Cleveland Clinic Researcher Recaps Successes and Stumbles in Dual HER2 Targeting

Alberto J. Montero, MD, MBA

Although dual HER2 blockade strategies have become an important part of the treatment paradigm for patients with HER2-positive breast cancer, the complexities of administering these therapies continue to unfold. This was evident in recent findings from the APHINITY trial, which demonstrated a benefit with the addition of pertuzumab (Perjeta), a HER2-targeting agent, to trastuzumab (Herceptin) plus chemotherapy compared with the standard of care as adjuvant, postoperative therapy for patients with early breast cancer.

Patients who received pertuzumab along with trastuzumab and chemotherapy had an invasive disease-free survival (iDFS) rate of 94.1% after 3 years’ follow-up versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00). In all, 4805 patients participated in the study. The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. After a follow-up of 4 years, the iDFS rate for patients with node-positive disease was 89.9% with pertuzumab versus 86.7% with standard therapy (HR, 0.77; 95% CI, 0.62-0.96; P = .019). For participants with hormone receptor— negative disease, the iDFS rate with pertuzumab was 91.0% after 4 years compared with 88.7% in the control group (HR, 0.76; 95% CI, 0.56-1.04; P = .085).

What role does dual HER2 blockade currently play in the treatment of patients with HER2-positive breast cancer?

Alberto J. Montero, MD, MBA, who specializes in breast cancer, discussed dual HER2-targeting strategies in an interview with OncologyLive®. Montero is an associate professor of hematology oncology at Cleveland Clinic in Ohio. His research interests include the development of novel targeted therapies to improve clinical outcomes in patients with breast cancer. He has led more than 30 clinical trials and published more than 70 peer-reviewed research papers.In both nonmetastatic and metastatic settings, dual monoclonal antibody (mAb) therapy with trastuzumab/pertuzumab is considered the standard of care.

In the neoadjuvant setting, dual mAb therapy in combination with chemotherapy (either anthracycline or nonanthracycline) is associated with a very high pathologic complete response rate that, at least in hormone receptor—negative/HER2- positive breast cancer, is a surrogate for better survival. In the neoadjuvant setting, only 6 cycles of pertuzumab are given with chemotherapy.

The data from the APHINITY trial in the adjuvant setting showed a mostly disappointing but statistically significant—although some would argue perhaps not very clinically significant—benefit with 1 full year of pertuzumab/trastuzumab after chemotherapy plus dual mAb therapy.

Do you think dual HER2 blockade regimens eventually will be used without chemotherapy for certain patients?

In the metastatic setting, a taxane plus dual mAb therapy is the recommended first-line treatment for metastatic HER2-positive disease in patients who are candidates for chemotherapy. This is based on the CLEOPATRA trial, which showed an unprecedented improvement in both median overall survival (OS) and progression-free survival (PFS) with dual mAb therapy. In this study, docetaxel was given every 3 weeks in combination with dual mAb therapy (pertuzumab/trastuzumab) for a minimum of 6 cycles, and then chemotherapy could be stopped with dual mAb therapy continued until progression or toxicity.Not in the foreseeable future. The MARIANNE trial tried to look at an antibody-alone combination in the metastatic setting as first-line therapy in HER2-positive breast cancer. This was a traditional superiority study design looking at whether T-DM1 [trastuzumab emtansine; Kadcyla] in combination with pertuzumab would be superior to trastuzumab plus a taxane or T-DM1 alone. Because this study was designed prior to the CLEOPATRA trial results, there was no taxane/pertuzumab/trastuzumab arm.

MARIANNE was essentially a negative study that failed to show superiority of the T-DM1 groups compared with taxane/trastuzumab. Remember the idea was that targeted delivery of chemotherapy with an antibody [T-DM1] would be better than nontargeted chemotherapy plus trastuzumab. So as a result, you could consider a MARIANNE-like T-DM1 approach (plus or minus pertuzumab) in a patient unfit for chemotherapy as first-line therapy, but this shouldn’t be the preferred approach in patients fit for chemotherapy, based on results from the CLEOPATRA trial.

What are the most significant safety concerns with dual blockade?

What are the major limitations or unanswered questions regarding dual HER2 blockade?

Although cross-trial comparison is problematic, nevertheless docetaxel/pertuzumab/trastuzumab had a median PFS close to 19 months, whereas T-DM1/pertuzumab in the MARIANNE trial had a median PFS of 15 months. Hence, the standard of care should be treating as per CLEOPATRA, unless the patient is felt to be not fit for chemotherapy. This won’t change until new data demonstrate a better approach.In all the pertuzumab/trastuzumab trials, there were exceedingly low severe grade 3/4 toxicities. Cardiac toxicity is very low, in the 1% to 2% range, and as long as anthracyclines are not combined with dual mAb therapy, the little cardiac toxicity that is seen is almost always temporary. For example, left ventricular ejection fraction typically returns to normal after withholding mAb therapy.There are many unanswered questions. A major limitation in the metastatic setting is that, although the CLEOPATRA approach provided an unprecedented improvement in OS and PFS, it is still not curative and the cost is prohibitive in most parts of the world.

Brain metastases are a problem in HER2- positive breast cancer, and dual antibody therapy can’t prevent this from happening. The sad truth is that the extension of life means that the risk of brain metastases becomes an even bigger clinical problem for which we have no good solution.

The main unanswered question in the neoadjuvant/adjuvant setting is whether 6 cycles of TCH-P [docetaxel, carboplatin, trastuzumab, pertuzumab] would be enough. The APHINITY trial looked at 1 year of pertuzumab/trastuzumab versus trastuzumab alone and no pertuzumab. So, until we have more data, we don’t know what to do in patients who received TCH-P in the neoadjuvant setting and have residual disease. Should they get more pertuzumab? Would a shorter course of pertuzumab provide an equivalent benefit to 1 full year?

The overall results for APHINITY were very underwhelming and it reamins unclear exactly why. Certainly, in higher-risk patients one should consider it, but the benefit in patients with stage II breast cancer is rather limited and oncologists need to select well which patients to treat as per APHINITY.