Research efforts to develop novel treatment options for breast cancer took another step forward recently with the announcement of new Phase II clinical trials for Pfizer’s novel Cyclin Dependent Kinase 4/6 (CDK4/6) inhibitor, Palbociclib, which was announced at this year’s American Association for Cancer Research conference.
The results for the clinical trial PALOMA-1 were reported by Dr. Richard S. Finn, MD, of the University of California Los Angeles. The trial involved treatment of 165 postmenopausal women with Estrogen Receptor (ER) positive, HER-2 negative breast cancer. A subset of the same trial population, which included 99 women, had elevated levels of Cyclin D1 (CCND1), Retinoblastoma (Rb) protein, and lower levels of P16. Both were given doses of Palbociclib in combination with Letrozole (an aromatase inhibitor which blocks the action of estrogen on the ERs). This combination helped in increasing the Progression Free Survival rate (PFS – the time span during the course of treatment during which the condition does not worsen) to 20.2 months as compared to 10.2 months with Letrozole mono therapy.
CDK4/6 are important regulators for the cell cycle, helping them to progress from the G1 phase to the S phase and doubling their DNA content. Activation of CDK4/6 during cancer leads to uncontrolled growth and division of cells. This also results in elevated levels of CCND1 and Rb and lower levels of P16, all of which contribute to tumor development. Palbociclib, a novel CDK4/6 inhibitor, inhibits the activity of CDK4/6, helping in restoring the normal cell cycle. Letrozole, on the other hand, being an ER antagonist, blocks the attachment of estrogen to the ERs. Because estrogen is necessary for development of breast cancers, combination therapy with both Palbociclib and Letrozole act synergistically in killing the tumor cells and increasing the PFS.
Previously, individual studies involving treatment of the same kind of breast cancer with Letrozole have been led by Dr. Amita Patnaik, MD, of South Texas Accelerated Research Therapeutics in San Antonio, which revealed the drug’s safety profile in patients. However, the overall survival (OS) of these patients when treated individually with Palbociclib did not increase as significantly as expected, in comparison to that of Letrozole. However, the specialists working on this research project were not too concerned with the results, as the net result (hindering progression of breast cancer) was decidedly positive, and it served the endpoint of the trial. According to Elizabeth Mittendorf, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, “It is also worth considering that some patients with ER-positive metastatic breast cancer can live for many years on therapy so, consistent with the comment about the trial not powered to detect overall survival benefit, [there was] likely too few patients, too short of follow-up.”
Commenting on the progress and results of this trial, its chief author, Dr. Finn, said in an interview to Medscape, “The beneficial effect of Palbociclib’s effect is consistently observed in secondary measures of efficacy, including objective response rate and clinical benefit rate, and in all clinical subgroups. The safety profile is acceptable and manageable with uncomplicated neutropenia as the most frequently reported adverse event. The results confirm the preclinical observations made with Palbociclib in breast cancer models.”
Adding to Dr. Finn’s comments, José Baselga, MD, PhD, physician-in-chief at the Memorial Sloan-Kettering Cancer Center in New York City, said, “The results were striking and showed a very impressive improvement in progression-free survival. It has been a long journey from the discovery of CDK 4 and 6. The data presented are very positive, and it could represent a new standard of care in the treatment of metastatic breast cancer.”
Phase III studies involving combinations of Palbociclib with either Letrozole or Fulvestrant, both ER antagonists, have already begun.
Discussing about future prospects of this promising breast cancer regimen, Larry Norton, MD, of the Memorial Sloan-Kettering Cancer Center in New York City, said “My hypothesis is that the next big step in therapy will be the combination of anti-metastatic agents with anti-mitotics, which was not tested here.”
However, there have been cases where, despite encouraging results in phase II clinical trials, phase III trials have failed to live up to researchers’ expectations. As pointed out by Dr. Aditya Bardia, MBBS, MPH, a breast cancer specialist from the Massachusetts General Hospital Cancer Center in Boston, “We have to be cautiously optimistic. The first issue is that it was open-label. We need the complementary phase 3 results so we can be confidant about these results. Right now, we have phase 2 results that are promising.” Hence it will be a matter of time until this new regimen is actually prescribed to patients.