Three new drugs are in the pipeline to treat human epidermal growth factor receptor (HER) type 2-positive metastatic breast cancer (MBC). Two appear to have the potential to provide incremental gains, and one looks like a game changer.
T-DM1
The one getting the most attention at recent oncology conferences is T-DM1, a first-in-class conjugate of the monoclonal antibody trastuzumab and DM1, a derivative of maytansine. Maytansine is an antimicrotubule agent that proved too toxic to use alone a couple of decades ago. The key to taming it for use today is a linker that attaches DM1 to trastuzumab and is cleaved once the drug has been internalized in cells overexpressing HER2, releasing the DM1 inside. The drug is almost undetectable in the circulation (LoRusso P, et al. San Antonio Breast Cancer Symposium; 2009. Abstract 5099).
Ian Krop, MD, PhD, and coworkers reported on a phase 2 study of 110 patients with HER2-positive MBC previously treated with an anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab. Patients received singleagent T-DM1 at a dose of 3.6 mg/kg intravenously every 3 weeks. Even in this population of heavily pretreated patients with more than 2 years of HER2-directed therapy, the overall response rate (ORR) was 30%, more than 46% had stable disease, and the clinical benefit rate (CBR) was 40% to 45%. The median time to progression was 7.3 months (San Antonio Breast Cancer Symposium; 2009. Abstract 5090).
In another phase 2 study of 112 heavily pretreated patients with MBC, T-DM1 showed good efficacy and tolerability. The ORR was 26.7% by in dependent review and 38.9% by investigator assessment, with a median progression-free survival of 4.6 months (Vogel CL, et al. J Clin Oncol. 2009; 27[15S]:Abstract 1017). In the 66 patients in that trial who were previously treated with lapatinib and trastuzumab, T-DM1 produced very similar re sponse rates (24.2% and 34.8%, respectively).
The main adverse effects, as exemplified in the Krop study, were fatigue, nausea, and brief, transient thrombocytopenia. Most have been grade 1 or 2. Phase 3 trials are ongoing, comparing TDM1 to other combined therapies.
Carlos Arteaga, MD, professor of medicine at Vanderbilt University in Nashville, Tennessee, is very positive about T-DM1, especially for heavily pretreated patients. “The conjugate has shown remarkable activity as a third line in HER2-positive metastatic breast cancer,” he said.
Harold Burstein, MD, PhD, of Dana- Farber Cancer Institute in Boston, noted that T-DM1 may have efficacy as a single agent “because it is, in essence, chemotherapy plus trastuzumab.” And, he added, “It does not seem to cause significant alopecia, which is very exciting for patients.”
Although some patients have done well on trial for more than 1 year, and in some cases 2 years, Eric Winer, MD, director of breast oncology at Dana- Farber, cautioned that “We have not treated a sufficient number of patients for years to know for certain that there isn’t a low level of cumulative toxicity.”
Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh, remains very optimistic about T-DM1. “It will have a major role in clinical practice... at least be equivalent to capecitabine/lapatinib with probably fewer side effects,” he said.
In a more general sense, the linker technology used to join DM1 with trastuzumab may be applicable to use with other monoclonal antibodies against other tumor types, “the so-called targeted chemotherapy concept that has been the Holy Grail for everybody for so many years,” according to Luca Gianni, MD, director of medical oncology and clinical pharmacology at Italy’s National Tumor Institute in Milan.
Neratinib
Another drug in development is nera-tinib, an oral small molecule, pan-ERBB irreversible tyrosine kinase (TK) inhibitor, meaning it inhibits the TKs associated with the HER1, HER2, and HER4 cell surface receptors. The consensus among oncologists is that neratinib shows good activity as a single agent as well as in combination with trastuzu mab after progression on trastuzumab. “There is activity of neratinib in both trastuzu maband lapatinib-pretreated [patients],” said Debu Tripathy, MD, director of the Women’s Cancer Program at the University of Southern California in Los Angeles.
In the past, the most prevalent concern about neratinib was the high incidence of diarrhea; however, at the San Antonio Breast Cancer Symposium in December 2009, researchers said that the diarrhea is manageable with medication and appears to diminish in frequency and severity over several weeks of treatment.
In a small phase 1/2 study using 240 mg/day of neratinib, Awada and coworkers found a 100% incidence of diarrhea among patients with MBC who were previously treated with lapatinib and a 93% incidence if no prior lapatinib exposure. ORRs were 43% if no prior lapatinib and 25% with prior exposure. CBRs were 57% and 50%, respectively (San Antonio Breast Cancer Symposium; 2009. Abstract 5095).
Burstein and coworkers found the same incidence of early-onset diarrhea using 240 mg/day of neratinib and reported that it could be controlled with antidiarrheal medications and dose reductions. Vomiting occurred in 29% of patients. The drug appeared to have acceptable cardiovascular safety, with no grade 3/4 toxicity that was considered related to neratinib. In a cohort of 67 patients, only 3% had a left ventricular ejection fraction <50% (San Antonio Breast Cancer Symposium; 2009. Abstract 5096).
Both Burstein and Gabriel Hortobagyi, MD, of The University of Texas M. D. Anderson Cancer Center in Houston, commented that studies indicate that the response rate to neratinib is probably higher than to lapatinib in similar groups of patients. “We are much more excited about neratinib now than we are about lapatinib,” said Hortobagyi.
Thinking ahead, Sandra Swain, MD, medical director of the Washington Cancer Institute at Washington Hospital Center in Washington, DC, said diarrhea is manageable with neratinib in the metastatic setting, but it may be “a significant problem if you’re going to take it in the adjuvant setting.”
Pertuzumab
Pertuzumab is a recombinant monoclonal antibody that inhibits dimerization of HER2 with itself (homodimers) and with other HER receptors (heterodimers), thereby preventing the activation of HER signaling pathways. It has limited potency alone but appears to synergize with trastuzumab.
A group led by Jose Baselga, MD, director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, enrolled patients with HER2- positive MBC whose disease had progressed on trastuzumab in a phase 2 trial. Patients received pertuzumab alone (840 mg loading dose then 420 mg every 3 weeks) and, if their disease progressed, trastuzumab was added. In the pertuzumab-only group (n = 29), the ORR was 3% and the CBR was 10%. For the combined therapy group (n = 16), ORR was 21%, and CBR was 43% (San Antonio Breast Cancer Symposium; 2009. Abstract 5114).
Baselga stressed the need for “total HER2 blockade,” involving both the homodimer and heterodimer signaling pathways. He speculated that either trastuzumab or lapatinib would block the homodimer pathway but not the heterodimer one. “Half the problem is equal to the whole problem,” he said.
Arteaga commented that as the proportion of HER2/HER3 heterodimers increases, the tumor becomes more sensitive to pertuzumab, which blocks heterodimerization. In addition, HER3 has powerful phosphorylating activity for HER2, driving HER2 activity.
Brufsky believes dimers involving HER3 are “an extremely important target” not only in breast cancer but also in lung (HER1/HER3), ovarian (HER3/ HER4), and other tumors, and, thus, pertuzumab may have activity in those tumors as well.