HER2+ Breast Cancer Treatment Evolving With New Data, Novel Agents

Erika P. Hamilton, MD

The end of 2018 brought intriguing data in the HER2-positive breast cancer space, specifically with updates in adjuvant treatment and the duration of trastuzumab (Herceptin) therapy, as well as a nod toward emerging potential options in the metastatic setting, explained Erika P. Hamilton, MD.

For example, results from the phase III KATHERINE trial, which were presented at the 2018 San Antonio Breast Cancer Symposium (SABCS), showed that ado-trastuzumab emtansine (T-DM1; Kadcyla) could be a new standard of care for patients with HER2-positive disease with residual invasive disease after neoadjuvant treatment. T-DM1 was found to reduce the risk of invasive disease recurrence or death by 50% versus trastuzumab, and the 3-year invasive disease-free survival rate was 88.3% with T-DM1 compared with 77.0% with trastuzumab.^1,2

Secondly, the optimal duration of trastuzumab as adjuvant therapy continued to be explored. Final results of the PHARE trial, conducted by the French National Cancer Institute, showed that a shorter, 6-month duration of trastuzumab for patients with early HER2-positive breast cancer failed to be noninferior to the standard 12-month course of therapy.³ This was a step away from the 5-year follow-up results of the randomized PERSEPHONE trial, in which the 4-year disease-free survival (DFS) rate was 89.8% with 12 months of trastuzumab compared with 89.4% with 6 months of treatment, which met the criteria for noninferiority (HR, 1.07; 90% CI, 0.93-1.24; P = .01).⁴

Furthermore, Hamilton emphasized that novel agents continue to move through the metastatic pipeline, such as DS-8201, tucatinib, and neratinib (Nerlynx), the latter of which is currently approved as an extended adjuvant treatment for patients with early-stage, HER2-positive breast cancer following postoperative trastuzumab.

OncLive^®: What are the most recent findings in HER2-positive breast cancer?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Hamilton, director, Breast and Gynecologic Research Program, Sarah Cannon Research Institute, reflected on the latest data in HER2-positive breast cancer and additional therapies moving through the pipeline.Hamilton: There are 2 big categories in HER2-positive breast cancer right now. The first is optimal duration of therapy. There have been some recent abstracts with the HERA, PERSEPHONE, and PHARE trials, which were studies that tried to define the most beneficial length of trastuzumab. We have learned that 2 years [of trastuzumab] is not better than 1 year, and the 6-month story is a little bit debatable.

PHARE and PERSEPHONE had conflicting results, but the results were kind of similar. It is just that they defined their statistical boundaries differently. In reality, probably 1 year is a little bit better than 6 months [of trastuzumab]. However, it’s really up to the individual patient. For patients with comorbidities, elderly patients, those who have trouble traveling, etc., you’re probably not losing a lot by giving 6 months of therapy. However, with the average patient, I will probably continue to use 12 months.

The other category is for high-risk patients in the adjuvant setting. There have been a lot of exciting data with neratinib and pertuzumab (Perjeta) in the adjuvant setting, and now T-DM1—coming out of the 2018 SABCS. T-DM1 stole the show with an 11% improvement in DFS benefit. For those patients who are high risk—have residual disease after neoadjuvant chemotherapy—that magnitude of benefit is wonderful; the magnitude surprised a lot of us.

The other category in HER2-positive breast cancer are new drugs that are coming, and there are a lot of them. We have antibodies, bispecifics, antibody-drug conjugates, and novel TKIs. One of the 2 drugs I am the most excited about may be DS-8201, which is an antibody-drug conjugate. The data were presented at the 2018 ASCO Annual Meeting, and showed a more than 50% response rate and over a 90% clinical benefit rate, which is really hard to match.

Now that there are encouraging data with T-DM1 in the adjuvant setting, where does this leave the role for the other agents approved here?

