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Novel Agents May Change Paradigm for Advanced HER2+ Breast Cancer

Meir Rinde
Published: Monday, Mar 11, 2019

Sara A. Hurvitz, MD
Sara A. Hurvitz, MD
The treatment of patients with advanced HER2-positive breast cancer could be reshaped in the next several years as clinical trials of a number of exciting new drugs begin to yield results, according to Sara A. Hurvitz, MD.

These agents include the oral tyrosine kinase inhibitors (TKIs) neratinib (Nerlynx) and tucatinib (ONT-380), the antibody–drug conjugate trastuzumab deruxtecan (DS-8201), and the monoclonal antibody margetuximab (MGAH22), said Hurvitz, director of Breast Cancer Clinical Research and an assistant professor of medicine at David Geffen School of Medicine at the University of California, Los Angeles.

She reviewed key data involving these drugs and other emerging agents during a presentation on current and new strategies in the treatment of advanced HER2-positive disease at the 36th Annual Miami Breast Conference® (MBCC) on Friday.

“Head-to-head studies comparing some of these newer agents to standard of care are just beginning,” Hurvitz said in an interview in advance of her presentation. “So in anywhere between 5 and 10 years, 1 or 2 of these molecules may challenge the frontline or second-line standard that we have today, if their benefits and toxicity profile look better than our standard therapy.”

The impetus for developing new HER2-targeting strategies is driven by the need to overcome treatment resistance, which arises in most patients who take trastuzumab (Herceptin), Hurvitz said in her conference abstract. Although multiple HER2-directed therapies are available, “the pace of discovery has sped up in the last several years, resulting in the appearance of multiple novel agents entering clinical trials, many with promising results in early-phase testing,” Hurvitz said.

Hurvitz noted in the interview that the current firstline standard of care for HER2-positive metastatic breast cancer remains dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab plus chemotherapy. The CLEOPATRA study showed that adding pertuzumab to trastuzumab and docetaxel improved median overall survival (OS) by almost 16 months compared with placebo plus trastuzumab and docetaxel. The triplet extended median OS to 56.5 months versus 40.8 months with the standard therapy (HR, 0.68; 95% CI, 0.56-0.84; P = .0002).1

“For the majority of patients, that should be offered frontline,” Hurvitz said. “There are a lot of controversies in the management of breast cancer itself, but this is one area that’s not controversial.”

Likewise, in the second-line setting after progressing on trastuzumab-based therapy, patients should receive ado-trastuzumab emtansine (T-DM1; Kadcyla), she said. In the phase III EMILIA trial comparing the antibody–drug conjugate or lapatinib (Tykerb) plus capecitabine, T-DM1 extended median OS by 5.8 months (30.9 months vs 25.1 months, respectively). The HR for death from any cause was 0.68 [95% CI, 0.55-0.85; P <.001], and was associated with fewer adverse effects.2 Hurvitz noted that lapatinib-based therapies continue to be used after T-DM1.

Neratinib

In terms of development, the most advanced of the new HER2 options is neratinib, which was approved in July 2017 for extended adjuvant treatment of adults with early-stage HER2-positive breast cancer following postoperative trastuzumab. In the ExteNET trial, the rate of invasive disease-free survival (iDFS) at 24 months was 94.2% in patients treated with neratinib compared with 91.9% in those receiving placebo (HR, 0.66; 95% CI, 0.49-0.90; P = .008).3

The benefit with neratinib was more pronounced among patients with hormone receptor–positive disease, with an iDFS of 95.6% versus 91.5% with placebo. In terms of lymph nodes, patients with ≥4 positive nodes experienced a higher rate of iDFS benefit with neratinib versus placebo (91.4% vs 87.3%, respectively) than did those with negative nodes or 1 to 3 positive nodes.3

The phase III NALA trial is comparing neratinib plus capecitabine with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer who failed 2 or more prior lines of HER2-directed therapy. Overall, 621 patients have been randomized 1:1 to receive oral neratinib at 240 mg once daily plus capecitabine at 1500 mg/m2 daily in 2 doses or oral lapatinib at 1250 mg once daily combined with capecitabine at 2000 mg/m2 daily in 2 doses.

The neratinib regimen led to a statistically significant improvement (P = .0059) in centrally confirmed progression-free survival (PFS) compared with lapatinib and capecitabine, according to Puma Technology, the manufacturer of neratinib.4 The neratinib combination also improved overall survival, but the difference was not found to be statistically significant (P = .21), the company said.


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