Some Excitement, Some Disappointment

Adam M. Brufsky, MD, PhD

Inside ASCO 2015: Breast Cancer

For breast cancer specialists, much of the excitement at ASCO revolved around the emerging field of checkpoint inhibition in breast cancer and other tumors; however, there were four non-checkpoint presentations in breast cancer that also proved provocative.

NSABP-B35

The proper treatment for ductal carcinoma in situ (DCIS) continues to evolve. The latest step forward in the treatment of DCIS was presented during the breast cancer oral abstract session.[1] The NSABP-B35 trial tested anastrozole vs tamoxifen for 5 years after resection and radiation for DCIS. The trial was large (over 3,000 patients), randomized, double-blinded, and placebo-controlled; median follow-up was 8.6 years. Of the women taking anastrozole, 93.5% were free of disease (breast cancer–free survival) at 10 years, compared with 89.5% of those taking tamoxifen (P  = .03). Most of this improvement came from a decrease in contralateral breast cancer, and was in women younger than 60 years of age. Women who were given tamoxifen also had higher rates of uterine cancer (17 vs 8 events) and thromboembolic events (41 vs 12 events), although the use of anastrozole resulted in more fractures (69 vs 50). While anastrozole’s lack of benefit over tamoxifen was surprising in women older than 60, the better side-effect profile of anastrozole likely now makes this the treatment of choice for postmenopausal women with DCIS. However, this trial does not answer the overarching question: Which patients with DCIS should not be aggressively treated? We await further research to shed light on this issue.

PALOMA-3

CDK4/6 inhibition for estrogen receptor (ER)-positive metastatic breast cancer will now likely enter the mainstream. The results of PALOMA-3 reinforced the positive results from the initial randomized PALOMA-1 study of letrozole with or without palbociclib as first-line therapy for metastatic breast cancer.[2] In PALOMA-3, 521 women with ER-positive metastatic breast cancer who had progressed on a nonsteroidal aromatase inhibitor were randomized to fulvestrant with or without palbociclib. The trial was stopped early by its data safety monitoring committee when a stopping boundary for efficacy was crossed. The median progression-free survival (PFS) with fulvestrant plus palbociclib was 9.2 months, compared with 3.8 months for fulvestrant alone (P < .000001). Toxicity was as expected, with 62% of patients experiencing grade 3 or 4 neutropenia with palbociclib, while only 0.6% had fever and neutropenia (same as in the fulvestrant-alone arm). These new data are consistent with the phase II study that led to FDA approval of palbociclib, which is reassuring since the observed benefit has now also been seen in a phase III trial. Palbociclib will now likely enter the mainstream as therapy for ER-positive metastatic breast cancer, with FDA approval in the first-line setting and label expansion likely to include second-line settings and perhaps beyond. Results from the larger first-line PALOMA-2 trial (phase III palbociclib and letrozole) are eagerly awaited, as are data from large phase III trials of other CDK4/6 inhibitors such as abemaciclib and ribociclib, which will be announced in the coming years.

MARIANNE

Antibody-drug conjugates for HER2-positive metastatic breast cancer continue to surprise us; the MARIANNE study is an example of an unexpected disappointment.[3] TDM-1 (trastuzumab-emtansine) was clearly superior to lapatinib-capecitabine in the second-line EMILIA study, and randomized phase II data from TDM-1 in the first-line HER2-positive metastatic breast cancer setting suggested a PFS benefit of 14 months, compared with 12 months with docetaxel-trastuzumab. Additionally, the CLEOPATRA study demonstrated an overall survival (OS) benefit of 56 months when pertuzumab was added to docetaxel-trastuzumab (OS ~ 40 months). Therefore, hopes were high for MARIANNE, which tested docetaxel-trastuzumab, TDM-1, and TDM-1 + pertuzumab as first-line therapy for HER2-positive metastatic breast cancer. An intent-to-treat analysis of the 1,095 patients enrolled in this study showed no statistically significant difference in PFS in any of the three arms: 13.7 months for docetaxel-trastuzumab; 14.1 months for TDM-1 (P = .31 vs docetaxel-trastuzumab); and 15.2 months for TDM-1 + pertuzumab (P = .14 vs docetaxel-trastuzumab). Side effects, particularly neutropenia, febrile neutropenia, and alopecia, were greatly reduced in the TDM-1 arms. TDM-1 is therefore a less toxic first-line therapy than docetaxel-trastuzumab, with similar efficacy. However, based on CLEOPATRA, pertuzumab-trastuzumab-docetaxel (THP) appears to have better efficacy than docetaxel-trastuzumab. There are no comparisons of THP vs TDM-1 or TDM-1 + pertuzumab, so for now it appears that the first-line recommendation of pertuzumab for HER2-positive metastatic breast cancer therapy remains unchanged for the majority of patients. Interestingly, in the 226 patients with metastatic breast cancer who had received trastuzumab and/or lapatinib in the adjuvant or neoadjuvant setting, the PFS for docetaxel-trastuzumab was 10.5 months, compared with 15 months for TDM-1. This finding, which corresponds to the scenario of most women with HER2-positive metastatic breast cancer treated in the United States, deserves more attention as we try to place these data into context.

ExteNET

Finally, the adjuvant treatment of HER2-positive early-stage breast cancer continues to undergo refinement. The HERA study demonstrated that 2 years of adjuvant trastuzumab had no benefit over 1 year. Additionally, the ALTTO study demonstrated no benefit to the adjuvant combination of lapatinib and trastuzumab over trastuzumab alone. Therefore, the results of the ExteNET study of adjuvant neratinib after 1 year of adjuvant trastuzumab were greeted with interest.[4] Neratinib is an irreversible inhibitor of the intracellular kinase domain of the HER2 molecule. In the ExteNET study, 2,840 women with HER2-positive early-stage breast cancer who had completed 1 year of adjuvant trastuzumab were randomly assigned to an additional year of neratinib or placebo. Invasive disease–free survival at 2 years of follow-up (approximately 36–48 months after diagnosis) was 93.9% in the neratinib arm vs 91.6% in the placebo arm (P = .002). This benefit appeared to be confined to the ER-positive/HER2-positive subgroup in this trial, and most of the benefit was a result of a reduction in distant recurrence (52 vs 73 events). Approximately 40% of patients who received neratinib experienced substantial diarrhea (grade 3 or 4), which resolved with dose reduction or dose discontinuation, and required intensive loperamide (16 mg/day) as prophylaxis. Based on these data, neratinib does appear to be an advance in the treatment of HER2-positive early-stage breast cancer; however, the unusual choice of 2-year disease-free survival as an endpoint in this trial, as well the substantial diarrhea seen, may limit its eventual adoption as therapy in this patient population. Nonetheless, in women with HER2-positive early-stage breast cancer and a high risk of recurrence, neratinib, if approved by the FDA and eventually marketed, may have a role to play in the adjuvant setting.

Financial Disclosure:Dr. Brufsky has served as a consultant for Novartis, Pfizer, and Roche.

References:

1. Margolese RG, Cecchini RS, Julian TB, et al. Primary results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA500.

2. Turner, NC, Ro J, Andre F, et al. PALOMA3: a double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr LBA502.

3. 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. Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 507.

4. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). Presented at the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago. Abstr 508.