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HER2-Positive Metastatic Breast Cancer: Current Status and Promising Agents

Adam M. Brufsky, MD, PhD
Released: April 13, 2020

Overview of HER2 Therapies in MBC

Targeted Therapies for HER2-Positive Breast Cancer

During the past 20 years, multiple targeted therapies have been approved and more are in development for HER2-positive breast cancer, particularly MBC. These agents have changed the natural history of this disease and improved outcomes for patients with HER2-positive MBC.[1,2] We will now review the key HER2-targeted therapies used in this setting.

As shown here, trastuzumab binds to a specific extracellular domain of the HER2 protein and blocks downstream signaling. Pertuzumab blocks the dimerization of HER2 to HER3. The combination of these drugs has improved the standard of care for patients with early-stage breast cancer.

HER2-targeted tyrosine kinase inhibitors (TKIs) include lapatinib, which reversibly binds to the intracellular tyrosine kinase domain of HER2 and HER3. By contrast, the TKI neratinib irreversibly binds HER2. The TKI tucatinib is similar to neratinib in that it also irreversibly binds the tyrosine kinase domain of HER2, but tucatinib is not associated with diarrhea as severe as that observed with neratinib.

The HER2-targeted antibody–drug conjugates (ADCs) include T-DM1, which is trastuzumab bound to emtansine. Trastuzumab deruxtecan (T-DXd) is another ADC that was recently approved by the FDA for HER2-positive MBC.

Combination strategies that have been investigated include pairing HER2-targeted agents with mTOR inhibitors blocking downstream cell signaling, such as everolimus and temsirolimus, or with AKT or PI3K inhibitors.

Finally, phase II trials are investigating proteasome inhibitors for HER2-positive MBC. These agents accelerate or decelerate the breakdown of HER2, acting synergistically with HER2-targeted agents.

Guideline-Recommended Regimens for HER2-Positive Recurrent or Stage IV Breast Cancer

For HER2-positive recurrent or stage IV breast cancer, current guidelines recommend pertuzumab/trastuzumab plus a taxane as the preferred first-line regimen. Options in later lines of therapy include T-DM1; trastuzumab plus chemotherapy; lapatinib plus capecitabine; trastuzumab plus lapatinib; and trastuzumab plus other agents. Recently approved options include neratinib plus capecitabine and trastuzumab deruxtecan, which I will discuss later in detail.

CLEOPATRA: Standard First-line Treatment for HER2-Positive MBC With Pertuzumab, Trastuzumab, and Docetaxel

At ASCO 2019, Swain and colleagues[3] presented an update from the phase III CLEOPATRA study, which evaluated first-line docetaxel plus trastuzumab, with or without pertuzumab, in women with HER2-positive MBC (N = 808). In 2015, at 50 months of follow-up, there was a median OS benefit of 15.7 months with the addition of pertuzumab as well as a median PFS benefit of 6.3 months.[4] These important results substantially changed the natural history of the disease.

The long-term follow-up data presented at ASCO 2019 demonstrated that 37% of the patients with MBC who received first-line trastuzumab plus docetaxel with pertuzumab remained alive 8 years later vs 23% with trastuzumab plus docetaxel alone (HR: 0.69).[3] The median OS was 57.1 months in the pertuzumab arm vs 40.8 months in the comparator arm. Of note, the vast majority of these patients had visceral disease.

MARIANNE: First-line T-DM1 in HER2-Positive MBC

The ADC T-DM1 was approved for the treatment of patients with HER2-positive MBC who had previously received trastuzumab and a taxane.[5] Since its initial approval in 2013, T-DM1 has continued to be evaluated in breast cancer. For example, in the phase III MARIANNE study, first-line treatment with T-DM1 monotherapy was compared with T-DM1 plus pertuzumab and with trastuzumab plus a taxane in more than 1000 patients with HER2-positive MBC.[6]

Results showed little difference in OS, with a median OS of approximately 52 months for all 3 arms. There does seem to be a slight trend in favor of T-DM1 vs trastuzumab plus a taxane, but it is not statistically significant. Overall, these results showed no benefit for T-DM1 as monotherapy or in combination with pertuzumab vs the standard-of-care treatment of trastuzumab plus a taxane. For this reason, most oncologists usually do not recommend T-DM1 as a first-line therapy, either as monotherapy or in combination with pertuzumab.

