused on the treatment of MBC. Several promising combination therapeutic strategies for HR⁺HER2^– MBC were presented, providing potential alternatives for patients who develop resistance to endocrine therapy. In this article, Erika Hamilton, MD, director of Breast Cancer Research at the Sarah Cannon Research Institute in Nashville, Tennessee, provides insights into recent advances that were discussed at the 2023 ASCO Annual Meeting.

Use of the antigen Ki-67 as a prognostic marker in breast cancer has generated considerable controversy. To determine the utility of Ki-67 in guiding adjuvant abemaciclib therapy, Patel et al examined the relationship between the Ki-67 level and the 21-gene recurrence score in patients with lymph node-positive HR⁺HER2^– early breast cancer.¹ Can you discuss the clinical implications of this study?

Ki-67, a nuclear protein associated with cellular proliferation, has been linked to a higher risk of recurrence and worse survival in patients with early breast cancer.² Previously, the FDA had approved the use of adjuvant abemaciclib (a CDK4/6 inhibitor) only in patients with lymph node-positive HR⁺HER2^– early breast cancer who had a Ki-67 level of 20% or higher.³
 
Patel and colleagues reported results from a study of 50,222 women with HR⁺HER2^– early breast cancer. Ki-67 levels were defined as below 20% (low) and 20% or higher (high). Overall, the study showed fair agreement between Ki-67 level and recurrence score. However, the results revealed disagreement between ASCO Ki-67 criteria and FDA Ki-67 criteria in terms of patient eligibility for adjuvant abemaciclib therapy.¹
 
Notably, in March 2023, the FDA revised its criteria for adjuvant abemaciclib. Now, a Ki-67 level of 20% or higher is no longer required to qualify for the treatment; any patient with HR⁺HER2^– disease and 4 or more lymph nodes, or 1 to 3 lymph nodes and either grade 3 metastatic disease or a minimum tumor size of 50 mm, can qualify for adjuvant abemaciclib (regardless of Ki-67 level).⁴ Much of the previous confusion has now been resolved; the FDA criteria are now consistent with the ASCO/National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines.

TKIs were an important topic of discussion at this year’s ASCO meeting. Can you discuss the use of HER2 TKIs in HER2⁺ MBC?

HER2 is overexpressed in 15% to 20% of primary breast cancers.⁵ In the United States, there are 3 approved HER2-targeting TKIs: neratinib, lapatinib, and tucatinib.^6-8 Other HER2-targeting strategies under investigation include monoclonal antibodies (eg, trastuzumab and pertuzumab) and ADCs (eg, ado-trastuzumab emtansine [T-DM1] and trastuzumab deruxtecan [T-DXd]).⁹ Although multiple HER2-targeting agents have been approved, resistance can develop; therefore, novel therapies are needed to treat these cancers.
 
Particularly promising TKIs include pyrotinib and ZN-1041. At the meeting, Yan and colleagues reported 3-year follow-up results from a phase 2 trial that examined the combined use of pyrotinib and capecitabine in patients with HER2⁺ MBC. In that study, 78 patients received 21-day cycles of pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m², twice daily). In the radiotherapy-naive cohort, the median progression-free survival (PFS) and overall survival (OS) were 10.7 months and 35.9 months, respectively. In the radiotherapy-treated cohort, the PFS and OS were 5.6 months and 31.4 months, respectively.¹⁰ Overall, these findings suggest that a combination pyrotinib and capecitabine regimen offers a long-term survival benefit, consistent with the outcomes of multiple TKI plus chemotherapy combinations in patients with HER2⁺ breast cancer.
 
Ma et al presented evidence from an ongoing open-label phase 1 trial examining the safety, pharmacokinetics, and antitumor activity of ZN-1041 in the treatment of HER2⁺ breast cancer brain metastases. ZN-1041 was well tolerated and demonstrated a tumor objective response rate of 78.9%.¹¹

You were among several presenters at the meeting who discussed trastuzumab combination therapy in the treatment of HER2⁺ MBC.^12-14 What are the unique benefits of this combination regimen?

In many areas of oncology, we have learned that combinations of targeted agents can be more effective than monotherapy. Similarly, combination therapies are routinely used in the treatment of HER2⁺ MBC. Trastuzumab and pertuzumab are 2 monoclonal antibodies that target different domains of the HER2 receptor. Currently, the combination of trastuzumab, pertuzumab, and a taxane is the first-line standard treatment for HER2⁺ MBC.¹⁵ However, several patients with HER2⁺ MBC exhibit disease progression during maintenance with this regimen.
 
