Hudis on ExteNET, APHINITY, and What's Next for Adjuvant HER2+ Breast Cancer

Clifford A. Hudis, MD, FACP

In 2006, trastuzumab (Herceptin) was approved as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of women with node-positive, HER2-overexpressing breast cancer, based on evidence of a significant prolongation in disease-free survival compared to chemotherapy alone.

While this approval was practice changing, challenges still remain for adjuvant treatment of HER2-positive breast cancer, says Clifford Hudis, MD, medical oncologist, vice president for Government Relations and chief advocacy officer, Breast Medicine Service, Memorial Sloan Kettering Cancer Center.

“Since trastuzumab’s benefit was shown, there have been efforts to improve upon it for several reasons,” says Hudis. “Some patients still relapse despite getting this treatment. Not every patient responds in the same way. Trastuzumab continued for a second year of therapy versus just 1 year did not lower risk in a meaningful way, so we have some confidence that 1 year of trastuzumab as an average is all we are going to get in terms of benefit.”

Several therapies are on the horizon that could potentially offer that improvement, says Hudis.

Pertuzumab (Perjeta) is currently being investigated in the phase III APHINITY trial, which will test the drug in combination with trastuzumab and chemotherapy to determine if it will improve invasive disease-free survival in the adjuvant setting. Results of this pivotal trial are highly anticipated.

Neratinib has also shown activity in the adjuvant setting. The phase III ExteNET study looked at 2840 patients who remained disease-free following 1 year of treatment with adjuvant trastuzumab and chemotherapy, and found that neratinib immediately following adjuvant trastuzumab plus chemotherapy resulted in a 33% reduction in the risk of disease recurrence in patients with early-stage, HER2-positive breast cancer.

Further data are needed to fully understand if neratinib is a good treatment option for HER2-positve breast cancer in the adjuvant setting, says Hudis, and the answer may be complicated depending on whether or not the APHINITY trial is positive.

OncLive: How has HER2-targeted treatment evolved in recent years?

In interview with OncLive, Hudis explains the role that both the APHINITY and ExteNET trials may play in determining the future adjuvant treatment paradigm for patients with HER2-positive breast cancer.Hudis: The discovery of HER2, with its negative prognostic value, but its positive predictive value, has been one of the key advances in the treatment of breast cancer over the past few decades. It helps us identify what is a subset of breast cancer anatomically, but in a sense, it’s a different disease.

The treatment paradigm for advanced, incurable metastatic HER2-positive disease is now distinct line after line from the way we treat other types of breast cancer. One of the biggest public health benefits has been in the early-stage adjuvant setting, where the use of trastuzumab has resulted in a real change in natural history for us.

In 2005, we got the first results of the randomized trials that proved that trastuzumab added to conventional chemotherapy lowered the risk of recurrence and, ultimately, improved survival. There are some data out there that the actual extent of metastatic HER2-positive disease in the population has fallen as a consequence of that. That is a nice public health validation of the impact.

What is the significance of the ExteNET study data?

Trastuzumab has been shown to be an appropriate therapy in the adjuvant setting. Pertuzumab has been approved by the FDA as a neoadjuvant therapy and we are waiting for the results of a big adjuvant trial (APHINITY). Critically, that adjuvant trial would represent part of the conversion of pertuzumab from a preoperative accelerated label into a full approval. If the APHINITY trial is positive for its primary endpoint, that would provide evidence that the current accelerated approval should be made full. So ExteNET tests neratinib in a space that is currently unfilled. It is for patients that have finished their standard course of adjuvant trastuzumab, have some residual risk, and are being monitored. Everybody is worried about recurrence.

Neratinib has a track record, it is an effective therapy with its own set of toxicities, but it is certainty a tolerable drug. It has activity in the metastatic setting, and it is similar to the lapatinib and capecitabine data that has been presented in the past. It is worth noting that lapatinib in the ALTTO trial was not able to improve upon the disease-free survival we get with trastuzumab. While lapatinib is active and it is a HER2-targeting TKI with oral administration, it is not used in the adjuvant setting on a routine basis.

Are there any concerning toxicities with neratinib?

With the recent update of the ExteNET data, the bottom line is that this drug in this setting, lowers the risk of recurrence several percentage points, and possibly does it even more so in the estrogen receptor (ER)-positive group. That later exploratory observation may be important because the mechanism of action for these TKIs is different than the antibodies. The antibodies have generally shown lesser marginal benefit in ER-positive disease. The drug comes with toxicities, diarrhea being the most notable one. This is certainly a complication that can be overcome, but it requires clinical teams to have a plan in place and to monitor patients, especially in the first weeks and months of therapy. After that, it usually settles down. It will represent a complexity that has to be addressed as clinical use is considered.

What impact could an approval of neratinib have in the adjuvant setting?

It’s a challenging question. It is important to note that overall survival has not been reported in this setting, or any setting for the drug right now. Further more, if pertuzumab is shown to be effective in the adjuvant setting, that will raise the performance of the putative control arm. That would raise the bar for showing a benefit. That would create questions on whether the marginal benefit seen in the ExteNET trial is relevant. There are more questions at this point than answers.

In a simple sense, one can say that neratinib appears to be active and it can be tolerable. Whether that degree of activity should be practice changing or will be relevant in the evolving field of HER2-positive disease treatment remains to be seen. If the drug is approved, given what we know about it, I think that certain subsets of patients with high-risk disease and maybe patients with ER-positive disease may elect to pursue this therapy. A lot of this will depend on data we have not yet seen.

Now there are new antibodies in the mix. These include straightforward antibodies like pertuzumab, more complex molecules like trastuzumab with chemotherapy bound to it­—that’s the TDM-1 approach­—as well as small molecule tyrosine kinase inhibitors (TKIs) that interact with the HER2 system in a different way. What they do is prevent the downstream signaling from the tyrosine kinase activation that would normally occur. There has been a drug available in that space for years, lapatinib. The next critical one to make it into broad clinical testing is neratinib.