The verdict is in: Pfizer’s Ibrance didn’t improve the life span of patients with newly diagnosed HR-positive, HER2-negative breast cancer in a first-of-its-kind clinical trial.
After a median follow-up of seven and a half years, Ibrance, used alongside Novartis’ hormone therapy Femara, failed to extend the lives of those breast cancer patients compared with Femara alone, according to data presented at the 2022 American Society of Clinical Oncology annual meeting.
In the final overall survival analysis of the phase 3 PALOMA-2 trial, patients on the Ibrance-Femara combo lived a median 53.9 months, versus 51.2 months for those in the solo Femara group. The trial was statistically designed to detect a 26% reduction in the risk of death, but Ibrance only showed a 4.4% advantage.
The latest setback leaves Ibrance the only CDK4/6 inhibitor without an overall survival win from a phase 3 clinical trial. In an interview with Fierce Pharma before the data readout, Debu Tripathy, M.D., chair of breast medical oncology at the University of Texas MD Anderson Cancer Center, said if PALOMA-2’s overall survival data turned out negative, more doctors will start leaving Ibrance, and the drug could lose its market share “little by little,” even though it’ll likely still remain the class leader.
The PALOMA-2 investigators pointed out that after all these years, many patients weren’t available for the final overall survival analysis, including 13% originally enrolled to receive Ibrance and 21% in the control group.
Excluding those dropouts, Ibrance showed a slightly better number, slashing the risk of death by 13.1%. In patients who enjoyed longer than a year of disease-free status, Ibrance cut the risk of death by 27.2%.
“Interpretation of [overall survival] in PALOMA-2 is limited by the large and disproportionate censoring of patients with missing survival data between treatment arms,” Chris Boshoff, M.D., Ph.D., Pfizer’s oncology chief development officer, said in a statement. “We remain confident in the compelling benefits that Ibrance plus endocrine therapy offers to this patient population, which is underscored by data from PALOMA-2 showing delayed time to chemotherapy, maintenance of quality of life and a consistent safety profile.”
For a trial in first-line treatment, it’s naturally difficult to parse out Ibrance’s work from subsequent treatment; in PALOMA-2, of those who stopped their on-trial treatment, 81% in the Ibrance arm received later lines of systemic therapy, and so did 88% in the control arm.
But this isn’t the first time Ibrance has disappointed on the overall survival marker. Previously, Ibrance and AstraZeneca’s hormone therapy Faslodex narrowly missed the life extension goal in the phase 3 PALOMA-3 trial. In both cases, Ibrance met the primary goal of stalling tumor progression or death.
Ibrance also failed in two phase 3 trials, dubbed PALLAS and PENELOPE-B, which tested it as a postsurgery adjuvant therapy in slightly different patient populations with early-stage HR+/HER2- breast cancer.
Ibrance’s lack of an overall survival showing comes in contrast to its two rivals, Novartis’ Kisqali and Eli Lilly’s Verzenio. Kisqali, used in different combos, boasts survival improvements from the MONALEESA-2, -3 and -7 trials in various patient populations.
Verzenio showed its combination with Faslodex could reduce death risks in pretreated patients in the MONARCH 2 trial. Unlike Ibrance, the Lilly drug recently moved up to become a postsurgery adjuvant treatment to prevent cancer from returning in certain patients with high-risk HR+/HER2- early breast cancer.
Without an overall survival success from a clinical trial, Pfizer has been leaning on real-world analysis to demonstrate Ibrance’s benefit. For example, an observational study showed that adding Ibrance to Femara as a first-line treatment—same as the current PALOMA-2 setting—could cut the risk of death by 34%. Another retrospective study of nearly 2,900 patients found that adding Ibrance to an aromatase inhibitor could cut the risk of death by 24% in patients with newly diagnosed metastatic HR+/HER- breast cancer.
But MD Anderson’s Tripathy noted that real-world data aren’t as statistically rigorous as a clinical trial because some differences in patient population are “very hard to scrub” from a real-world analysis. For example, doctors generally tend to put patients with better health status on a CDK4/6 inhibitor like Ibrance, he said.
“If the clinical trial did not show a survival benefit, people are not as confident that the real-world data reflects the truth,” Tripathy said.
Nevertheless, Tripathy argued that the outcome of PALOMA-2 is “more important psychologically than it is clinically.” After all, the trial did hit its primary goal of progression-free survival a long time ago. He also pointed out that running cross-trial comparisons comes with problems, because the patient populations could be different. Ibrance also appears to have the best toxicity profile among the CDK4/6 inhibitors, he added.
Ibrance has started to see some sales declines lately. In the first quarter, its sales dropped 5% in the U.S., which Pfizer attributed to more patients getting the drug through a patient assistance program. But IQVIA data have shown that Ibrance’s new-to-brand share is declining even though it has maintained a remarkable lead in total scripts. By comparison, both Kisqali and Verzenio are expanding their script numbers on both fronts.