Pegram Points to Progress, Ongoing Efforts in Advanced HER2+ Breast Cancer

Physicians treating patients with HER2-positive metastatic breast cancer (MBC) have had their share of wins with treatment advances in the past few years.

In the general breast cancer space, the FDA approved fulvestrant (Faslodex) in 2002 and trastuzumab (Herceptin) in 2006, adding then-new tools to the armamentarium. Since then, the agency has approved agents such as alpelisib (Piqray), palbociclib (Ibrance), and the combinations including trastuzumab plus capecitabine and ribociclib (Kisqali) plus letrozole.

For all that success, this is still a patient population in need of more treatment options, Mark Pegram, MD, said during the 20th Annual International Congress on the Future of Breast Cancer® West, a program hosted by Physicians’ Education Resource®, LLC.¹ He is the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology at Stanford University School of Medicine and associate director of clinical research at Stanford Comprehensive Cancer Institute.

The upside, he said, is that there are a number of novel therapies under investigation that may fill that unmet need. Investigators demonstrated the value of dual-targeting HER2 and estrogen receptor (ER) more than a decade ago. However, data from the SYSUCC-002 trial (NCT01950182) presented at the 2021 ASCO Annual Meeting demonstrated how trastuzumab plus endocrine therapy could benefit patients with luminal B2 breast cancer.

Zhong-Yu Yuan, MD, of the Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues enrolled 392 patients with hormone receptor­–positive/HER2-positive advanced breast cancer on the open-label, noninferiority, randomized, controlled phase 3 trial at 9 hospitals in China. From September 2013 to December 2019, patients were randomized 1:1 to trastuzumab plus endocrine therapy or trastuzumab plus chemotherapy.²

In the intent-to-treat population, the HR for PFS was 0.88 (95% CI, 0.71-1.09; P non-inferiority <.0001), demonstrating noninferiority between the 2 groups. 

Moreover, the endocrine therapy group experienced fewer grade 3 or higher adverse events (AEs) vs the chemotherapy arm. Forty-one patients in the chemotherapy group experienced grade 3/4 leukopenia compared with 1 in the endocrine therapy group. Thirty-six of those assigned to chemotherapy experienced grade 3 alopecia compared with none in the endocrine group.

“Trastuzumab plus endocrine therapy was noninferior, statistically, to chemotherapy and trastuzumab, and had fewer toxicities than trastuzumab plus chemo in patients with triple-positive disease in an exploratory subset analysis,” Pegram said. “It suggests the endocrine therapy plus trastuzumab was likely more beneficial in patients who had longer disease-free intervals of greater than 24 months. The question remains: Does this principle established by this randomized, phase 3 trial…apply to the pertuzumab [Perjeta] era? We do not have data on that in randomized fashion just yet, but at least this gives us confidence when we do face patients from time to time who are not suitable candidates for chemotherapy or who refuse chemotherapy for first-line treatment of triple-positive disease…now we have data suggesting that antiestrogens combined with trastuzumab can be highly effective and well tolerated.”

Investigators are conducting the open-label, phase 3 PATINA trial (NCT02947685) further exploring endocrine therapy plus HER2-targeted therapy. Patients (N = 496) with histologically confirmed HR-positive/HER2-positive MBC will be randomly assigned to trastuzumab with or without pertuzumab in combination with an aromatase inhibitor or fulvestrant with or without palbociclib until disease progression. The primary objective is to demonstrate a PFS benefit with combination of palbociclib plus HER2-targeted therapy and endocrine therapy compared with HER2-targeted therapy plus endocrine therapy.

Immunotherapy Shows Promise

Pegram said that investigators have recently seen evidence that immune checkpoint inhibition in combination with the antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1; Kadcyla). Previous findings from the EMILIA trial (NCT00829166) of 991 adults with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane showed that T-DM1 improved median overall survival (OS) compared with capecitabine plus lapatinib (Tykerb; 29.9 vs 25.9 months; HR, 0.75; 95% CI, 0.64-0.88).³

In the international, randomized, double-blind, placebo-controlled, phase 2 KATE2 trial (NCT02924883), researchers evaluated the anti­­–PD-L1 monoclonal antibody atezolizumab (Tecentriq) in combination with T-DM1 in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. A total 133 patients were randomized to the combination and 69 to placebo.⁴

At a median follow-up of 8.5 months, the median PFS was 8.2 months for patients assigned atezolizumab vs 6.8 months for those assigned placebo (stratified HR, 0.82; 95% CI, 0.55-1.23; P = .33).

