COUNTERPOINT: HER2-Targeted Combinations in Advanced HER2-Positive Breast Cancer

Oncology (Williston Park). 29(11):797, 801.

Mark D. Pegram, MD

Which Agents to Use Together, Which Alone, and When

The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial was a phase III, double-blind, randomized, placebo-controlled trial that evaluated dual humanized anti–human epidermal growth factor receptor (HER) 2 antibody blockade with both single-agent pertuzumab and single-agent trastuzumab in combination with docetaxel as first-line therapy in metastatic HER2-positive disease. This trial originally showed that the combination of pertuzumab, trastuzumab, and docetaxel, compared with docetaxel and trastuzumab plus placebo, significantly prolonged progression-free survival (PFS), with an increase of 6.1 months at the median (12.4 vs 18.5 months; hazard ratio [HR], 0.62 [95% confidence interval (CI), 0.51–0.75]).[1] Recently, the final prespecified overall survival (OS) results were reported, with a median follow-up duration of 50 months.[2] The median OS was 56.5 months (95% CI, 49.3 months to not reached [NR]) in the subjects randomized to the pertuzumab combination, compared with 40.8 months (95% CI, 35.8–48.3 months) in the subjects randomized to the placebo combination (HR, 0.68 [95% CI, 0.56–0.84]; P < .001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group; therefore, the magnitude of the difference in median OS is likely a conservative value. Moreover, no new safety signals emerged, with long-term cardiac safety maintained in both arms.

Building on the Success of the CLEOPATRA Combination Regimens

Since most of the observed toxicity in both arms of the CLEOPATRA trial resulted from docetaxel, there has subsequently been enthusiasm to investigate pertuzumab and trastuzumab in combination with weekly paclitaxel, which is arguably less toxic than docetaxel. In a phase II trial of pertuzumab and trastuzumab with weekly paclitaxel, patients with metastatic HER2-positive breast cancer who had received up to one prior therapy were treated with paclitaxel, 80 mg/m² weekly, plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) every 3 weeks.[3] Altogether 69 patients were treated: 51 (74%) in the first-line metastatic setting and 18 (26%) in the second-line metastatic setting. With a median follow-up of 21 months (range, 3–38 months), 6-month PFS (the primary study endpoint) was 86% (95% CI, 75%–92%). Median PFS was 24.2 months (95% CI, 14 months to NR) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. There was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. These results suggest that paclitaxel given weekly with trastuzumab and pertuzumab is an effective alternative to docetaxel-based combination therapy.[3]

T-DM1 Alone and T-DM1 Combinations: When Superior, When Not

The preferred status of CLEOPATRA-like regimens in the first-line HER2-positive metastatic breast cancer setting has recently been challenged by antibody-drug conjugate regimens based on ado-trastuzumab emtansine (T-DM1). The MARIANNE trial randomly assigned 1,095 patients with locally recurrent unresectable or previously untreated HER2-positive metastatic breast cancer to receive T-DM1 plus pertuzumab (363 patients), T-DM1 plus placebo (367 patients), or trastuzumab plus docetaxel or paclitaxel (365 patients)-with this last regimen being the standard of care for this patient population at the time the trial was initiated.[4] With a median follow-up of 35 months, both T-DM1–containing regimens demonstrated noninferiority, but not superiority, to taxane + trastuzumab. The median PFS was 15.2 months in the T-DM1 + pertuzumab arm (HR, 0.87 [95% CI, 0.69–1.08]; P = .14) and 14.1 months with T-DM1 alone (HR, 0.91 [95% CI, 0.73–1.13]; P = .31), compared with 13.7 months for the taxane + trastuzumab control.[4] Thus, T-DM1 + pertuzumab is insufficient to replace CLEOPATRA-like regimens in the first-line HER2-positive metastatic breast cancer setting, based on efficacy considerations. For HER2-positive metastatic breast cancer patients with disease progression following prior treatment with a taxane and trastuzumab (or relapsed within 6 months of completion of an adjuvant trastuzumab regimen), T-DM1 has been shown to be significantly superior to lapatinib + capecitabine, for both PFS and OS, and is arguably better tolerated.[5] Therefore, under the assumption that T-DM1 remains superior to lapatinib + capecitabine following a taxane, trastuzumab, and pertuzumab, T-DM1 is the logical treatment choice for consideration as next in sequence in the second-line setting.

In the Third-Line Setting and Beyond

Upon further disease progression following a prior pertuzumab/trastuzumab–containing regimen and T-DM1, lapatinib-based regimens (either lapatinib + capecitabine or lapatinib + trastuzumab) are a logical next choice.[6,7] However, neither of these regimens has efficacy data available in the setting of prior progression after multiple HER2-targeting antibody–based strategies. In later lines of treatment, clinicians regularly default to sequential salvage chemotherapeutics given in combination with trastuzumab in multiple lines, although this practice is not based on randomized trial evidence beyond the second line.[8]

Financial Disclosure:Dr. Pegram serves as a consultant for Genentech.

References:

1. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.

2. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-34.

3. Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2015;33:442-7.

4. Ellis PA, Barrios CH, Eiermann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. J Clin Oncol. 2015;33(suppl):abstr 507.

5. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-91.

6. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006; 355:2733-43.

7. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-92.

8. von Minckwitz G, Schwedler K, Schmidt M, et al; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011;47:2273-81.