Palbociclib Combined with Letrozole Doubles PFS in Advanced Breast Cancer

By Will Boggs MD

NEW YORK (Reuters Health) - Palbociclib combined with letrozole nearly doubles progression-free survival (PFS), compared with letrozole alone, in women with advanced estrogen-receptor (ER)-positive, HER2-negative breast cancer, according to results from a phase 3 study.

"The efficacy and safety profile of the combination of palbociclib and letrozole make a compelling case for the combination in this indication," Dr. Richard S. Finn from David Geffen School of Medicine at the University of California, Los Angeles in Santa Monica told Reuters Health by email. "I believe that the overwhelming majority of women with ER+ breast cancer, who would otherwise get an aromatase inhibitor alone, will be getting this combination given the significant improvement in PFS with a very manageable safety profile."

"The development of palbociclib, the first CDK 4/6 inhibitor to be FDA approved, grew out of pre-clinical observations made at UCLA in collaboration with Pfizer," he explained.

Dr. Finn and colleagues in the Pfizer-funded PALOMA-2 trial assessed the safety and efficacy of palbociclib plus letrozole as first-line therapy in 666 postmenopausal women with ER-positive, HER2-negative advanced breast cancer.

By the final analysis cutoff date, 43.7% of women in the palbociclib-letrozole group had experienced disease progression or death, compared with 61.7% of women in the placebo-letrozole group, according to the November 17th report in The New England Journal of Medicine.

Median progression-free survival, the primary endpoint, was 24.8 months in the palbociclib-letrozole group versus 14.5 months in the placebo-letrozole group (p<0.001).

Final overall survival analysis will occur after there have been 390 deaths (per protocol).

Neutropenia, leukopenia, anemia, and thrombocytopenia were much more common with palbociclib-letrozole than with placebo-letrozole.

"The important thing to remember is that the neutropenia with palbociclib is different from that seen with cytotoxic chemotherapy," Dr. Finn explained. "It is not commonly associated with serious complications. Unlike the neutropenia seen with chemotherapy, the neutropenia with palbociclib is not associated with a very long recovery time and is not associated with deep nadirs. The mechanism is different in that it does not appear to irreversibly damage bone marrow precursors like chemotherapy."

Dr. Antonio C. Wolff from Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, who wrote an editorial related to this report, told Reuters Health by email, "The addition of a CDK4/6 inhibitor to endocrine therapy is a new standard in advanced ER+ breast cancer. The observed improvement in PFS was clinically and statistically significant, though no data yet on improvement in overall survival."

"This is important in that clinical benefit (response or stable disease for at least 6 months) is achieved in 70% of the patients on the control arm (letrozole alone) in each of the two studies, with the addition of ribociclib or palbociclib adding just another 10-15% of patients," he explained. "Hence, what is notable is that patients can derive clinical benefit with letrozole alone, and that is good news."

"No question that this extra 10-15% will be important for many patients and that the prolongation of median PFS (the primary endpoint) is even more important," Dr. Wolff said. "However, many patients with advanced breast cancer present with small volume disease, are asymptomatic, and may have durable/prolonged benefit (stability or response) with just endocrine therapy without a CDK4/CDK6 inhibitor."

"The challenge, of course, is to be able to identify who those patients are," he said. "But if we do, we can spare them early on the potential costs and modest (but real) toxicities of a CDK4/CDK6 inhibitor, and reserve it for subsequent use."

Dr. Katalin Boer from St. Margaret Hospital, Budapest, Hungary, who has researched the impact of palbociclib combinations on PFS in women with advanced ER-positive, HER2-negative breast cancer, told Reuters Health by email, "Based on the PALOMA-2 data, it is confirmed that, for patients eligible to receive first-line endocrine treatment for hormone receptor-positive metastatic breast cancer, patients should receive endocrine therapy in combination with palbociclib, as those given the drug combination remained progression-free for more than two years."

"The addition of palbociclib to letrozole does increase the rate of toxicity, but overall, considering the magnitude of clinical benefit, there is definitely a benefit to be gained with this type of therapy," she said. "In addition to ER positivity, identification of other predictive markers would be useful to select those patients who are likely to benefit the most from the addition of palbociclib to endocrine therapy."

"In my opinion we should consider this combination as the standard of care for our patients," Dr. Boer concluded. "Based on the results, I can see no reason to justify the use of endocrine therapy without palbociclib in postmenopausal women with advanced breast cancer."

SOURCE: https://bit.ly/2fj84aP and https://bit.ly/2fz50bj

N Engl J Med 2016.

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