Can We De-escalate Therapy for HER2-Positive Metastatic Breast Cancer?

In this issue of Clinical Cancer Research, Shagisultanova and colleagues report the safety and efficacy of an all-oral combination of tucatinib, letrozole, and palbociclib (TLP) in patients with hormone receptor–positive (HR⁺) and HER2⁺ metastatic breast cancer (MBC) who had received ≥2 prior lines of HER2-targeted therapy in any setting and up to two lines of endocrine therapy (ET) for metastatic disease (1).

Tremendous advances have occurred in the treatment of HER2⁺ MBC; a current treatment algorithm is shown in Fig. 1. In the first-line setting, the standard of care is taxane chemotherapy in combination with the HER2 antibodies trastuzumab and pertuzumab (THP) based on the Cleopatra study (2). In the second- and third-line setting, treatment may be triaged on the basis of active central nervous system (CNS) disease, with trastuzumab deruxtecan (T-DXd) given first for those without active brain metastases based on the Destiny Breast-03 study (3), and the combination of tucacinib, trastuzumab, and capecitabine preferred for those with brain-dominant disease based on the HER2-Climb study (4). Further lines of therapy include T-DM1 (5), margetuxumab + chemotherapy (6), trastuzumab + lapatinib (7), neratinib + capecitabine (8), and trastuzumab + chemotherapy, with multiple ongoing clinical trials. While existing regimens are highly effective, chemotherapy combinations or antibody–drug conjugates (ADC) can have significant toxicity, requiring intravenous access and infusion time. Therefore, an all-oral, chemotherapy-free regimen is appealing for patients with HR⁺/HER2⁺ MBC given their need for lifelong therapy.

After response to first-line THP, chemotherapy is discontinued, and patients continue on trastuzumab + pertuzumab until disease progression. It is common practice to add maintenance ET for patients whose disease is also HR⁺ (9). Targeting both the HR and HER2 as primary treatment has been studied in multiple trials. Initial trials showed a modest improvement in progression-free survival (PFS) with trastuzumab or lapatinib + ET compared with ET alone, but did not improve overall survival (OS; refs. 10, 11). More recently, the randomized phase II PERTAIN study evaluated first-line trastuzumab plus an aromatase inhibitor with or without pertuzumab in HR⁺/HER2⁺ MBC, reporting a median PFS of 18.9 months for trastuzumab + pertuzumab and 15.8 months for trastuzumab (9). A phase III study in China demonstrated noninferiority of trastuzumab + ET versus trastuzumab + chemotherapy with a similar PFS (19.2 months in the ET group, 14.2 months in chemotherapy group) in patients with HR⁺/HER2⁺ MBC (12). In the later line setting, the phase II SOLTI-1303 PATRICIA trial evaluated the combination of palbocicilb and trastuzumab with or without letrozole in patients with HR⁺/HER2⁺ MBC in the third- to fifth-line setting, revealing a 6-month PFS rate of 42.8% for palbociclib + trastuzumab and 46.4% for palbociclib, trastuzumab, and letrozole. Collectively, these studies demonstrated encouraging PFS with ET + HER2-targeted therapy, without improvement in OS. Therefore, the clinical utility of these regimens remains unclear and none are yet considered standard therapy aside from the use of ET with trastuzumab + pertuzumab as maintenance after first-line THP.

Within this context, the current phase Ib/II multi-site study was designed to evaluate the safety and efficacy of the potent new oral tyrosine kinase inhibitor tucatinib in combination with letrozole and palbociclib (TLP) in patients with HR⁺/HER2⁺ MBC. Eligiblity included at least two HER2-targeted agents in the adjuvant or metastatic setting; patients were generally heavily pretreated, with a median of two lines of prior therapy in the metastatic setting. All patients had received prior trastuzumab and pertuzumab, nearly half received prior T-DM1, and only one had prior T-DXd. Prior use of ET was not reported. Most patients (n = 30, 71%) had visceral disease and over one-third had brain metastases (n = 15, 37.5%; 2 untreated).

