Novel TKI Examined in Metastatic Breast Cancer Patients with HER2 Mutation

Cynthia Ma, MD, PhD

Neratinib, an experimental TKI being developed for breast cancer, achieved a 36% clinical benefit rate in a phase II trial, according to a poster presented June 5, 2016 at the ASCO Annual Meeting in Chicago.¹

The study analyzed the confirmed complete, partial, and stable death responses of at least six months in patients with HER2 mutated, non-amplified metastatic breast cancer in the single-arm study.

The trial was deemed a success, although enrollment was halted earlier than anticipated due to ethical concerns, according to Cynthia Ma, MD, PhD, associate professor at Washington University, St. Louis, who presented the poster.

Thereafter, the investigators amended the protocol to add fulvestrant in patients with an estrogen receptor (ER) mutation.

While the drug is being developed for breast cancer patients with amplified ER mutation, this trial was unique in that the drug showed a benefit even in the small subset of patients with a mutation that is not amplified, Ma said.

Possible Therapy for Those with Rare, Non-amplified Form of HER2 Mutation

“About 15% of breast cancer patients are HER2 positive in the sense that they have the gene amplified multiple times on the same chromosome,” Ma explained. “Another 80% of those normal copy numbers are not over-expressed, but in about 2% of patients the number of HER2 genes is normal, but the gene can still activate kinase activity because of changes in the amino acid sequence,” Ma explained.

Scientists have long pondered the role of these unamplified HER2 mutations, according to Ma.²

“In these patients, drugs such as herceptin, for example, don’t get a response, because you don’t have HER2 being amplified. Usually if the patient progresses on hormonal therapy or a combination, the doctors would give them chemotherapy because it’s the only thing we have.”

In the study, researchers recruited 16 subjects with pretreated metastatic breast cancer between May 2013 and August 2015. The patients had a median age of 58, and had been on a median of 3 prior regimens (range 2-10). Of the cohort, 14 had known HER2 mutations, while 2 had HER2 mutations of unknown significance. The subjects received neratinib, an experimental EGFR-targeted agent.

Median PFS was 5 months. Among those subjects with known activating mutations, 36% enjoyed clinical benefit, including 3 patients with stable disease, 1 partial response, and 1 complete response. Study authors noted, however, that the patients with mutations of unknown significance did not benefit from the study.

Fourteen patients withdrew from the study, 13 due to disease progression, and 1 due to an adverse event. Two patients continued to receive neratinib as of January 30, 2016, 1 of whom had been on therapy for over a year, according to Ma.

Rare Mutation More Common in Patients with Lobular Disease

In the process of accrual, 517 participants underwent genetic testing, which was successful in 381 patients. While the rareness of the unamplified form of the HER2 mutation was confirmed by the study at a 2.4% rate of incidence, Ma and colleagues found that the rate was considerably higher in those with lobular (7.8%) rather than ductal disease (1.6%)(P = .026).      

“We don’t know why the rate was higher, but it’s an interesting phenomenon. Most of those with lobular cancer were ER positive, and there could be cross-talk between the estrogen receptor and HER2,” noted Ma. Within the study, 5 patients had lobular disease and 15 patients were ER positive.

“We don’t differentiate between ductal and lobular disease when we treat breast cancer; this may not be effect treatment, but from a diagnostic point-of-view, if we see a patient with lobular disease, we might check them for unamplified HER2 mutation because the frequency is higher,” she added.

As mentioned, enrollment in the two-stage trial was halted early to add fulvestrant. Since then, the trial has added 4 new patients and screening is ongoing.

“I think it will take a while for new data to be available; we need a lot of collaboration, because we need to screen a large number of patients to find the small subset of those who might benefit,” Ma added.

Ma C, Bose R, Gao F, et al. Phase II trial of neratinib for HER2 mutated, non-amplified metastatic breast cancer (HER2mut MBC).J Clin Oncol2016;34 (suppl; abstr 516).

Bose R, Kavuri S, Searleman A, et al. Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer. [Published online December 7, 2012.]Cancer Discov.doi: 10.1158/2159-8290.CD-12-0349.