Combining palbociclib with letrozole failed to result in any significant overall survival (OS) benefit over letrozole alone in women with ER-positive (ER+), HER2-negative metastatic breast cancer, according to data presented at the 2017 ASCO Annual Meeting (Abstract 1001).
Although the international phase II PALOMA-1/TRIO-18 trial was not sufficiently powered for OS analysis, the data showed a statistically non-significant trend towards improvement, said lead investigator Richard S. Finn, MD, in the Division of Hematology/Oncology at Geffen School of Medicine at the University of California Los Angeles.
Palbociclib is an oral agent that inhibits the cyclin D-cyclin dependent kinase activity (CDK4 and CDK6), which appears to promote tumor cell proliferation in hormone-receptor positive breast cancer. Letrozole is an aromatase inhibitor that stops production of estrogen in the ovaries and is used as hormone therapy.
“PALOMA-1 was the impetus to drive CDK4/6 inhibition in ER+ HER- breast cancer. This study, which has gained a lot of importance, was really designed to validate a laboratory hypothesis,” said Finn.
“At this point we have about a median of 5 years of data, although some patients have now been on this combination for more than 6 years, so there will be much more survival data to analyze,” he told Oncology Times. “We have analyzed about 70 percent in both arms and we still see a 3-month improvement in overall survival, but clearly not statistically significant.”
Final results from the phase III PALOMA-2 trial showed the combination extended progression-free survival (PFS) from 14 months to 24 months in postmenopausal women with ER+ HER- breast cancer. The results, based on randomization of 666 patients, led to accelerated approval by the FDA as a first-line therapy in such patients.
The larger study, PALOMA-2, was sufficiently powered to better assess survival of patients treated with the combination. It confirmed the efficacy and safety of the combination as first-line treatment for postmenopausal women with ER+ advanced breast cancer.
“Hopefully, survival data from the phase III, PALOMA-2 study will give us a better assessment,” Finn noted.
Palbociclib was granted accelerated approval in February 2015, in combination with letrozole for the treatment of estrogen ER+ HER2- advanced breast cancer as initial endocrine based therapy in postmenopausal women. The FDA granted palbociclib regular approval in February 2016, in combination with fulvestrant for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression following endocrine therapy.
In March 2017, the FDA granted regular approval to palbociclib in combination with an aromatase inhibitor as initial endocrine based therapy for postmenopausal women.
The data were confirmed in the phase III PALOMA-2 trial; however, at the time of the final PFS analysis, OS data were immature, with only 61 events in both arms and a median follow-up of less than 30 months with a trend in favor of palbociclib plus letrozole versus letrozole.
The new data show that the addition of palbociclib to letrozole increased median PFS to 20.2 months, compared to 10.2 months in patients who received letrozole alone.
“The big question now, with PALOMA-2 and PALOMA-3, as well as the new findings from MONALEESA-2 and now with abemaciclib in the MONARCH-2 trial, is if the observation that these agents can improve progression-free survival can they improve overall survival,” noted Finn.
PALOMA-1 was a two-part study. Part 1 included postmenopausal women using only ER+/HER2– status, while the second part added patients with CCND1 amplification and/or loss of p16. Progression-free survival was the primary endpoint, while secondary endpoints included objective response rate, OS, safety, and correlative biomarker studies.
In the trial, 165 women were randomized, with 66 in Part 1 and 99 in Part 2, and baseline characteristics were balanced between both arms. Patients were randomized 1:1 to receive palbociclib plus letrozole or letrozole alone, and OS data were collected.
By December 2016, 116 OS events had occurred in the patients, with median OS of 37.5 months with palbociclib plus letrozole (95% CI: 31.4, 47.8) compared to 34.5 months among women who only received letrozole (95% CI: 27.4, 42.6).
Among patients in the combination cohort, 78.6 percent received post-study systemic therapy versus 86.4 percent in the letrozole arm, and more women in the letrozole alone group received ≥3 lines of therapy (37% vs. 18%).
“It is very exciting. These are the first survival data coming out,” said Lisa A. Carey, MD, the Preyer Distinguished Professor in Breast Cancer Research and Chief of the Division of Hematology-Oncology, UNC School of Medicine Lineberger Cancer Center, Chapel Hill.
“Until the phase III data are in, people's enthusiasm should remain for inclusion of CDK4/6 inhibitors, although it is possible that we will see a more modest effect than we anticipated.”
Gabriel N. Hortobagyi, MD, the Connally Chair in Breast Cancer at MD Anderson Cancer Center, University of Texas, Houston, believes that because the study was not powered to detect OS it is moreimportant to await survival data in the larger PALOMA-2 before drawing any conclusions.
“Even if there had been a significant survival benefit, the long and short of it is that study was too small,” he told Oncology Times.
Hortobagyi is lead investigator of the MONALEESA-2 trial that tested CDK4/6 inhibitor ribociclib plus letrozole as a first-line treatment for ER-positive/HER2- advanced breast cancer (Abstract 1038).
Data from two MONALEESA-2 studies presented by Hortobagyi during the conference showed additional evidence safety and efficacy data on use of the CDK4/6 inhibitor ribociclib plus fulvestrant letrozole as a first-line treatment for women with advanced ER+ HER2- cancer. According to the findings, PFS at 2 years with the combination was better than with letrozole alone. PFS rates after 18 months were 63.0 percent (95% CI [54.6%, 70.3%]) and 42.2 percent.
Kurt Samson is a contributing writer.