That said, there are potential situations where first-line T-DM1 is warranted, generally because of its tolerable safety profile. As shown here, trastuzumab plus a taxane was associated with the highest incidence of neutropenia in this trial (19% vs 4.4% with T-DM1 monotherapy). Likewise, the incidence of febrile neutropenia was 6.5% with trastuzumab plus a taxane vs 0% in both T-DM1 arms. Diarrhea was infrequent with T-DM1 (4.2% with trastuzumab plus a taxane vs 0.3% with T-DM1 monotherapy).

There were substantial differences between the treatment arms in the proportion of patients experiencing reversible increases in alanine aminotransferase/aspartate aminotransferase: < 1% with trastuzumab plus a taxane vs 3% to 7% in the T-DM1 arms. Grade 3/4 thrombocytopenia, which is also reversible, was observed in up to 9% of T-DM1–treated patients vs 0% of those treated with trastuzumab plus a taxane. Of note, there was no alopecia, which can be important for patients with poor performance status and/or those who simply do not want to lose their hair.

EMILIA and TH3RESA: Standard Second-line Therapy for HER2-Positive MBC With T-DM1 After Progression on HER2-Targeted Agents

T-DM1 has largely been beneficial in the second line and beyond in MBC. In the phase III EMILIA study, the use of T-DM1 in patients with HER2-positive MBC and progression on HER2-targeted agents improved median OS by 5.6 months compared with lapatinib plus capecitabine (HR: 0.68).[7] In the phase III TH3RESA study, the use of T-DM1 in this population improved the median OS to 22.2 months vs 15.8 months with the physician’s choice of therapy (HR: 0.68; P = .007).[8]

Similar to the MARIANNE data in the first-line setting, the adverse events (AEs) of note with second-line T-DM1 were increased liver function test values and thrombocytopenia.[7] This is a fairly safe drug but clinicians who have been giving this drug for many years occasionally observe neutropenia or more serious thrombocytopenia with prolonged use.

Should HER2-Targeted Therapy Be Continued Beyond Progression in HER2-Positive MBC?

An important question is whether HER2-targeted therapy should be continued beyond progression. I think the answer is yes. Shown here are trials reporting that patients with HER2-positive MBC who progressed on trastuzumab and a taxane had improved outcomes with capecitabine and trastuzumab,[9] capecitabine and lapatinib,[10,11] and lapatinib and trastuzumab[12,13] vs with the control treatments of either capecitabine or lapatinib alone.

Summary of Standard of Care in the First-line and Second-line Settings

The current standard of care for first-line treatment of HER2-positive MBC is trastuzumab plus docetaxel (or paclitaxel) and pertuzumab; most patients receive this regimen. Likewise, almost all patients in the United States with HER2-positive MBC will receive T-DM1 as second-line therapy after progression. Other recommended regimens for HER2-positive MBC include trastuzumab combinations (eg, with vinorelbine, capecitabine, lapatinib, or docetaxel), and T-DXd.

What’s New in HER2-Targeted Agents?

MBC therapy is constantly evolving, with new drugs being investigated and approved by the FDA. Of the HER2-targeted TKIs, neratinib is now approved for MBC and the investigational agent tucatinib is under priority review as of March 2020.[14] Of the HER2-targeted ADCs, T-DXd is approved, and I expect that trastuzumab duocarmazine (SYD985) will also be approved based on the ongoing phase III TULIP trial (planned N = 345).[15,16] Lastly, re-engineered HER2 antibodies are in development for MBC, such as margetuximab.

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