“In subset analysis, the PD-L1–positive subset had a signal in an exploratory subset analysis for a PFS benefit,” Pegram said. “On that basis, a randomized phase 3 KATE3 trial in PD-1/PD–L1-positive, HER2-positive patients is now ongoing, so stay tuned for further updates on this front. As you know, T-DM1 is also being combined with tucatinib [Tukysa] in the metastatic disease setting as well.”

Durable Results from HER2CLIMB

Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano and the head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy, presented updated results from the phase 2 HER2CLIMB trial (NCT02614794) during the 2021 ASCO Annual Meeting.

Tucatinib maintained an OS benefit of 5.5 months in the total study population (N = 612) at a total follow-up of 29.6 months. The median OS in the tucatinib arm was 24.7 months (95% CI, 21.6-28.9) vs 19.2 months (95% CI, 16.4-21.4) in the placebo arm (HR, 0.73; 95% CI, 0.59-0.90; P = .004). Tucatinib also significantly reduced the risk of disease progression or death by 30% (HR, 0.70; 95% CI, 0.55-0.89; P = .004) in patients with brain metastases and by 20% (HR, 0.80; 95% CI, 0.48-1.3; P = .36) in patients with visceral metastases.⁵

The HER2 TKI also maintained an investigator-assessed PFS benefit was maintained with longer follow-up (HR, 0.57; 95% CI, 0.47-0.70; P < .00001). The median PFS was 7.6 months (95% CI, 6.9-8.3) in the tucatinib arm compared with 4.9 months (95% CI, 4.1-5.6) in the placebo arm.

“Tucatinib in combination with trastuzumab and capecitabine continues to improve progression-free and overall survival in patients with HER2-positive breast cancer,” Curigliano had said during a presentation on the findings. “This combination has the potential to become a new standard of care in this patient population.”

Investigators enrolled patients with unresectable, locally advanced or metastatic HER2-positive breast cancer were enrolled in the study. All had been previously treated with trastuzumab, pertuzumab, and T-DM1.

Furthermore, in prior data tucatinib demonstrated superior OS and intracranial objective response rate (ORR-IC) in patients with brain metastases. The ORR-IC was 47.3% vs 20.0% favoring the tucatinib arm. The TKI improved OS by 51% (HR, 0.49) in those with active brain metastases and by 42% (HR, 0.58) in those with all brain metastases.

Pegram added that brain-lesion free survival also favored the experimental arm (HR, 0.52; 95% CI, 0.33-0.82), suggesting that a tucatinib-based regimen may be able to delay or prevent new brain metastatic lesions. “That could be clinically very impactful because it could lead to a delay, or hopefully, eliminate need for local measures such as neurosurgery or ionizing radiation.”

Other HER2-directed therapies have shaken up the paradigm in recent years, including margetuximab (Margenza), fam-trastuzumab deruxtecan-nxki (Enhertu), and neratinib (Nerlynx), noted Pegram.

References

1. Pegram M. Integrating novel therapies for HER2+ metastatic breast cancer. Presented at: 20th Annual International Congress on the Future of Breast Cancer; July 30-31, 2021; Dallas, TX.
2. Yuan Z, Huang J-J, Hua X, et al. Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for metastatic breast cancer with hormone receptor-positive and HER2-positive: The SYSUCC-002 randomized clinical trial. J Clin Oncol. 2021;39:(suppl 15; abstr 1003). doi: 10.1200/JCO.2021.39.15_suppl.1003
3. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742. doi: 10.1016/S1470-2045(17)30312-1
4. Emens LA, Esteva FJ, Beresford M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020;21(10):1283-1295. doi:10.1016/S1470-2045(20)30465-4
5. Curigliano G, Mueller V, Borges V, et al. Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with or without brain metastases, J Clin Oncol. 2021;39(suppl 15; abstr 1043). doi:10.1200/JCO.2021.39.15_suppl.1043