During the phase Ib portion of the study, the authors observed that tucatinib increased the AUC_{10–19 hours} of palbociclib by 1.7-fold, requiring the palbociclib dose to be reduced to 75 mg for the phase II portion of the study. Even after this change, 17% discontinued palbociclib and continued tucatinib and letrozole (TL). TLP was associated with grade ≥3 neutropenia (64.3%), diarrhea (19.0%), fatigue (14.3%), and thrombocytopenia (9.5%). Abnormal liver function tests led to discontinuation of therapy in 1 patient.

In terms of efficacy, the median progression-free survival (mPFS) was 8.4 months in the 40 evaluable patients. Although this did not reach the prespecificed threshold of a 50% improvement over historical control [Th3resa trial (5), mPFS 6.2 months], these efficacy data are still quite encouraging. Some patients had a prolonged duration of response, including 25% (n = 10) for ≥1 year and 10% (n = 4) for ≥2 years. Notably, the mPFS was similar in the 15 patients with brain metastases versus those without (8.2 vs. 10.0 months, P = 0.9) and 26.6% of patients in the CNS cohort (n = 4) remained on study for ≥1 year.

The PFS and response data with TLP are encouraging, but the potential utility of the regimen in clinical practice is still unclear. The addition of pertuzumab to trastuzumab and a taxane in the first-line setting improved both PFS and OS (2), and similary the use of T-DXd in the second line improved both PFS and OS compared with T-DM1 (13). Tucatinib combined with capecitabine and trastuzumab improved PFS and OS compared with capecitabine and trastuzumab, including in patients with active brain metastases (4). These trials treated patients with HR⁺ and HR⁻ disease, with similar efficacy. Given that trials combining ET + HER2-targted therapy have not demonstrated OS benefit to date, there has been considerable discussion about how to apply these regimens to the current treatment algorithm. One potential utility would be to use regimens like TLP in patients with responding or stable disease. For example, TLP could be used as maintenance therapy after first-line THP instead of trastuzumab + ET, particularly in patients with CNS disease. Of particular interest given the toxicity of ongoing treatment with the ADC T-DXd, TLP could be utilized as maintenance after response to T-DXd, although the efficacy of TLP post-TDXd is unknown and only 1 patient had progressed on prior T-DXd in this trial. Alternatively, TLP could have a role as primary therapy in select settings, such as older patients with limited nonvisceral disease or those who cannot tolerate or decline chemotherapy.

On the basis of preclinical data in HER2⁺ cell lines, as well as efficacy in HR⁺ disease, palbociclib was added to the TL combination. The additional benefit of adding palbociclib is unclear, and comes with some toxicity—particularly the neutropenia observed in this study, and may have contributed to fatigue and thrombocytopenia. Future studies should clarify whether the addition of palbociclib increases the efficacy of this regimen.

Future multi-drug, non-chemotherapy regimens could evaluate the combination of tucatinib with other targeted agents and/or novel oral ETs such as oral selective estrogen receptor degraders. It is also possible that adding trastuzmab could further enhance the efficacy of this combination without a significant increase in toxicity, although it adds the need for intravenous access. Additional combinations of ET and HER2-targeted therapies for both early-stage and advanced HR⁺/HER2⁺ breast cancer as primary or maintenance therapy are of significant interest.

In summary, in this study TLP had a manageable safety profile and encouraging efficacy data, particularly considering that this is an all-oral, chemotherapy-free regimen. The combination warrants further investigation, and may eventually be a reasonable option for patients with HR⁺/HER2⁺ disease, particularly as maintenance or primary therapy for select patients.

H.S. Rugo reports institutional research support (grants) from AstraZeneca, Daiichi Sankyo, Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., GlaxoSmithKline, Lilly, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Sermonix, Stemline Therapeutics, Taiho Oncology, Inc., and Veru Inc and consultancy/advisory work with Puma, NAPO, Blueprint, Scorpion Therapeutics, Daichi Sankyo, and Mylan. No disclosures were reported by the other author.