Mohammad Jahanzeb, MD, discusses the designs of landmark trials in early HER2-positive targeted therapy and the adverse events associated with those treatments.
Mohammad Jahanzeb, MD
In his talk at the Miami Breast Cancer Conference®, Mohammad Jahanzeb, MD, focused on the designs of landmark trials in early HER2-positive targeted therapy and the adverse events associated with those treatments.
Multiple pivotal trials have established the value of the HER2-positive growth blockers trastuzumab (Herceptin) and pertuzumab (Perjeta), and recently the phase III ExteNET trial has shown promising results for the tyrosine kinase inhibitor (TKI) neratinib (HKI-272), according to Jahanzeb, medical director of the Sylvester Comprehensive Cancer Center, Deer Field Beach, Florida.
ExteNET, a randomized placebo-controlled trial, evaluated the safety of neratinib in patients with early-stage HER2-positive breast cancer after trastuzumab adjuvant therapy.1Of 2840 patients, 1420 were treated with neratinib and 1420 were given a placebo. It was concluded that 1 year of neratinib improved invasive disease-free survival.
The randomized phase III PHARE trial evaluated the standard 1 year of treatment of adjuvant trastuzumab in patients with HER2-positive early breast cancer.2The trial randomly assigned 1693 patients to 6 months of trastuzumab and 1691 patients to the standard 1 year course of the same drug. It was shown that 1 year of trastuzumab was superior to 6 months, which supported the standard of care.
Whereas the longer course of trastuzumab was efficacious in the PHARE trial, 2 years of trastuzumab in the HERA trial failed to show additional survival benefit, and Jahanzeb urges caution in interpreting the meaning of that result. “I want people to keep an open mind about 2 years of therapy versus truncating it at 1 year in light of the ExteNET results. Interestingly, we are perfectly OK with contemplating 5 versus 10 years of therapy for an estrogen receptor (ER)-positive patient, but for HER2-positive patients we had settled for 1 year as optimal duration after trials such as HERA and PHARE were reported. There seems to be additional benefit to be gained with a different HER2 blocking agent, particularly in hormone receptor HR-positive patients,” he said.
In 2014, results from the much-anticipated phase III ALTTO trial failed to show additional benefit from combining lapatinib (Tykerb) and trastuzumab compared with trastuzumab alone. ALTTO was designed to determine whether the combination of trastuzumab and lapatinib was more effective when combined with chemotherapy than either agent alone. However, results of the phase III APHINITY trial, eagerly awaited, may change the treatment paradigm, Jahanzeb said. This trial is comparing pertuzumab plus trastuzumab and chemotherapy with trastuzumab and chemotherapy alone.
TARGETED ONCOLOGY:How do you rate neratinib for extended adjuvant treatment of HER2-positive breast cancer?
Neratinib will be an option in the future. The ExteNET trial met primary endpoints and rates of disease-free survival overall were about 2.5% improved for the whole group. Patients with centrally confirmed HER2-positive disease have a nearly 4% benefit. The analysis showed patients who were HR-positive actually had much greater improvement, and when you combine the 2when you look at those who were HR positive and centrally confirmed—that is really is a more substantial benefit. As for adverse events, diarrhea prophylactic loperamide made a difference—our poster at San Antonio showed how much loperamide can help.
In the past, we have changed our practice based on low single-digit differenceswhen we incorporated taxanes to anthracyclins in the adjuvant therapy of high-risk patients—and perhaps we should not dismiss this single-digit difference in the case of neratinib. While there is room for improving outcomes in HER2- positive patients, past attempts with 2-year treatment with trastuzumab, or addition of bevacizumab (Avastin) or lapatinib, have not proven beneficial. Neratinib given sequentially has shown initial promise in the adjuvant setting at the cost of significant diarrhea. The treatment paradigm may be affected by the results of the APHINITY trial. Promising approaches are being studied in metastatic disease that can be brought to early stage breast cancer, and individualized approaches are being developed.
TARGETED ONCOLOGY:What challenges still exist with early-stage HER2-positive breast cancer?
Despite having targeted therapies and knowing the biomarker, there are still patients who don’t seem to benefit. We really have to keep honing our skills to find the mechanisms of resistance and circumvent them. Maybe in some patients a hybrid approach will work, and in others chemotherapy plus trastuzumab with HER2 blockade is not enough, such as in the ER-positive populationwhich is why those patients are more likely to relapse. For example, the ratio of ER-positive and ER-negative patients used to be 50:50 among the HER2-positive population prior to the adjuvant use of trastuzumab, but this ratio is now 70:30 based on observations in 2 sequential registries of HER2- positive patients who enrolled in the pre- and postadjuvant trastuzumab era.
This could mean that ER-positive patients are relatively resistant to the chemotherapy plus trastuzumab approach and they are more likely to relapse than the ER-negative patients, thus changing the ratio and providing the rationale for giving such patients an extra year of neratinib, which is consistent with the ExteNET trial results.
TARGETED ONCOLOGY:Do you think immunotherapy could have an impact on HER2-positive breast cancer?
In lung cancer immunotherapy is now an everyday practice and I’ve treated a lot of patients with this approach. I am also familiar with immunotherapy data in breast cancer, and it appears that the triple-negative subset may be a place for immunotherapy, but not really a revolutionary one. However, in other subsets of breast cancer immunotherapy really has not shown much promise yet.
It seems to work well against carcinogen-induced tumors with heavy mutation burden, such as melanoma with UV radiation, or lung cancer with smoking, and seems to be less effective against hormonally driven or single-driver mutation-driven disease.
TARGETED ONCOLOGY:Are there any other approaches that you are particularly excited about?
There are these hybrid approaches, chemo-immunoconjugates, or bispecific antibodies such as HER2-TDB, which looks promising because it attaches to HER2 and attracts T lymphocytes to the tumor to kill it. That hybrid approach might work, but the checkpoint inhibitors are less likely to be very effective in HER2-positive breast cancer.