Previously, in the HER2CLIMB trial (ClinicalTrials.gov identifier: NCT02614794), we found that the use of the TKI tucatinib, in conjunction with a trastuzumab and capecitabine regimen, significantly improved PFS and OS in patients with HER2⁺ MBC.¹⁶ Prior to HER2CLIMB, the EGF104900 trial (ClinicalTrials.gov identifier: NCT00320385) showed that, even after progression on trastuzumab, the addition of lapatinib in combination with trastuzumab (another HER2-targeting TKI) led to a significant improvement in OS compared with lapatinib alone.¹⁷
 
In the ongoing HER2CLIMB-05 trial (ClinicalTrials.gov identifier: NCT05132582), we are investigating whether the addition of tucatinib to the first-line standard treatment can extend PFS and preserve quality of life in patients with HER2⁺ MBC.¹⁴ By combining trastuzumab, pertuzumab, and tucatinib, we are attempting to block the HER2 signaling pathway from multiple directions.

At the meeting, several presenters discussed using ADCs in the treatment of breast cancer.^18-22 Can you describe these therapeutics and their particular benefits in the treatment of MBC?

ADCs contain a cytotoxic (ie, chemotherapeutic) payload that is linked to a targeting antibody. The main benefit of ADCs is that they can selectively deliver a cytotoxic payload to cancer cells while sparing many of the body’s healthy cells. As a result, many patients experience more manageable adverse effects, compared with conventional chemotherapy.²³ Currently approved ADCs include: T-DXd, which targets both HER2-low and HER2-high breast cancers; sacituzumab govitecan, which targets trophoblast cell-surface antigen 2 (TROP2; a glycoprotein belonging to the tumor associated calcium signal transducer family); and T-DM1, which targets HER2-high breast cancer.^24-27

Abelman and colleagues presented results from a study examining the sequential use of ADCs.¹⁹ Can you explain the clinical implications of their findings?

Because several ADCs have been approved for clinical treatment of MBC, it is important to optimize their sequential use. In their study, Abelman and colleagues analyzed 193 patients with MBC who had received a median of 4 lines of treatment before initiation of the second ADC.¹⁹ A subset of 17 patients showed cross-resistance after prior use of an ADC. Notably, cross-resistance was reduced when the first and second ADCs targeted different proteins. PFS was shorter during receipt of the second ADC, but this was not surprising — all patients had received multiple lines of treatment, and there is evidence that PFS significantly decreases with each subsequent treatment for metastatic disease.²⁸
 
Some key questions remain: Despite the shorter PFS during receipt of the second ADC, does the second ADC outperform conventional chemotherapy options? There is also a need to investigate cross-resistance to ADCs that contain similar payloads.

You presented evidence from a phase 2 clinical trial examining the efficacy of the ADC HER3-DXd in the treatment of patients with HR⁺HER2^– MBC and patients with triple-negative MBC.²⁹ What were the key findings of your study, and how do you plan to proceed with the trial?

HER3-DXd is a molecule that has a linker and an exatecan payload identical to the components of T-DXd; however, it targets HER3, rather than HER2.³⁰ In our 3-part phase 2 trial, we are examining the safety and efficacy of HER3-DXd across MBC subsets to define the patient population most likely to experience a clinical benefit. In part A of the trial, we observed an objective response rate of 35% across patients with HR⁺ or triple-negative breast cancer (n=60) who had a median of 5 prior lines of treatment for metastatic disease. Patients tended to tolerate the treatment well; only 15% required any dose reduction. Furthermore, nausea, fatigue, and diarrhea were the most common adverse effects; none were reported by more than 50% of patients, and no grade 3 or 4 adverse events were reported by more than 7% of patients. The level of HER3 expression in cancer cells did not appear to affect the response — patients with low HER3 expression and patients with high HER3 expression had similar outcomes.²⁹
 
Thus, in part B of the study, we will enroll patients with HR⁺ breast cancer and patients with triple-negative breast cancer, regardless of HER3 expression. To understand ADC resistance and sequential use of ADCs, part B will include the enrollment of patients who were previously treated with ADCs (eg, sacituzumab govitecan or T-DXd). In part Z of the study, we will enroll patients with HER2⁺ breast cancer who previously received T-DXd.

ASCO 2023 concluded with discussions of several novel therapies for HR⁺HER2^– MBC. What are your thoughts about research progression in this area?

Advances in the treatment of HR⁺HER2^– MBC are currently among the most exciting areas in breast cancer research, and overall survival with CDK4/6 inhibitors now exceeds 3 years.³¹ Nevertheless, many patients develop endocrine resistance and must receive chemotherapy. Notable advances include the development of targeted agents that can be administered with endocrine therapies; for example, PI3K inhibitors and AKT inhibitors allow prolonged use of endocrine agents, whereas novel endocrine-based agents (eg, selective estrogen receptor degraders and proteolysis-targeting chimeras) offer new mechanisms for controlling target proteins.
 
