SAN DIEGO, Calif.—The drug palbociclib (PD-0332991), an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, significantly improved progression-free survival when administered as a first-line treatment along with the aromatase inhibitor letrozole, in patients with ER-positive HER2-negative metastatic breast cancer. These results from the Phase II PALOMA-1 study were presented here at the American Association for Cancer Research Annual Meeting (Abstract CT101).
Median progression-free survival was 20.2 months for the 84 patients receiving the palbociclib-letrozole combination versus 10.2 months for 81 patients receiving letrozole alone, reported Richard S. Finn, MD, Associate Professor of Medicine at UCLA.
The progression-free survival hazard ratio for women taking the combination was 0.49 compared with women receiving letrozole alone. Overall survival was trending in favor of palbociclib-letrozole, Finn said, but the difference was not statistically significant.
The study's senior author is Dennis Slamon, MD, PhD, Professor of Medicine at UCLA's Jonsson Comprehensive Cancer Center and Director of the Revlon/UCLA Women's Cancer Research Program, where the preclinical work was performed. The study was sponsored by Pfizer Oncology.
Cyclin-dependent kinases have been around for some time. The Nobel Prize in 2001 was awarded to scientists responsible for the discovery and identification of cyclin, CDKs, and cell cycle checkpoints—Leland H. Hartwell, PhD; Sir Tim Hunt, FRCS; and Sir Paul M. Nurse, PhD.
Palbociclib blocks the transition from G1 to S phase in the cell cycle where CDK-4 and -6 play a critical role in regulating cell metabolism.
Finn said that palbociclib is unlike earlier CDK inhibitors which were “pan CDK inhibitors,” while this second-generation CDK-4/6 inhibitor is very specific in blocking CDK-4/6, leading to less toxicity.
PALOMA-1 comprised two parts, based on biomarkers: Part 1 included ER-positive patients; women in Part 2 also had ER-positive disease and their tumors also showed changes in cyclin D1 and/or loss of p16. This was intended to test whether or not biomarkers could further define appropriate candidates for treatment.
Patients in both parts were randomly assigned to receive letrozole at 2.5 mg daily continuously with or without palbociclib at 125 mg on a three-weeks-on/one-week-off treatment course. About one-third of patients had prior hormonal therapy and chemotherapy in the adjuvant setting.
ER-Negative Status Best Biomarker
Flinn said that ER-negative status was the best biomarker for selecting patients, and changes in cyclin D1 and/or loss of p16 were not as predictive.
But interestingly, while progression-free survival was superior for all patients on the combination arms, progression-free survival did differ by biomarker status.
Among patients in part 1 of the study, selected by ER-positive status, median progression-free survival was 26.1 months for the 34 patients taking palbociclib-letrozole versus 5.7 months for the 32 patients taking letrozole alone.
For those in part 2, selected by other biomarkers, compared with patients in part 1, median progression-free survival was less for the 50 patients taking palbociclib-letrozole, at 18.1 months, but higher for the 40 patients taking letrozole alone, at 11.1 months.
Finn said he thought that might reflect how cyclin-D selection affects the response to letrozole.
The best overall response also favored palbociclib-letrozole, with a 43 percent objective response rate for the combination versus 33 percent for letrozole alone.
Overall Survival Data Not Mature
The outcome most anticipated for the trial was overall survival, and Finn did report a trend favoring palbociclib-letrozole: Median overall survival was 37.5 months for palbociclib-letrozole versus 33.3 months for letrozole alone—but this was not a statistically significant difference.
“Survival events in ER-positive breast-cancer take time to evolve, but we are very encouraged by the overall survival,” Finn said. “This is a positive trend in the right direction—we're seeing a clear separation between the two arms and hopefully, this will be maintained over time.”
The most common toxicity with palbociclib was neutropenia: 20 percent of patients had grade 2, 48 percent had grade 3, and 6 percent had grade 4. For the letrozole-alone arms the rates of neutropenia by grade were four percent, one percent, and none, respectively.
But Finn said this was not the neutropenia seen with chemotherapy.
“This neutropenia is self-limited, patients recover easily, and most importantly, we do not see neutropenic fever.”
He said neutropenia is an on-target, anti-proliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow.
Leukopenia, fatigue, and anemia were also more common in the combination arm of the study.
Treatment was discontinued by 50 percent (42/84) of the palbociclib-letrozole patients and 70 percent (57/81) of the letrozole-alone patients, due to progressive disease.
Palbociclib received Breakthrough Therapy designation from the Food and Drug Administration in April 2013 based on interim data from this trial (OT 5/10/13 issue).
Before the meeting, market analysts had speculated about whether palbociclib would be a blockbuster drug for Pfizer. That remains to be seen, and will depend on how overall survival rates develop, how soon the drug is submitted for FDA approval, and whether it is approved.
Flinn commented in an interview after his presentation here that “for patients, it is looking like it is going to be a blockbuster. To double progression-free survival in this setting is unprecedented —there has never been an agent added to endocrine therapy that has had this degree of impact.”
Palbociclib is being tested in randomized, double-blind Phase III trials, in combination with letrozole (PALOMA-2) and fulvestrant (PALOMA-3) for patients with late-stage, metastatic breast cancers, and in combination with standard endocrine therapy (PENELOPE-B) for early-stage HER2-positive and HER2-negative breast cancers.
Baselga: ‘Results Positive, But Wait for Phase III Data’
The Discussant for the study, José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center, said that although overall survival data were not mature, “these results are strikingly positive, and with a large potential impact to patients with ER-positive breast cancer.”
Baselga did note that palbociclib still lacks a predictive biomarker that correlates with efficacy other than ER status. “Further work needs to be done here,” he said, suggesting that looking for the presence of nuclear D1 would be a good place to start.
He also pointed out that in this open-label trial the primary endpoint—progression-free survival—was assessed by the investigators, which allows a potential for bias.
“But the elephant in the room is some negative results we have had with randomized Phase II studies,” Baselga said. “Many of you will remember the so-called PARP-inhibitor iniparib that showed very positive progression-free survival, and even an improvement in survival, and yet [publication of Phase II results] was followed by a totally negative Phase III study.”
Baselga also noted that the progression-free median survival of 10.2 months in the letrozole-alone control arm in PALOMA-1 was less than that seen in other recent aromatase inhibitors trials—specifically, the FIRST trial, with 13.1 months; and the SWOG S0226 trial, with 13.5 months.
He said he thought that the double-blind randomized Phase III PALOMA-2 study, now accruing patients, will eliminate some of these questions.
“It has been a long journey from the discovery of cyclin D and CDK-4 and -6 to today's clinical results,” Baselga concluded. “The palbociclib results presented today are very positive, and if confirmed by the ongoing Phase III study, palbociclib in combination with hormonal therapy would be a new standard of care in the therapy of patients with advanced ER-positive disease.”