Optimizing HER2-Targeted Therapy

Sara A. Hurvitz, MD

The introduction of HER2-targeted therapies has drastically improved long-term survival for patients with HER2-positive breast cancer and provided numerous treatment options for all stages of the disease. “The good side to HER2-positive disease is the number of therapies we have available,” Sara Hurvitz, MD, director of the Breast Cancer Clinical Research Program at the University of California, Los Angeles (UCLA), and associate professor at the David Geffen School of Medicine at UCLA said in an interview with OncLive. “Women can live a long time with this disease.”

To Escalate or De-escalate Therapy?

Choosing which patients benefit from treatment beyond the standard first-line regimen and where new HER2-targeted agents and therapeutic approaches fit into treatment algorithms will be the next steps moving forward, according to Hurvitz and Sunil Verma, MD, professor and head of the Department of Oncology at the University of Calgary, who also shared his insight in an interview with OncLive.Although targeted therapies are a mainstay of treatment, results from recent research show that management of HER2-positive breast cancer should not be a one-size-fits-all approach (Table). Identifying the low-risk patients who can receive standard-of-care treatment and the high-risk patients who should receive additional therapy is important to individualizing treatment and were the the central theme of Verma's talk, “Individualizing Therapy for Early-Stage HER2+ Breast Cancer: To Escalate or De-escalate?" at the recent Miami Breast Cancer Conference^® (MBCC).

TABLE. Novel Agents Explored for Potential in Individualized HER2-Targeted Therapy

A 7-year follow-up analysis of data from the APT trial¹ showed that adjuvant paclitaxel (Taxol) plus trastuzumab (Herceptin) for 12 weeks, followed by weekly trastuzumab for 39 weeks, led to a disease-free survival (DFS) rate of 93.3% and incidences of distant and local/regional recurrences of 1.0% and 1.2%, respectively, among patients with small HER2-positive lesions and negative lymph nodes. Because the standard approach of taxane-based chemotherapy plus trastuzumab “appears to be very effective,” Verma said, additional HER2-targeted therapy is likely unnecessary for low-risk patients.

Data from the APHINITY trial² suggest that the standard approach may also be adequate for patients with high-risk node-negative disease. Although the addition of pertuzumab (Perjeta) to standard adjuvant chemotherapy plus 1 year of trastuzumab significantly improved 3-year invasive DFS in patients with node-positive or highrisk node-negative disease (94.1% vs 93.2% with placebo), the improvement was driven primarily by the node-positive subgroup, as the invasive DFS was not different between pertuzumab and placebo in patients with node-negative disease (97.5% vs 98.4% with placebo).

However, Verma noted that patients at higher risk for recurrence or metastases, such as those with node-positive disease or significant residual disease after neoadjuvant therapy, may benefit from treatment beyond the standard chemotherapy and trastuzumab. Although the improvement was modest in the overall intent-to-treat population, the 3-year rate of invasive DFS was significantly improved with pertuzumab in the node-positive subgroup (92.0% vs 90.2% in the placebo group) and was sufficient for FDA approval for pertuzumab in the adjuvant setting in December 2017.

Extended treatment with neratinib (Nerlynx) may also benefit high-risk patients, although Verma said that the benefits appear to be restricted to patients with HER2-positive and hormone receptor (HR)-positive disease. An exploratory subgroup analysis from the phase III ExteNET trial³ showed that neratinib lowered the risk of recurrence by 51% in HR-positive patients versus 7% in HR-negative patients.

Optimal Therapy in HER2+ Metastatic

However, Verma stated that more discourse is needed to identify which patients are high risk. “Is 1 [positive] lymph node considered high risk? What about patients who have larger tumor size but are node-negative? Should all patients receiving neoadjuvant therapy for small tumors receive chemotherapy, trastuzumab, and pertuzumab? There are still unanswered questions in this area, so one has to consider patient- and tumor-related factors to help individualize treatment decisions.”Taxane-based chemotherapy, trastuzumab, and pertuzumab is the standard first-line regimen for HER2-positive metastatic breast cancer, based on results from the CLEOPATRA study,⁴ which showed improved progression-free survival (PFS) over docetaxel plus trastuzumab. Ado-trastuzumab emtansine (T-DM1; Kadcyla) is the standard second-line therapy, and multiple options are available in subsequent-line settings, although a standard of care has not been established.

Verma noted that selecting the optimal therapeutic sequence depends on several factors, which he discussed at MBCC during his talk, “Clinical Algorithm for HER2-Positive Metastatic Breast Cancer.” Although he said that trastuzumab, pertuzumab, and taxane-based chemotherapy is generally appropriate if patients have had a diseasefree interval greater than 12 months after stopping trastuzumab, the optimal approach for patients with a shorter disease-free interval is still debated among experts. Additionally, Verma stated that the increased use of pertuzumab in the neoadjuvant and adjuvant settings over the past few years could change the treatment approach for patients who relapse into metastatic disease. “The impact of adjuvant therapy on treatment choice in the first-line metastatic setting has not been fully addressed in the clinical trial events,” said Verma.

