Novel CDK4/6 Inhibitor Shows Strong Promise in Breast Cancer

But Experts Urge Caution

Roxanne Nelson

April 07, 2014

SAN DIEGO — A novel drug for breast cancer, palbociclib (Pfizer), has shown a significant clinical benefit in a subgroup of women with advanced breast cancer in a phase 2 trial, known as PALOMA-1, presented during a plenary session here at the American Association for Cancer Research 2014.

These results have been highly anticipated by pharmaceutical analysts, who have hope that this drug will attain blockbuster sales; they even made a splash in the New York Times.

However, an expert at the meeting warned that the results come from a phase 2 trial, and that such results are not always confirmed in larger phase 3 trials.

Impressive Improvement in Progression-free Survival

Palbociclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, inhibits cell proliferation and cellular DNA synthesis by preventing cell-cycle progression from G1 to S phase, which is where CD6 plays a critical role in cell metabolism, explained lead author said Richard S. Finn, MD, associate professor of medicine at the University of California, Los Angeles. Palbociclib is very specific for CDK 4 and 6.

In PALOMA-1, as a first-line treatment in patients with hormone-receptor-positive metastatic breast cancer, progression-free survival, the primary end point of the study, was significantly better with palbociclib plus letrozole than with letrozole alone (20.2 vs 10.2 months; hazard ratio [HR], 0.488; P = .0004).

"These results confirm the preclinical observations made with palbociclib in breast cancer models," explained Dr. Finn.

In addition, a beneficial effect was consistently observed in the secondary measures of overall response rate and clinical benefit ratio, and in all subgroups, he reported.

At this time, the overall survival analysis shows a positive trend in favor of the combination, he said, but the survival data are not yet mature.

Elephant in the Room

"The results were striking and showed a very impressive improvement in progression-free survival," said study discussant José Baselga, MD, PhD, physician-in-chief at the Memorial Sloan-Kettering Cancer Center in New York City.

"It has been a long journey from the discovery of CDK 4 and 6," he explained. The data presented are very positive, and it could represent a new standard of care in the treatment of metastatic breast cancer, he noted.

However, he pointed out the "elephant in the room," which is that promising results from phase 2 studies don't always pan out in further trials.

A recent example of this comes from the phase 2 trial of the PARP inhibitor iniparib (sanofi-aventis), which showed significantly better survival in women with triple-negative breast cancer when it was added to a chemotherapy regimen. A subsequent phase 3 clinical trial did not find a benefit, he reported.

There is also the highly publicized story of bevacizumab (Avastin) in metastatic breast cancer, which was granted accelerated approval by the US Food and Drug Administration on the basis of 1 clinical trial, but then had the approval rescinded after larger phase 3 trials gave mixed and nonsignificant results. Looking back, one breast cancer expert said that when the early data first came out, "there was too much hype over what this drug could do," as reported at the time by Medscape Medical News.

Activity Seen in Early Research

Results of preclinical research identified an association between luminal estrogen-receptor-positive breast cancer cell lines (with elevated expression of cyclin-D1 and Rb and reduced p16 expression) and palbociclib sensitivity. Synergistic activity was also observed when palbociclib was combined with tamoxifen.

A small lead-in phase 1 study showed that palbociclib plus letrozole could be given safely as a combination regimen, and there were signs of possible efficacy, explained Dr. Finn.

Those data led to PALOMA-1, which involved 165 postmenopausal patients with hormone-receptor-positive HER2-negative metastatic breast cancer. Of the 165 patients, 99 had alterations in the cyclin D1 and/or p16 genes. Both of these genes are markers of sensitivity to palbociclib.

Patients were randomly assigned to the combination of daily palbociclib 125 mg for 3 weeks followed by 1 week off plus continuous daily letrozole 2.5 mg, or to daily letrozole. Treatment continued until disease progression, unacceptable toxicity, or withdrawal from the study, and tumors were assessed every 2 months.

With the combination, there was no significant difference in median progression-free survival for the women without gene alterations (26.1 months; HR, 0.299; P < .0001) and those with gene alterations (18.1 months; HR, 0.508; P = .0046).

However, for letrozole alone, median progression-free survival was worse in those without the gene alterations (5.7 vs 11.1 months).

Dr. Finn said that he is very encouraged by the data so far. "Median overall survival increased from 33.3 months with letrozole alone to 37.5 month with letrozole and palbociclib," he reported.

Overall response rate, a secondary end point, was also better with the combination than with letrozole alone (43 vs 33 patients). In each study group, 1 patient experienced a complete response.

In patients with measurable disease, the clinical benefit ratio was better with the combination than with monotherapy (55% vs 39%). One patient in the combination group had a complete response using this parameter, but no patients in the monotherapy group did.

Dr. Finn noted that palbociclib appears to be well tolerated and does not add an undue burden of toxicity. The most common adverse events associated with the agent were neutropenia, leukopenia, fatigue, and anemia, and all were manageable.

Cautiously Optimistic

Despite the impressive results, Aditya Bardia, MBBS, MPH, echoed Dr. Baselga's concerns. "We have to be cautiously optimistic," said Dr. Bardia, a breast cancer specialist from the Massachusetts General Hospital Cancer Center in Boston, who was approached by Medscape Medical News for independent comment.

"The first issue is that it was open-label. We need the complementary phase 3 results so we can be confidant about these results," he said. "Right now, we have phase 2 results that are promising."

He explained that overall survival is a "hard end point" and that those data are not yet available. "It is a very definite end point and gives you more data about the drug. The downside is that it will take much longer to get those data, and this is a first-line therapy."

The findings were also enriched for 2 biomarkers, but the numbers were very small. "A phase 3 trial will also be larger and give us better and more details about that," Dr. Bardia explained.

In fact, a randomized phase 3 study (PALOMA-2/TRIO-22) in a similar patient population is ongoing.

The study was funded by Pfizer. Dr. Finn has disclosed no relevant financial relationships.

AACR Annual Meeting American Association for Cancer Research (AACR) 2014: Abstract CT101. Presented April 6, 2014.

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