Outcomes for patients with HER2-positive metastatic breast cancer are improving as a result of blockade strategies, and more novel agents are in the pipeline.
Mohammad Jahanzeb, MD
Treatment-refractory HER2-positive metastatic breast cancers are becoming increasingly rare due to the recent advent of multitargeted HER2 receptor blockade mechanisms that utilize novel antibodies and antibody—drug conjugates even as the roster of new therapies under study for this patient population continues to expand, according to Mohammad Jahanzeb, MD.
“The landscape is really shifting,” said Jahanzeb, a breast and lung cancer expert who is medical director of the University of Miami’s Sylvester Comprehensive Cancer Center at Deerfield Beach and a professor of medicine at the UM Miller School of Medicine, during a presentation at the 14th Annual International Congress on the Future of Breast Cancer that Physicians’ Education Resource (PER) hosted in Huntington Beach, California, in July.
Jahanzeb said many novel agents including antibody—drug conjugates, bispecific antibodies, and immunotherapies are being evaluated for patients with recurrent disease at a time when outcomes are improving. “The field is very rich,” he said. “Actually, what is not so rich is access to these patients [for clinical trials]. Luckily for them, fewer are relapsing.”
Nevertheless, he said it is important for researchers to continue to explore mechanisms of resistance in order to be able to individualize therapies.
HER2 Blockade Combinations
As it stands now, Jahanzeb said the preferred treatment regimen for patients with HER2-positive metastatic breast cancer is the combination of trastuzumab (Herceptin), pertuzumab (Perjeta), and a taxane (docetaxel or weekly paclitaxel), or trastuzumab with chemotherapy. He said he reserves the administration of hormone-targeting therapies for patients in this population with low burden, minimally symptomatic estrogen receptor (ER)—positive disease. Upon progression, the preferred second-line approach is trastuzumab emtansine (T-DM1; Kadcyla), with later lines of therapy offering several options including regimens containing lapatinib (Tykerb) or trastuzumab.
Jahanzeb said multiple-blockade strategies appear more effective than single-blockade approaches for patients with HER2-positive metastatic breast cancer, even beyond progression. He noted that HER2 receptor blockade with trastuzumab plus chemotherapy was first shown to increase overall survival (OS) of patients with HER2-positive metastatic breast cancer in a study published in 2005.1 Even after progression of disease on trastuzumab, continuation of HER2 blockade with lapatinib plus capecitabine,2 or trastuzumab plus lapatinib3 increased progression-free survival (PFS) and OS, indicating the clinical benefit of HER2 blockade during second-line therapy and beyond.
Follow-up studies indicate that using more than one agent for HER2 blockade may produce further benefits. Pertuzumab binds to a different portion of the HER2 cell receptor and acts synergistically with trastuzumab to inhibit HER2 signaling. The CLEOPATRA trial showed addition of pertuzumab to a regimen containing trastuzumab plus docetaxel significantly improved PFS (18.7 months vs 12.4 months; P <.0001) and OS (56.5 months vs 40.8 months, P = .0001).4.5
“We had never shown 56-month survival with metastatic disease in any setting,” noted Jahanzeb.
Emtansine (DM1), a derivative of maytansine, is a naturally occurring antitumor antibiotic that has potent in vitro activity on tumor cells but has high clinical toxicity. T-DM1, an antibody—drug conjugate, targets delivery of DM1 to the HER2-positive tumor cells to improve drug’s clinical effectiveness, reduce its toxic effects on noncancerous tissues, and maintain the biological effect of trastuzumab. A phase II study showed that the conjugate significantly improved PFS and lowered rates of neutropenia, thrombocytopenia, and leukopenia relative to the group receiving trastuzumab and docetaxel6 and yielded a nearly 5-month improvement in OS over a capecitabine plus lapatinib regimen.7 Furthermore, the TH3RESA trial showed that patients who received T-DM1 as a third-line therapy had a 3-month improvement in PFS over those treated with other physician-chosen regimens, even if they included trastuzumab.8
According to Jahanzeb, the majority of the patients in the trials investigating anti-HER2 regimens present with de novo metastasis and the results may not be applicable for patients who have developed further metastasis after disease stabilization. He indicated that patients with HER2-positive metastatic breast cancer have variable sensitivity to anti-HER2 drugs and that investigating methods of resistance to anti-HER2 treatment regimens is important to predict the efficacy of second-line treatments and beyond.
Jahanzeb described a study by Dennis Slamon and colleagues9 that used genetic analyses of tumor samples from the BOLERO-1 and BOLERO-3 trials, both of which included patients with locally advanced or metastatic HER2-positive breast cancer. Patients with mutant PIK3CA or low to no PTEN expression, which are associated with hyperactive activity of the PI3K pathway and subsequent tumor cell proliferation, benefited from the addition of everolimus (Afinitor) to trastuzumab and chemotherapy, whereas those with wild-type PIK3CA or high PTEN expression did not. According to Jahanzeb, assessing subgroups of patients using genomic analysis is important for future prescription of treatment regimens.
“When you come up empty-handed [in the results of clinical trials], it is very frustrating…and we may be missing the subgroup that may actually benefit from these trials,” said Jahanzeb.
Novel Therapies on Horizon Antibodies
A variety of novel therapies are aimed at further targeting the HER2 receptor synergistically with other therapies. According to Jahanzeb, antibody—drug conjugates such as T-DM1 are likely to become more prevalent, and the molecular techniques used to synthesize these conjugates may target tumor tissue more effectively and reduce toxicity in healthy tissues.
Specifically, Jahanzeb discussed these novel antibodies currently under study:
Another approach that is generating excitement involves interrupting the cell cycle with the CDK4/6 inhibition.
Palbociclib (Ibrance) was approved earlier this year for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer and is now being evaluated in HER2-positive settings. One trial will evaluate palbociclib in combination with T-DM113 while another study will pair the drug with trastuzumab with or without letrozole.14
Other drugs under study in this category include abemaciclib, which is being tested in an 8-arm phase I trial in combination with different standard regimens.