We have learned that we can improve outcomes by overcoming resistance through combined signal blockade targeting different parts of the HER pathway. We are already doing so by adding lapatinib to trastuzumab, and have seen that pathologic complete response rates are high … though lapatanib does add toxicity.
—Hope S. Rugo, MD
From the initial discovery of the HER2 family of receptors in the mid-1980s to the present, a “wealth of riches” has been uncovered in terms of agents that can target pathways relevant to this aggressive breast cancer type, notes Hope S. Rugo, MD, Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco. “We have seen HER2-positive breast cancer go from being the worst type of breast cancer to one in which we can offer a lot of hope to our patients.”
Elaborating on this theme, Dr. Rugo described the emerging landscape of HER2-positive breast cancer and what this means for oncologists.
HER2-positive Breast Cancer Today
What are the main “truths” about HER2-positive breast cancer in 2013?
The addition of trastuzumab (Herceptin) to taxane-based first-line chemotherapy for metastatic breast cancer improves response rate, progression-free survival, and overall survival, and we should continue HER2-directed therapy through progression. In early-stage disease, the addition of trastuzumab to adjuvant chemotherapy results in remarkably early and sustained improvement in disease-free survival and overall survival. Most recently, we have learned that trastuzumab is as effective when combined with a non–anthracycline-based regimen as it is when combined with anthracycline-containing therapy.
The optimal duration of therapy for early-stage disease continues to be evaluated, but at the 2012 European Society for Medial Oncology (ESMO) Congress and San Antonio Breast Cancer Symposium we learned from the HERA1 and PHARE2 trials that 1 year is as effective as 2 years of therapy and more effective than 6 months. So 1 year is the standard of care unless future studies prove otherwise.
We have also seen approval of an exciting new agent, pertuzumab (Perjeta), when added to standard first-line therapy for metastatic breast cancer. Pertuzumab is an antibody similar to trastuzumab that blocks heterodimerization of HER2 to HER3, and is able to overcome at least some pathways of resistance to standard trastuzumab-based therapy.
Interestingly, pertuzumab is most effective when given with trastuzumab. The combination (plus docetaxel) proved very promising in the CLEOPATRA study,3 which treated patients not previously exposed to trastuzumab. Progression-free survival reached 1.5 years—the longest duration we have seen in any metastatic trial treating HER2-positive disease.
Updated CLEOPATRA data presented at San Antonio 20124 demonstrated a significant improvement in survival in patients receiving the triplet compared to those receiving trastuzumab and docetaxel alone. These benefits were achieved with little additional toxicity, an advantage seen with many antibodies used in targeted therapy for cancer and a striking difference from the unpredictable toxicity seen with oral small-molecule tyrosine kinase inhibitors.
The survival impact achieved with pertuzumab/trastuzumab/docetaxel is practice-changing, and this regimen is now FDA-approved as first-line treatment for advanced breast cancer. National Comprehensive Cancer Network (NCCN) guidelines support using the combination in either the first- or second-line settings in combination with any taxane.
Ongoing and future studies will help to determine how best to utilize pertuzumab. The phase II PERTAIN study includes 250 women with HER2-positive, estrogen receptor–positive previously untreated metastatic disease, randomly assigning them to trastuzumab/taxane or trastuzumab plus an aromatase inhibitor, with or without pertuzumab. The phase II VELVET trial of 210 previously untreated patients evaluates pertuzumab/trastuzumab plus vinorelbine; sequential cohorts will test sequential vs combination antibody administration.
In the neoadjuvant setting, pertuzumab added to trastuzumab in the Neosphere trial resulted in pathologic complete response rates of 40% to 52%.5 The APHINITY trial randomly assigns patients with early-stage disease who have completed primary surgery to chemotherapy plus trastuzumab alone or trastuzumab plus pertuzumab for 1 year.
Metastatic HER2-positive Disease
How can anti-HER2 treatment be improved for patients with metastatic disease?
Despite high response rates, the majority of patients eventually develop progressive disease, though the occasional patient has long-term stability on HER2-directed therapy—appearing to be cured of what we previously thought was incurable disease. We would like to know how to improve upon our upfront therapies to create the long remissions we see in this small minority of patients.
We have learned that we can improve outcomes by overcoming resistance through combined signal blockade targeting different parts of the HER pathway. We are already doing so by adding lapatinib (Tykerb) to trastuzumab, and have seen that pathologic complete response rates are high—47% to 60%—though lapatanib does add toxicity. As a single agent (combined with chemotherapy) lapatanib is inferior to trastuzumab, probably because it is difficult to administer easily (due to unpredictable toxicity, especially diarrhea).
In addition to the data seen in the neoadjuvant setting, the single-agent lapatinib arm in the eagerly awaited adjuvant ALTTO study was closed due to futility, meaning that lapatinib with chemotherapy in the adjuvant setting was inferior to trastuzumab or the combination of trastuzumab and lapatinib. This is in keeping with other studies showing that lapatinib by itself is inferior, though it can be an important partner to trastuzumab. Other means of combined HER family blockade are needed.