Newer HER2-Targeted Approaches

Because patients with HR- and HER2-positive disease can benefit from hormonally targeted approaches, Verma and Hurvitz suggested that regimens that combine aromatase inhibitor (AI) combinations or tamoxifen with HER2-targeted therapy may reduce or eliminate the need for chemotherapy in patients with HR- and HER2-positive breast cancer. Verma noted that even if a chemotherapyfree regimen with 2 HER2-targeted agents and an AI does not improve overall survival (OS), it may offer a better quality of life than regimens containing chemotherapy. Data from the phase III ALTERNATIVE trial⁵ showed that an AI with lapatinib and trastuzumab significantly improved PFS, with a similar incidence of adverse events compared with an AI with either lapatinib or trastuzumab. However, prospective studies comparing combinations of HRand HER2-targeted regimens with chemotherapybased regimens are needed to determine whether chemotherapy can be delayed or eliminated from the treatment regimen, said Hurvitz.Although the multiple HER2-targeted therapies have drastically improved the prognosis for patients with HER2-positive breast cancer, Verma and Hurvitz agreed that central nervous system (CNS) metastases remain a major treatment challenge. Verma estimated that up to 60% of patients with HER2-positive breast cancer develop brain metastases—which decrease the survival rate substantially—over the course of the disease. Because most HER2-targeted agents do not cross the blood—brain barrier, treatment options for brain metastases have been limited to surgery, stereotactic radiosurgery, whole-brain radiation therapy, or some combination of the 3 depending on the number of metastatic lesions. However, these treatments typically yield short-term responses, do not significantly improve OS, and can cause significant toxicity, such as decline in cognitive function with whole-brain radiotherapy.

Hurvitz said that tucatinib (ONT-380), an antiHER2 tyrosine kinase inhibitor (TKI) that has demonstrated activity in the CNS, is an exciting new HER2-targeted agent that she discussed in detail in her talk, “Newer HER2-Targeted Approaches,” at MBCC. Additionally, tucatinib selectively targets HER2, which reduces the incidence of the diarrhea and rash often seen in agents that target HER2 and HER1, such as lapatinib and neratinib. A phase Ib study⁶ presented at the 2016 San Antonio Breast Cancer Symposium showed that tucatinib, capecitabine, and trastuzumab produced a CNS response in 42% of patients with brain metastases. The ongoing phase III HER2CLIMB trial will evaluate capecitabine and trastuzumab with tucatinib or placebo in patients with locally advanced or metastatic HER2-positive breast cancer, including those with progressing brain metastases.

“Most studies do not allow patients who have brain metastases that are actively growing,” said Hurvitz. “I think it’s a very exciting drug.” The antibody—drug conjugate DS-8201 (trastuzumab deruxtecan) is another promising option that has shown “incredible activity” in heavily pretreated HER2-positive metastatic breast cancer and in low–HER2-expressing breast cancer, Hurvitz said. DS-8201 received an FDA Breakthrough Therapy designation in August 2017 for patients with HER2- positive locally advanced or metastatic breast cancer previously treated with trastuzumab plus pertuzumab and who progressed on T-DM1, based on an ongoing phase Ib study⁷ showing overall response and disease control rates of 40% and 90%, respectively, with responses observed in 4 of 14 patients with low HER2 expression.

Pyrotinib (HTI-1001), an oral, irreversible panErbB receptor TKI, is another novel HER2-targeted agent that showed promising activity in patients with previously treated HER2-positive metastatic disease, according to Hurvitz. A randomized phase II trial⁸ comparing capecitabine plus lapatinib or pyrotinib showed that the pyrotinib group had a significantly better objective response rate (78.5% vs 57.1%) and PFS (18.1 vs 7.0 months) than the lapatinib group.

Hurvitz said that the addition of immunotherapy to current HER2-targeted therapies is another promising approach for treatment-refractory disease because HER2-positive breast cancer tends to be more immune activated than other types of breast cancer. Recent data from the phase Ib/II PANACEA trial⁹ presented at the 2017 San Antonio Breast Cancer Symposium showed that pembrolizumab (Keytruda) plus trastuzumab led to a disease control rate of 24% in patients with PD-L1—positive, HER2-positive disease that was refractory to trastuzumab alone, with stromal tumor–infiltrating lymphocytes identified as a potential predictive marker of response.

Hurvitz predicted that these new approaches will most likely be used in third-line settings or beyond, as no studies have compared the novel agents with first- or second-line regimens. “Which of these drugs is going to come out as a front-runner and take the place as a third- or fourth-line drug is not clear,” she said. “We’re going to be sticking with the standard first- and second-line therapy, but in the next few years, we may be swapping out the order of our standard-of-care sequencing.”

Verma agreed that although the treatment of HER2-positive breast cancer has made great strides over the past several years, novel ways of targeting HER2-positive breast cancer will continue to improve treatment for high-risk and metastatic disease.

References

1. Tolaney SM, Barry WT, Guo H, et al. Seven-year (yr) followup of adjuvant paclitaxel (T) and trastuzumab (H) (APT trial) for node-negative, HER2-positive breast cancer (BC). J Clin Oncol. 2017;35(suppl 15):511. doi: 10.1200/JCO.2017.35.15_suppl.511.
2. von Minckwitz G, Procter M, de Azambuja E, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi: 10.1056/NEJMoa1703643.
3. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3.
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5. Johnston SRD, Hegg R, Im SA, et al. Phase iii, randomized study of dual human epidermal growth factor receptor 2 (HER2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer: ALTERNATIVE [published online December 15, 2017]. J Clin Oncol. doi: 10.1200/ JCO.2017.74.7824.
6. Hamilton, E, Borges V, Conlin A, et al. Efficacy of a phase 1b study of tucatinib (ONT-380), an oral HER2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Poster P4-21-01.
7. Doi T, Iwata H, Tsurutani J, et al. Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors. J Clin Oncol. 2017;35(suppl 15; abstr 108). doi: 10.1200/JCO.2017.35.15_suppl.108.
8. Xu B, Ma F, Ouyang Q, et al. A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD3-08.
9. Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.