Progress in HER2-Positive Breast Cancer Comes With Successes and Setbacks

Mohammad Jahanzeb, MD

Significant advances have made headlines in HER2-positive breast cancer treatment in recent years; however, there continue to be setbacks with some emerging agents, and HER2-resistance remains a lingering challenge.

The phase III CLEOPATRA study presented practice-changing results, with the triplet of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel showing a significant overall survival (OS) benefit of nearly 16 months in patients with HER2-positive metastatic breast cancer compared with trastuzumab and chemotherapy alone.

Results from the MARIANNE trial, a phase III randomized study of trastuzumab emtansine (T-DM1; Kadcyla) plus or minus pertuzumab versus trastuzumab plus a taxane for the first-line treatment of HER2-positive metastatic breast cancer, were met with less enthusiasm. In the study, the progression-free survival (PFS) noninferiority endpoint was met but not the superiority endpoint. There was noninferiority in PFS between the T-DM1—containing arms and the control arm. The results were surprising, as treatment with frontline T-DM1 had shown a statistically significant increase in PFS in a phase II study.

The phase III ExteNET study generated a more mixed response, with the novel TKI neratinib demonstrating efficacy, along with significant toxicity, in patients with HER2-positive early-stage breast cancer. The 2-year invasive disease-free survival (DFS) rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (HR = 0.67; 95% CI, 0.50-0.91; P = .009). However, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% was grade 3/4).

For a deeper understanding of the impact of these studies and other key issues in HER2-positive breast cancer, OncLive spoke with Mohammad Jahanzeb, MD, Medical Director of Sylvester Comprehensive Cancer Center at Deerfield Beach, Florida.

OncLive: What are your thoughts on the results of the MARIANNE trial?

Dr Jahanzeb: The MARIANNE trial examined patients with HER2 metastatic disease who could receive adjuvant trastuzumab in the first-line setting. About one-third of the patients had received adjuvant trastuzumab. Patients could receive the standard control arm of taxane and trastuzumab, a combination of T-DM1 with pertuzumab, or single-agent T-DM1.

There was rationale to include these arms. T-DM1 is approved for use in the second-line setting and this was an attempt to see if it is an appropriate therapy for first-line. It was widely anticipated that T-DM1 plus pertuzumab, which is a much less toxic approach, would be the winning arm. However, that did not pan out. When you look at the subset analysis of patients who were naive versus those who were previously exposed to trastuzumab, you see about the same benefit of 5 to 6 months in patients who were previously exposed to trastuzumab as were seen in the CLEOPATRA trial. Nevertheless, that is the provocative part of MARIANNE. It is an exploratory, hypothesis-generating type of conclusion.

Where does this leave us in terms of optimal sequencing in HER2-positive breast cancer?

For first-line, NCCN guidelines recommended using a CLEOPATRA-like regimen, which is docetaxel, trastuzumab, and pertuzumab. However, based on limited safety data with the weekly paclitaxel, which is far better tolerated than every-3-week docetaxel, NCCN now gives us permission to use either one. Personally, I use weekly paclitaxel with trastuzumab and pertuzumab.

For second-line, the preferred approach is T-DM1. For third-line and beyond, there are a number of options. Trastuzumab could be resumed with a different chemotherapy, or two anti-HER2 approaches of lapatinib and trastuzumab without chemotherapy could be given, or even the previous second-line standard regimen of lapatinib plus capecitabine.

HER2-resistance continues to be an issue. What are some of the potential mechanisms being investigated for overcoming it?

People have examined the addition of pertuzumab to block the dimerization of receptor signaling along with the anti-HER2 approach of trastuzumab. In this case, one attaches to domain two and the other to domain four of the intercellular portion of the HER2 receptor. Other options include using small molecule TKIs, such as lapatinib, that could work on an intercellular level or antibody-drug conjugates, such as T-DM1.

Downstream signaling is also possible at the mTOR level with drugs such as everolimus that has been examined in BOLERO-1 and BOLERO-3. The problem is in BOLERO-1, which showed a 7-month improvement in PFS, the results did not quite reach statistical significance. In BOLERO-3, the results were statistically significant, but the benefit was barely 5 weeks. Those will remain as experimental approaches. There are a lot of other experimental options on the horizon, so it is a very exciting time.

Another issue that emerges in this setting is CNS metastases. Why is this such a pervasive problem in HER2-positive breast cancer?

HER2-positive breast cancer and triple-negative breast cancer have tendencies to relapse in the brain. Up to 40% of patients with HER2-breast cancer will develop brain metastases during their lifetime. It is a big problem. Trastuzumab, being a large molecule, doesn’t penetrate well. We thought that lapatinib, also being a small molecule, would be a better choice.

However, a randomized trial that was designed to look at this very issue had to be stopped after accrual of 540 patients instead of the 650 who should have been enrolled because the PFS was inferior in the lapatinib arm when compared with the trastuzumab arm. The incidence of brain metastases was 3% in the lapatinib arm and 5% in the trastuzumab arm, which was not statistically different. Currently, ongoing trials are looking at intrathecal trastuzumab. The dose in that case is 6 mg total, compared with the common dose of 6 mg/kg for trastuzumab. The brain is about 1 kg, so it makes sense to just give 6 kg total.

And looking at investigational agents in the HER2-positive setting, what are your thoughts on the III neratinib data presented at the 2015 ASCO Annual Meeting?

That was the ExteNET trial, which was very interesting. It was in the subsequent setting after finishing 1 year of trastuzumab-based therapy. The average time from finishing trastuzumab-based therapy to going on neratinib was about 4.5 months. In this trial, everyone had received chemotherapy and everyone had received trastuzumab. Two-thirds of patients had chemotherapy concurrently with trastuzumab, while the remaining one-third had chemotherapy and trastuzumab sequentially.

The results were interesting. There was already 2.3% absolute benefit in DFS at the 2-year mark. More follow-up is needed but, at this point, it seems to be a positive study. When you look at preplanned subset analyses of patients with center verification of HER2 and HER amplification by FISH, those patients had an 8% actual benefit. That is intriguing. The other interesting point is that the HR-positive group seemed to benefit, while the negative group did not. That gives us an additional option. If the drug gets approved, there will be a role for this drug for HR-positive patients.