Early-stage HER2-positive Disease
Will it be possible to predict which patients with early breast cancer will benefit from certain anti-HER2 treatments?
We want to be able to define not only prognostic factors but also predictive factors in early-stage disease. In the recent NeoSphere trial,5 which evaluated various combinations of trastuzumab, pertuzumab, and docetaxel, we identified markers (PI3K mutations, PTEN loss) that we thought indicated resistance to trastuzumab. But while these predicted worse outcomes, they did not help us select patients who would benefit from novel targeted therapy. At this point, we have to give all drugs to all patients. We are not able to select the ones who will benefit from a specific strategy.
We also want to confirm that treatment benefits observed in the neoadjuvant setting will translate into benefits later. This would allow us to cure patients more easily, with less exposure to drugs, and to study these drugs in smaller patient populations.
Emerging HER2-directed Therapies
Trastuzumab emtansine (T-DM1) is an exciting investigational anti-HER2 agent. How will it impact the treatment of HER2-positive disease?
T-DM1 has proven superior to capecitabine (Xeloda)/lapatinib in terms of response rates, progression-free survival, overall survival, and safety. At the 2012 ESMO meeting, we heard updated results of the EMILIA trial,6 which showed a 6-month improvement in overall survival, including a 32% reduction in mortality risk at a median follow-up of about 20 months, from treatment with T-DM1 compared to lapatinib/capecitabine in patients whose cancer had progressed on trastuzumab and chemotherapy. T-DM1 will clearly become a new standard in the metastatic setting, and we expect FDA approval early in 2013.
We look forward to results from the MARIANNE trial, which is evaluating T-DM1 in 1,092 untreated patients with metastatic disease. The three arms of the study are trastuzumab plus taxane, T-DM1 plus placebo, and T-DM1 plus pertuzumab. This is a fascinating design because patients receiving T-DM1 will not receive a taxane and thus will not experience hair loss.
T-DM1 will also be studied in the late-line THERESA trial, which includes 795 women with prior exposure to trastuzumab, lapatanib, anthracyclines, taxanes, and capecitabine. The drug is also moving into trials in the neoadjuvant and adjuvant setting.
Further Overcoming Resistance
How is resistance to HER2-directed treatment being addressed clinically and as a research question?
Many drugs are being evaluated for their potential to overcome trastuzumab resistance, including the mTOR inhibitor everolimus (Afinitor). The phase III BOLERO-1 trial will compare trastuzumab and paclitaxel with and without everolimus, while the phase III BOLERO-3 trial will compare trastuzumab and vinorelbine with and without everolimus.
Other experimental approaches to overcoming resistance are evaluating HER1/2 inhibitors such as afatinib, pan-HER inhibitors, PI3K and other combined inhibitors, heat shock protein 90 inhibitors, insulin-like growth factor 1 receptor inhibitors, HER3 monoclonal antibodies, and vaccines. We can expect steep competition among new agents that might fulfill this role.
Can you distill all the data into a useful clinical context?
Here’s what the data mean for clinical practice:
T-DM1 is a new and effective treatment for HER2-positive metastatic patients who progress on trastuzumab; it has remarkable efficacy and modest toxicity and is likely to become FDA-approved early in 2013.
Pertuzumab is approved in the first-line setting in combination with trastuzumab and docetaxel and is a new standard of care.
Lapatinib is associated with more toxicity and less efficacy than trastuzumab in the first-line metastatic setting.
Lapatinib plus capecitabine is still an option for later-line therapy or in special settings, such as for patients with low ejection fractions or brain metastases.
These drugs might best be used in the following sequence: pertuzumab/trastuzumab/taxane first-line, then drop the chemotherapy after best response and continue the dual antibodies; then move to T-DM1 as a single agent; and as late-line therapy, give lapatinib plus capecitabine. ■
Disclosure: Dr. Rugo reported no potential conflicts of interest.
1. Gelber RD, Goldhirsch A, Piccart M, et al: HERA trial: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. 2012 ESMO Congress. Abstract LBA6. Presented October 1, 2012.
2. Pivot X, Romieu G, Bonnefoi H, et al: PHARE trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. 2012 ESMO Congress. Abstract LBA5. Presented October 1, 2012.
3. Baselga J, Cortes J, Kim S-B, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-111, 2012.
4. Swain SM, Kim S-B, Cortes J, et al: Confirmatory overall survival analysis of CLEOPATRA: A randomized, double-blind, placebo-controlled Phase III study with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract P5-18-26. Presented December 7, 2012.
5. Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32, 2012.
6. Verma S, Miles D, Gianni L: Updated overall survival results from EMILIA, a phase 3 study of trastuzumab emtansine (T-DM1) vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer. 2012 ESMO Congress. Abstract LBA12. Presented October 1, 2012.