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
“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:
MM-302—Liposomal encapsulation of doxorubicin causes the agent MM-302 to accumulate at tumor sites but avoid cardiac cells (which contain HER2 receptors) to potentially prevent the congestive heart failure often observed with multitargeted HER2 blockade. The agent is being evaluated in the phase II-III HERMIONE trial, in which researchers are seeking to randomize 250 patients with metastatic or locally advanced HER2-positive breast cancer to either MM-302 plus trastuzumab or chemotherapy of physician’s choice plus trastuzumab.10
MM-111—Bispecific antibodies under development include MM-111, which blocks both HER2 and HER3 to prevent the tumor from activating the HER3 axis in response to HER2 blockade. MM-111 is in early clinical development for patients with advanced HER2-positive metastatic breast cancer.
HER2-TDB—This agent, which targets HER2 and conditionally activates T cells to trigger an immune response, also is a bispecific antibody that has proved quite promising in preclinical studies. The agent was shown to kill cells that did not respond to T-DM1, trastuzumab, or lapatinib and may be even more effective when combined with anti-PD-L1 immunotherapy.11
Margetuximab (MGAH22-01)—This HER2-targeting monoclonal antibody, which is engineered for increased Fc-domain binding, demonstrated significant response rates among patients with heavily pretreated breast cancers in a first-in-human phase I study, including four patients with confirmed partial responses still ongoing at the time of the analysis and lasting from more than 10 weeks to more than 100 weeks.12
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.
Marty M, Cognetti D, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group [published pnline May 23, 2005]. J Clin Oncol. 2005;23(19):4265-4274.
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743.
Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study [published online June 11, 2012]. J Clin Oncol. 2012;30(21):2585-2592.
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer [published online December 7, 2011]. N Engl J Med. 2012;366(2):109-119.
Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer [published online February 4, 2013]. J Clin Oncol. 2013;31(9):1157-1163.
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer [published online October 1, 2012]. N Engl J Med. 2012;367(19):1783-1791.
Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial [published online May 2, 2014]. Lancet Oncol. 2014;15(7):689-699.
Slamon DJ, Hurvitz SA, Chen D, et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: combined exploratory analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2015;33(suppl; abstr 512).
NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02213744.
Junttila TT, Li J, Johnston J, et al. Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells [published online September 16, 2014]. Cancer Res. 2014;74(19):5561-5571.
Burris HA, Giaccone G, Im SA, et al. Updated findings of a first-in-human, phase I study of margetuximab (M), an FC-optimized chimeric monoclonal antibody (Mab) in patients (pts) with HER2-positiveadvanced solid tumors. J Clin Oncol. 2015;33(suppl; abstr 523).
NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01976169.
NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02448420.
NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02057133.