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Oncologists Debate Suitability of CDK4/6 Inhibitors at ASCO Given Long-Term Ibrance Data


NEW YORK – Researchers at the American Society of Clinical Oncology annual meeting debated how to choose a CDK4/6 inhibitor for front-line treatment of estrogen receptor (ER)-positive, HER2-negative advanced breast cancer amid data showing Pfizer's Ibrance (palbociclib), when given with an aromatase inhibitor, did not significantly improve long-term overall survival compared to hormone therapy alone.

Researchers presented final overall survival data after more than seven years of follow-up from the Phase III PALOMA-2 trial. The trial evaluated Ibrance and the aromatase inhibitor letrozole versus placebo and letrozole. The study enrolled 666 patients, 444 of which were randomized to the Ibrance arm. After a median of 90 months follow-up, 43 patients remained on Ibrance and letrozole and five patients remained on just letrozole treatment.

In the Ibrance arm, the median overall survival was 53.9 months versus 51.2 months in the placebo arm, a difference that was not statistically significant, according to Richard Finn, a professor of medicine at David Geffen School of Medicine at the University of California, Los Angeles, who presented the data at the ASCO meeting on Saturday.

"These results were not statistically significant, however, the median overall survival of more than 50 months in this population represents a significant improvement in the natural history of hormone receptor-positive breast cancer," Finn said.

He noted that there were limitations to the long-term data in this study due to missing data. About one-third of patients did not have survival data, 13 percent in the treatment arm and 21 percent in the placebo arm. He said these patients withdrew consent or were lost to follow-up.

In earlier results, PALOMA-2 met its primary endpoint of progression-free survival. Patients in the Ibrance arm saw median progression-free survival of 24.8 months, compared to 14.5 months in the placebo arm. Based on this data, in 2017 the agency granted full approval to the drug in this setting.

In a discussion of the PALOMA-2 data, Claudine Isaacs, codirector of the breast cancer program at the Lombardi Comprehensive Cancer Center at Georgetown University, noted that the study was "underpowered" to analyze overall survival. She also said the data suggests there are differences in the efficacy of approved CDK4/6 inhibitors in this setting. In the US, Novartis' Kisqali (ribociclib) and Eli Lilly's Verzenio (abemaciclib) are also approved as a first-line treatment in combination with an aromatase inhibitor for ER-positive, HER2-negative advanced breast cancer.

"It's certainly possible that this reflects the difference between the three approved CDK4/6 inhibitors," Isaacs said. "Unfortunately, there [is a] lack of prospective trials directly comparing the CDK4/6 inhibitors."

However, Isaacs noted there is one ongoing study, the Phase III HARMONIA trial, comparing Ibrance to Kisqali in HER2-enriched breast cancer patients, where there is an exploratory cohort of HR-positive, HER2-negative breast cancer patients. Researchers have not yet reported results from this exploratory cohort.

Finn and colleagues also looked at quality of life metrics in the PALOMA-2 trial to determine benefit from the Ibrance combination. The time to chemotherapy after treatment was longer for patients in the Ibrance arm, 38.1 months, compared to 29.8 months in the placebo arm.

"There was a significant improvement in the delay to the time to chemotherapy and the associated toxicities," Finn said.

The PALOMA-2 researchers also conducted an unplanned analysis in a subgroup of patients who had long responses to treatment. In this group of patients, who had a disease-free interval of greater than 12 months, there was a statistically significant overall survival benefit for patients in the Ibrance arm. Among these patients, median overall survival on the Ibrance combination was 66.3 months, compared to 47.4 months in the placebo-letrozole arm.

Isaacs noted the unplanned analysis of patients with disease-free intervals of longer than 12 months had limitations, specifically that this subgroup represented 35 percent of the patients in the trial and that patients without survival data should not have been excluded from the analysis.

Isaacs also compared the PALOMA-2 results to recently reported long-term overall survival data from the Phase III MONALEESA-2 study of Kisqali plus letrozole in the same patient population. At 6.6 years of follow-up, the Kisqali combination showed an improvement in median overall survival compared to placebo-letrozole, 63.9 months and 51.4 months, respectively.

She also said upcoming data on overall survival from the Phase III MONARCH-3 trial, investigating Verzenio plus an aromatase inhibitor in HR-positive, HER2-negative breast cancer, will also help "flesh out" the differences in long-term survival between the approved CDK4/6 inhibitors.

In a panel discussion of the PALOMA-2 data, Dejan Juric of Massachusetts General Hospital Cancer Center, who was not part of the trial, noted that this survival data should be considered when choosing a CDK4/6 inhibitor in practice.

"When we sit in front of a patient, we have to choose one," said Juric, director of the Termeer Center for Targeted Therapies at MGH. "Abemaciclib, ribociclib, and palbociclib have different structures, they have different side effects, and they do seem to have different clinical outcomes in the trials. We should start thinking whether we should really be referring to these agents as being part of the same class. These are three distinct drugs."

Isaacs urged colleagues to conduct more biomarker analysis to better understand which patients benefit from CDK4/6 inhibitor treatment in practice. These biomarkers could also help identify patients who are sensitive to endocrine therapy, specifically those who may benefit from single-agent endocrine therapy versus a combination of CDK4/6 inhibition and endocrine therapy that would have higher toxicity.

"It is clear that we need well-validated and ideally more comprehensive assays to identify which patients benefit, and conversely those who will not benefit from a particular targeted therapy," Isaacs said.

"Accomplishing this is a tall order. It is often challenging to identify biospecimens to validate the clinical utility," she continued. "Perhaps one way to address this is to develop real-world studies that collect longitudinal, clinically well-annotated biospecimens and importantly also reflect the diversity of the patients that we care for."