The other drug I am very excited about is tucatinib for a couple of reasons. One, it is an oral TKI. Two, it only blocks HER2—not HER1 or EGFR—so that translates to really great tolerability; this is because you don’t get rash and diarrhea as patients normally do when you block EGFR. Third, it has blood-brain barrier penetration. It is great for women with brain metastases, and there have been a couple of presentations where women with brain metastases who get tucatinib essentially have the same progression-free survival (PFS) and do just as well as those who don’t [have brain metastases]. We have never really seen data that exciting before.It is an interesting question. We certainly have some decisions to make for adjuvant therapy. The most important is to emphasize that we need to be giving patients neoadjuvant therapy. We used to really do that because that was the only setting that pertuzumab was approved in. Now that we have pertuzumab approved in adjuvant setting, some people get a little more lax about trying to catch those patients before surgery. However, it’s important to define who will be the good players, bad players, and who needs additional therapy.

There are some caveats. It is probably [patients with] hormonally driven and HER2-driven cancers who get the most benefit from neratinib—not those who are HR-negative and HER2-positive. For pertuzumab, there is a benefit; however, the tough thing about that adjuvant pertuzumab study is that patients didn’t get neoadjuvant pertuzumab. Therefore, for those who got neoadjuvant pertuzumab, we can’t answer the question of, “Is more pertuzumab better than already receiving it?”

We have spoken about tucatinib for a few years now. What will we see with this agent in 2019?

Reflecting on the 2018 SABCS, what other studies did you find to be most compelling?

Topline results of the NALA trial highlighted encouraging activity with neratinib in the metastatic setting. Are there still concerns with grade 3 diarrhea?

There have been a couple of biosimilars now approved for HER2-positive breast cancer. What are your thoughts on these agents?

The T-DM1 data are very compelling because it very clearly defines a subset of patients who need therapy; it’s those who received good neoadjuvant therapy and didn’t have that pathologic complete response (pCR) we were looking for. If you look at that trial, about 70% of patients had estrogen receptor—positive disease, and that is largely because those are the patients who are probably less likely to have a pCR. Again, it is a very high magnitude of benefit in DFS, so it is compelling.[The tucatinib trial] is accruing very well, so we'll see that trial wrap up in 2019 and we'll be waiting for the results. [The investigators] have increased their sample size so they can meet 2 endpoints: PFS overall and PFS in a brain metastases population. But again, the most encouraging thing about that compound is the tolerability compared with some of the oral HER2-targeted agents and how well it crosses the blood-brain barrier.The most exciting trial was KATHERINE with T-DM1; that kind of stole of the show. Probably quite exciting was just all of the new drugs that are coming. We have 3 TKIs, about 6 antibody-drug conjugates, about 5 bispecifics, and then also margetuximab. Really, all of them are showing quite good response rates. What is quite significant in HER2-positive disease is that we used to classify HER2 and triple-negative breast cancer as a bad prognosis. Now, in HER2-positive breast cancer, many women are doing very well with [HER2-directed therapy]. They are doing well for a number of years, so we are transitioning HER2-positive breast cancer to a more chronic disease.Something we have learned with neratinib is if you are aggressive in managing the side effects, that most women can tolerate the drug. Sometimes, the adverse events (AEs) that women are willing to tolerate are different in the metastatic setting versus the early-stage setting, when, most likely, they are cured anyway. Women with metastatic disease are, unfortunately, used to accepting a little more toxicity. We have gotten so much better with counseling patients that diarrhea is an anticipated AE and we aggressively use medications to control it. Most women can tolerate neratinib with supportive care medicines just fine.Biosimilars have an important role in decreasing costs and the molecules look incredible similar, and we don’t need to worry much about efficacy. However, their use in the market will be driven by the cost-benefit they provide, and [there will be] some regulatory issues with insurance requirements, so cost is the real big driver for biosimilars.

References

1. Geyer Jr CE, Huang C-S, Mano MS, et al. Phase III study of trastuzumab emtansine(T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: primary results from KATHERINE (NSABP B-50-I, GBG 77 and Roche BO27938). In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS1-10.
2. von Minckwitz G, Huang C-S, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [published online December 5, 2018]. New Engl J Med. doi: 10.1056/NEJMoa1814017.
3. Pivot X, Romieu G, Debled M, et al. PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. In: Proceedings from the 2018 San Antoinio Breast Cancer Symposium; December 1-4, 2018; San Antonio, TX. Abstract GS2-07.
4. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36 (suppl; abstr 506). doi: 10.1200/JCO.2018.36.15_suppl.506.