For patients with resistance to endocrine agents, ADCs can selectively deliver chemotherapy to cancer cells. Several agents are currently approved for this purpose, including T-DXd and sacituzumab govitecan.
 
This Q&A was edited for clarity and length.

Disclosures

Erika Hamilton, MD, reported affiliations with AbbVie, Inc; Acerta Pharma; Accutar Biotechnology; ADC Therapeutics; Akeso Biopharma Co, Ltd; Amgen, Inc; Aravive, Inc; ArQule, Inc; Artios Pharma; Arvinas, Inc; AstraZeneca Pharmaceuticals, LP; AtlasMedx, Inc; BeiGene, Ltd; Black Diamond Therapeutics; Bliss BioPharmaceutical; Boehringer Ingelheim; Cascadian Therapeutics; Clovis Oncology, Inc; Compugen; Context Therapeutics; Cullinan Oncology; Curis, Inc; CytomX Therapeutics; Daiichi Sankyo Company, Ltd; Dana Farber Cancer Institute; Dantari, Inc; Deciphera Pharmaceuticals; Duality Biologics; eFFECTOR Therapeutics; Ellipses Pharma; Eli Lilly and Company; Elucida Oncology, Inc; EMD Serono, Inc; FujiFilm; Genentech, Inc; Gilead Sciences, Inc; Greenwich LifeSciences, Inc; G1 Therapeutics, Inc; H3 Biomedicine, Inc; Harpoon Therapeutics; Hutchison MediPharma Ltd; ImmunoGen; Immunomedics, Inc; Incyte Corporation; Infinity Pharmaceuticals; Inspirna, Inc; InventisBio Co, Ltd; Jacobio Pharmaceuticals Group Co, Ltd; Janssen Pharmaceuticals, Inc; Jazz Pharmaceuticals; Karyopharm Therapeutics, Inc; K-Group Beta, Inc; Kind Pharmaceuticals, LLC; Leap Therapeutics, Inc; Loxo Oncology, Inc; Lycera Corp; Mabspace Biosciences; MacroGenics, Inc; Medical Pharma Services; MedImmune, LLC; Mersana Therapeutics; Merus; Millennium Pharmaceuticals; Molecular Templates, Inc; Novartis Pharmaceuticals Corporation; NuCana plc; Olema Pharmaceuticals; OncoMed Pharmaceuticals, Inc; Onconova Therapeutics, Inc; Oncothyreon, Inc; ORIC Pharmaceuticals, Inc; Orinove, Inc; Orum Therapeutics; Pfizer, Inc; PharmaMar; Pieris Pharmaceuticals, Inc; Pionyr Immunotherapeutics, Inc; Plexxikon, Inc; Prelude Therapeutics, Inc; ProfoundBio; Radius Health; Regeneron Pharmaceuticals, Inc; Relay Therapeutics; Repertoire Immune Medicines; SeaGen, Inc; Sermonix Pharmaceuticals, LLC; Shattuck Labs; StemCentRx; Stemline Therapeutics, Inc; Sutro Biopharma, Inc; Syndax Pharmaceuticals, Inc; Syros Pharmaceuticals, Inc; Taiho Oncology, Inc; TapImmune, Inc; Tesaro, Inc; Theratechnologies, Inc; Tolmar, Inc; Torque Therapeutics, Inc; Treadwell Therapeutics, Inc; Tubulis GmbH; Verascity Science, LLC; Verastem Oncology; Zenith Epigenetics, Ltd; Zentalis Pharmaceuticals; and Zymeworks, Inc.

References

1. Patel R, Bilani N, Tiersten A, Sparano JA. Utility of Ki67 in guiding adjuvant abemaciclib therapy for patients with hormone receptor (HR)-positive, early breast cancer (EBC). Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 559.
 
2. de Azambuja E, Cardoso F, de Castro G Jr, et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007;96(10):1504-1513. doi:10.1038/sj.bjc.6603756
 
3. FDA approves abemaciclib with endocrine therapy for early breast cancer. News release. US Food and Drug Administration. October 12, 2021. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer
 
4. FDA D.I.S.C.O. Burst Edition: FDA approval of Verzenio (abemaciclib) with endocrine therapy for patients with HR-positive, HER2-negative, node-positive, early breast cancer. News release. US Food and Drug Administration. March 24, 2023. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-verzenio-abemaciclib-endocrine-therapy-patients-hr-positive
 
5. Wolff AC, Hammond ME, Hicks DG, et al; American Society of Clinical Oncology; College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013. doi:10.1200/JCO.2013.50.9984
 
