October 2016 Edition Vol.11, Issue 10

Practice-Changing Potential for Breast Cancer

Practice-Changing Potential for Breast Cancer

By Kathy Boltz, PhD

ESMO 2016 brought promising progression-free survival (PFS) data on ribociclib for hormone receptor-positive, HER2-negative (HR+/HER2-) recurrent or metastatic breast cancer, and improved median PFS for fulvestrant over anastrozole. Furthermore, from ASCO 2016 comes highlights from the HERITAGE study on the trastuzumab biosimilar, Myl-1401O; the large phase 3, MA.17R trial that compared letrozole with placebo out to 10 years; the KRISTINE study that provides the first phase 3 data for a neoadjuvant regimen that omits standard chemotherapy for HER2-positive breast cancer; and finally, the PALOMA-2 study of palbociclib in women with advanced breast cancer who are estrogen receptor-positive and HER2-negative.

MONALEESA-2: Adding ribociclib to letrozole for HR+/HER2- superior to
letrozole alone

Progression-free survival was improved 44% by adding ribociclib (Novartis) to letrozole compared with letrozole alone (HR, 0.56; 95% CI, 0.43-0.72; P=.00000329).1 After 18 months, the PFS rate was 63.0% (95% CI, 54.6-70.3) in the ribociclib group and 42.2% (95% CI, 34.8-49.5) in the placebo group. Median PFS was not reached in the ribociclib arm at data cut-off, while it was 14.7 months in the placebo arm.

The MONALEESA-2 phase 3 trial was a randomized, placebo-controlled evaluation of the safety and efficacy of ribociclib, a selective CDK4/6 inhibitor, that was compared with letrozole for first-line treatment in 668 postmenopausal women with HR+/HER2-recurrent or metastatic breast cancer. The enrolled patients could not have received previous systemic therapy for advanced disease. The results were presented at ESMO 2016 and simultaneously published in the New England Journal of Medicine.

“This was THE definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone,” said principal investigator, Professor Gabriel Hortobagyi, MD, FACP, from the University of Texas MD Anderson Cancer Center. Hortobagyi suggested that these results are a compelling proof of principle. Further, he added that combinations of ribociclib with other inhibitors of various signalling pathways might be fruitful against several subtypes of breast cancer.

Grade 3 or 4 neutropenia (59.3% in ribociclib arm vs 0.9% in placebo arm), leukopenia (21.0% vs 0.6%), hypertension (9.9% vs 10.9%), elevated alanine aminotransferase (9.3% vs 1.2%), and elevated aspartate aminotransferase (5.7% vs 1.2%) were all more common in the ribociclib arm except hypertension. Rates of serious adverse events were below 5% in both arms. Prolonged QT interval, meaning an increase of more than 60 msec from baseline, occurred in 9 patients (2.7%) in the ribociclib group and none in the placebo group.

Novartis received breakthrough therapy status for ribociclib from the FDA in early August 2016 for HR+/HER2- advanced or metastatic breast cancer in combination with letrozole. These trial results keep it on track for expedited approval. Notably, this patient population overlaps with the same patient population that the CDK4/6 inhibitor palbociclib (Ibrance®, Pfizer) has approval for (see below for PALOMA-2 data on palbociclib in ER+/HER2-).

FALCON: Fulvestrant improves median PFS over anastrozole in
HR+ breast cancer

Median PFS was 2.8 months longer with fulvestrant (Faslodex®, AstraZeneca) than anastrozole (HR, 0.797; 95% CI, 0.637-0.999; P=.0486) as first-line treatment in postmenopausal women with hormone receptor-positive, locally-advanced or metastatic breast cancer.2 The phase 3 FALCON trial enrolled 462 patients who had not had prior hormonal treatment for hormone receptor-positive breast cancer.

After a median follow-up of 25 months, PFS was 16.6 months in the fulvestrant arm and 13.8 months in the anastrozole arm. Anastrozole was previously marketed by AstraZeneca, but lost patent protection in 2010.

“These data document a benefit for fulvestrant in delaying disease progression as a first-line therapy, an important goal for women with metastatic breast cancer,” said Dr. Matthew Ellis, principal investigator of the FALCON trial. “The results are supported by a previous trial, which also showed an advantage for fulvestrant over anastrozole. The results are clinically meaningful and suggest that fulvestrant could be used as a first-line therapy for women with advanced breast cancer.”

These results are an advance for the most common form of breast cancer. However, the study’s design excluded patients with advanced breast cancer who had had prior hormone treatment, yet many patients with advanced breast cancer have previously been treated for the primary breast cancer, as explained by Dr. Nicholas Turner, team leader at the Institute of Cancer Research and Medical Oncologist at the Royal Marsden, London, UK, in a press release.

Further, Dr. Turner stated that palbociclib has become the standard of care in the time since this study was designed. The 2.8 month benefit for PFS in this study seems unlikely to displace palbociclib in the first-line for most eligible patients. Patients whose disease had not spread to the liver or lungs at baseline had a larger PFS benefit (22.3 vs 13.8 months), and so these patients with non-visceral disease would be the most likely candidates for first-line fulvestrant.

Currently, fulvestrant has FDA approval as monotherapy for HR+ metastatic breast cancer in postmenopausal women with disease progression after antiestrogen therapy and in combination with palbociclib for HR+/HER2- advanced or metastatic breast cancer in women with disease progression after endocrine therapy. AstraZeneca has begun discussions with FDA authorities about a possible label extension for fulvestrant.


For related breast cancer videos, please check out our coverage of the ASCO 2016 annual meeting:


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