New Treatments for Triple-Negative; HER2+; and ER+, HER2- MBC

Kate M. O'Rourke


July 16, 2020

Several targeted agents and immunotherapy drugs have recently emerged on the rapidly evolving landscape of metastatic breast cancer (MBC) treatment, providing new therapeutic alternatives and improving progression-free survival (PFS) for patients with triple-negative; human epidermal growth factor receptor 2 (HER2)–positive; and estrogen receptor (ER)-positive, HER2-negative MBC.

"There are lots of new agents in development for triple-negative disease that I think are of interest," said Sara Tolaney, MD, MPH, a medical oncologist at Dana-Farber Cancer Institute in Boston. "HER2-positive MBC is also in a very dynamic state, with many new approvals and agents in development." This is true in the ER-positive, HER2-negative space, as well, according to Tolaney.

We asked breast cancer experts to give an overview of the use and management of these latest advances.

Immunotherapy for Triple-Negative MBC

"In metastatic triple-negative breast cancer (TNBC), the newer therapy is adding the immunotherapy drug atezolizumab to chemotherapy in programmed death ligand 1 (PD-L1) TNBC. That is an emerging area. There aren't any other approved nonchemotherapy drugs in TNBC, although many are in development," said Lisa Carey, MD, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, chief of the Division of Hematology/Oncology, and deputy director of clinical sciences at University of North Carolina-Chapel Hill.

In one study, atezolizumab (Tecentriq), a monoclonal antibody that inhibits PD-L1, plus nab-paclitaxel prolonged PFS in patients with metastatic TNBC, particularly in the PD-L1–positive subgroup, compared with nab-paclitaxel and placebo (7.2 months vs 5.5 months)."For metastatic triple-negative disease, if someone has a tumor that is PD-L1 positive, we are giving up-front taxane chemotherapy with atezolizumab," said Tolaney.

Immunotherapies, including atezolizumab, are associated with a unique spectrum of immune-related adverse events (AEs), but many oncologists are familiar with the management of these agents because they have already been prescribing them to treat patients with other types of cancer. "There are two groups of breast cancer clinicians. There are cancer clinicians who treat breast and many other types of cancer, and there are cancer clinicians who treat breast cancer only. For the doctors who treat breast cancer and everything else, none of this [management of immune-related AEs] is new," said Eric Winer, MD, also a medical oncologist at Dana-Farber Cancer Institute.

Antibody-drug conjugates have been introduced to breast cancer treatment in the past decade, and on April 22 of this year, the antibody-drug conjugate sacituzumab govitecan (Immunomedics) was granted accelerated approval by the US Food and Drug Administration (FDA) for metastatic TNBC. In a phase 1/2 trial of patients with refractory metastatic TNBC who had received a median of three previous therapies, sacituzumab govitecan delivered a response rate of 33.3%.The median duration of response was 7.7 months, the clinical benefit rate was 45.4%, median PFS was 5.5 months, and overall survival was 13.0 months."Sacituzumab govitecan is an antibody-drug conjugate, which is currently under FDA review for approval in the third-line and beyond setting for metastatic triple-negative disease," said Tolaney.

Novel Agents for HER2-Positive Disease and More

In HER2-positive breast cancer, trastuzumab deruxtecan (Enhertu) is among the newest treatments. "Trastuzumab deruxtecan is similar to T-DM1. It seems to be very active in patients who have had their disease progress after T-DM1, after pertuzumab, and after trastuzumab therapies," said Carey. As explained at the 2019 San Antonio Breast Cancer Symposium by Ian Krop, MD, PhD, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, trastuzumab deruxtecan, like T-DM1 (Kadcyla), is based on a monoclonal antibody targeted toward HER2. Unlike T-DM1, which has a microtubule inhibitor as the cytotoxic payload, trastuzumab deruxtecan has a topoisomerase 1 inhibitor as the payload. Trastuzumab deruxtecan has eight molecules of payload per antibody. That is twice as many as T-DM1.