6. FDA approves neratinib for metastatic HER2-positive breast cancer. News release. US Food and Drug Administration. February 26, 2020. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer
 
7. GSK’s Tykerb® receives accelerated approval for first-line combination treatment of hormone receptor positive, HER2+/ErbB2+ metastatic breast cancer. News release. GSK plc. January 28, 2010. Accessed June 27, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-s-tykerb-receives-accelerated-approval-for-first-line-combination-treatment-of-hormone-receptor-positive-her2pluserbb2plus-metastatic-breast-cancer/
 
8. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. News release. US Food and Drug Administration. April 20, 2020. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer
 
9. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22(2):101-126. doi:10.1038/s41573-022-00579-0
 
10. Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases: 3-year follow-up results from the phase 2 PERMEATE trial. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 1048.
 
11. Ma F, Li Y, Yao H, et al. Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 1040.
 
12. Yamashita T, Kawaguchi H, Masuda N, et al. Combination of eribulin with trastuzumab and pertuzumab for HER2 positive advanced or recurrent breast cancer: JBCRGM03. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e13031.
 
13. Han HS, Costa RL, Soliman HH, et al. Phase I study of adoptive T cell therapy following HER2-pulsed dendritic cell vaccine and pepinemab/trastuzumab in patients with metastatic HER2-positive breast cancer (MBC). Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract TPS1113.
 
14. Hamilton EP, O’Sullivan CC, Martin M, et al. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress). Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract TPS1108.
 
15. Schettini F, Conte B, Buono G, et al. T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study. ESMO Open. 2021;6(2):100099. doi:10.1016/j.esmoop.2021.100099
 
16. 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
 
17. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012;30(21):2585-2592. doi:10.1200/JCO.2011.35.6725
 
18. Gough M, Kwah K, He Y, Snell CE, Hooper JD, Kryza T. Development of a CUB domain-containing protein 1 (CDCP1)-targeting antibody-drug conjugate for triple-negative and metastatic breast cancer. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e15012.
 
19. Abelman RO, Spring L, Fell GG, et al. Sequential use of antibody-drug conjugate after antibody-drug conjugate for patients with metastatic breast cancer: ADC after ADC (A3) study. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 1022.
 
20. Anders CK, Lin NU, Chand A, et al. Preclinical and early clinical data of ZN-1041 in combination with trastuzumab deruxtecan to treat breast cancer with or without CNS metastases. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 1041.
 
21. Ali MA, Aiman W, Afzal F, et al. Efficacy of antibody-drug conjugates in breast cancer: A systematic review and meta-analysis of randomized clinical trials. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e13113.
 
22. Yang T, Guo P, Wei Q. A study of antibody conjugates for the treatment of inflammatory breast cancer. Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract e15016.
 
23. Dan N, Setua S, Kashyap VK, et al. Antibody-drug conjugates for cancer therapy: chemistry to clinical implications. Pharmaceuticals (Basel). 2018;11(2):32. doi:10.3390/ph11020032
 
24. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. US Food and Drug Administration. May 11, 2022. Accessed June 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer
 
25. FDA D.I.S.C.O. Burst Edition: FDA approval of Trodelvy (sacituzumab govitecan-hziy) for HR-positive breast cancer. News release. US Food and Drug Administration. March 1, 2023. Accessed June 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-trodelvy-sacituzumab-govitecan-hziy-hr-positive-breast-cancer
 
26. FDA approves ado-trastuzumab emtansine for early breast cancer. News release. US Food and Drug Administration. May 6, 2019. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer
 
27. Grinda T, Rassy E, Pistilli B. Antibody-drug conjugate revolution in breast cancer: the road ahead. Curr Treat Options Oncol. 2023;24(5):442-465. doi:10.1007/s11864-023-01072-5
 
28. Bailey CH, Jameson G, Sima C, et al. Progression-free survival decreases with each subsequent therapy in patients presenting for phase I clinical trials. J Cancer. 2012;3:7-13. doi:10.7150/jca.3.7
 
29. Hamilton EP, Dosunmu O, Shastry M, et al. A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). Abstract presented at: American Society of Clinical Oncology (ASCO) 2023 Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 1004.
 
30. Jänne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer. Cancer Discov. 2022;12(1):74-89. doi:10.1158/2159-8290.CD-21-0715
 
31. Goyal RK, Chen H, Abughosh SM, Holmes HM, Candrilli SD, Johnson ML. Overall survival associated with CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer in the United States: A SEER-Medicare population-based study. Cancer. 2023;129(7):1051-1063. doi:10.1002/cncr.34675
 
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cancer Therapy Advisor had no role in this content’s preparation.