In a three-part trial (phase 1, 2a, and 2b), with 184 patients receiving the recommended phase 2 dose of 5.4 mg/kg trastuzumab deruxtecan every 3 weeks, the objective response rate was 60.9%, with 6% of patients having a complete response and 54.9% having a partial response. Interstitial lung disease is a concerning and difficult-to-treat AE with trastuzumab deruxtecan. "This very novel antibody-drug conjugate delivers a topoisomerase payload that has demonstrated very robust activity with about a 60% response rate in the third-line and beyond setting," explained Tolaney.

Tucatinib (Tukysa) is a small molecule that, when added to chemotherapy and trastuzumab, is also very active in HER2-positive MBC. In the phase 3 HER2CLIMB trial of patients with HER2-positive MBC who had disease progression after therapy with multiple HER2-targeted agents, PFS at 1 year was 33.1% in the tucatinib plus trastuzumab and capecitabine group and 12.3% in the trastuzumab and capecitabine group. The median duration of PFS was 7.8 months and 5.6 months, respectively.

"In particular, HER2CLIMB [enrolled a high proportion of] patients with brain metastases because that is a real problem with HER2-positive breast cancer. In the trial, nearly 50% had brain metastases, and it looks like it worked as well with that group as others. This was predicted by the nature of the drug, which crosses the blood-brain barrier," said Carey. "In other studies, the compartment that seemed to be less helped by other drugs was the central nervous system. I anticipate tucatinib will be available pretty quickly because [HER2CLIMB] was a floridly positive trial."

Tolaney agreed with Carey. "Once tucatinib is approved, which we think should be very soon, that would be an alternative third-line option," said Dr Tolaney. "We would be able to choose between the HER2CLIMB regimen or trastuzumab deruxtecan, and what goes into that decision may be a factor of whether or not a patient has progressive brain metastases."

Another recent addition to the therapeutic agents for MBC is neratinib (Nerlynx), which recently extended its indication to the metastatic setting combined with capecitabine in HER2-positive pretreated MBC. In one study, the median PFS was 5.6 months for patients who received neratinib with capecitabine and 5.5 months for individuals receiving lapatinib with capecitabine.The PFS rate at 12 months was 29% compared with 15%, respectively. "Neratinib has ugly diarrhea complications that must be managed proactively," said Carey.

In ER-positive, HER2-negative MBC, alpelisib (Piqray) is the first PI3K inhibitor used in breast cancer treatment.Approved last year, the drug is being combined with fulvestrant (Faslodex) in second- and later-line therapy. "Inhibiting PI3K has been the Holy Grail for many, many years. It has been assumed that it is a rational target," said Carey. "You can test for PI3K in blood samples."

In a phase 3 trial, alpelisib outperformed placebo in PI3K mutant tumors that were ER- positive and HER2-negative who had received endocrine therapy previously. In the cohort of patients with PIK3CA-mutated cancer, PFS at a median follow-up of 20 months was 11.0 months in patients who received alpelisib and fulvestrant compared with 5.7 months in the placebo plus fulvestrant group (P < .001). The most frequent AEs of grade 3 or 4, which were higher in the alpelisib-fulvestrant group than in the placebo group, were hyperglycemia (36.6% vs 0.7%) and rash (9.9% vs 0.3%). "As far as AEs, alpelisib can give you diabetes and hyperglycemia, and it can give you a pretty nasty rash that has to be managed proactively with antihistamines," said Carey.

Despite the AEs associated with these novel therapies, which require monitoring, they have shown significantly improved PFS and offer alternative treatment options for some patients.

Dr Carey has disclosed no relevant financial relationships. Dr Tolaney disclosed relationships with AbbVie, Anthenex, AstraZeneca, Bristol-Myers Squibb, Celldex, Cyclacel, Eisai, Exelixis, Genentech/Roche, Immunomedics, Lilly, Merck, Nanostring, Nektar, Novartis, Odonate, Paxman, Pfizer, Puma, Sanofi, Seattle Genetics, and Silverback Therapeutics. Dr Winer disclosed relationships with Genentech, GlaxoSmithKline, Lilly, Roche, and Seattle Genetics.

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