PALLAS Trial: Palbociclib (Ibrance) - Stage II & III, ER+, HER2-

New info on Palbociclib (Brand name: Ibrance), a CDK4 and CDK6 inhibitor for ER+, HER2-.

Public Release: 8-Dec-2015

One-two punch of palbociclib and paclitaxel shows promise against advanced breast cancer

Philadelphia, Pennsylvania, USA - Combining the new breast cancer drug palbociclib with paclitaxel (Taxol) shrank tumors in nearly half of ER+ patients, according to new research from the Perelman School of Medicine at the University of Pennsylvania.

The results will be presented Saturday at the 2015 San Antonio Breast Cancer Symposium (Abstract P6-13-08).
A second study (Abstract P4-13-04), to be presented Friday provides new clues to how breast cancer develops resistance to the palbociclib, a common occurrence among many patients who take the drug.

"Results of the first study found that palbociclib and paclitaxel can be safely combined on an alternating dosing schedule," said Angela DeMichele, senior author on the study. "The high response rate we saw suggests this combination may hold benefits for patients over paclitaxel alone. Based on these results, a larger clinical trial to determine the benefits is warranted."

A Complementary Therapy

Palbociclib targets the rapid division of tumor cells by inhibiting the activity of the enzymes CDK4 and CDK6, which help drive cell division and are upregulated in most cancers. The researchers suspected that palbociclib's unique mechanism of action may make it a good partner for other breast cancer drugs such as paclitaxel, which kills dividing cells at a certain point in the cell division process (also known as the "cell cycle"). Palbociclib effectively halts the cell cycle before that point, and thus in principle can synchronize cancer cells in a way that makes them more vulnerable to a closely following dose of paclitaxel.

To begin to test this concept in the clinic, DeMichele and colleagues, including lead author Amy S. Clark, MD, treated 27 breast cancer patients with alternating doses of palbociclib - administered daily for several days at a time - and paclitaxel administered once per week. The researchers ultimately settled on an optimal palbociclib dose of 75 mg per day, combined with a standard dose of paclitaxel.

The chief aim of the study was to determine if this alternating dosing of the two drugs is safe enough to use in larger-scale trials. The results suggest this appeared to be the case. Though most participants developed the low-white-blood-cell count condition known as neutropenia, a common side-effect of palbociclib and other chemo drugs, DeMichele says in general it was not dangerous. Some participants had their palbociclib doses lowered as a result of the condition.

Although the trial wasn't designed to test whether the combination is more effective against breast tumors than paclitaxel, the patients' responses were promising. Nearly half showed long term shrinkage or disappearance of detectable tumors. "The partial or complete response rate among the entire population was 12 out of 27, or 44 percent, and four additional patients achieved stable disease for six months or longer," Clark said.

"That seemed better than what we would have expected from paclitaxel alone, but the only way to know the difference for certain is with a randomized clinical trial of the combination versus the single drug," DeMichele said.

The team now hopes to set up such a trial. They also plan a similar trial using a newly developed CDK4/6 inhibitor, Novartis's ribociclib.

Clues to Resistance

In a related study, DeMichele and her colleagues, collaborating with a team at palbociclib's maker Pfizer, looked for molecular clues to how breast cancer develops resistance to the drug. By examining samples taken from a patient through the course of her treatment with palbociclib, the team found that as the tumors became resistant, the cells more than doubled their expression of several cell-cycle-driving genes, including PLK1, TOP2A, CDK1, and BUB1. Lab dish studies of tumor cells that develop resistance to palbociclib revealed similar changes.

The study focused on a Penn Medicine patient who was first diagnosed with breast cancer in 1999. After more than a decade of standard therapies, the patient's cancer was found to have progressed in 2010. As part of an earlier clinical trial, she began treatment with palbociclib. The drug caused the woman's tumor to shrink, and her cancer remained progression-free for nearly three years, until a metastatic skin lesion was detected in 2013.

Notably, the resistant cancer cells did not appear to have lost the activity of the tumor suppressor RB1--a potential mechanism of resistance since the CDK4 and CDK6 enzymes drive cell division in part by suppressing RB1. The analysis also ruled out several other suspected mechanisms including alterations to CDK4/6 genes and estrogen receptor genes.

"It appears that while the drug blocks two important cell-cycle drivers, CDK4 and CDK6, other cell cycle genes can compensate with increased expression levels to enable tumor cells to start dividing again," DeMichele said. "That suggests that we might be able to prevent this resistance by adding a drug that blocks these other cell-cycle drivers."

@ALH49. Sorry for the slow response. No, she's not participating in the PALLAS clinical trial.

Here's some news about the trial and CDK 4/6 inhibitors from San Antonio Breast Cancer Symposium (SABCS)
Dec 8, 2016.

Next Big Thing in ER+ Breast Cancer: For Early-Stage Too?
SAN ANTONIO, TEXAS - Two agents that inhibit cyclin-dependent kinases 4 and 6 (CDK4/6) have yielded unprecedented results in progression-free survival in clinical trials involving postmenopausal women with ER+, HER2- metastatic breast cancer.
One drug, palbociclib (Ibrance, Pfizer), is approved by the US Food and Drug Administration in this metastatic setting, and the other agent, ribociclib (Novartis), is under priority review by regulators for use in the same setting.
Now, new data on the third agent in this class, the still experimental abemaciclib (Eli Lilly), show that the strategy of inhibiting CDK4/6 has effectiveness in even more patients – those with early-stage disease.
In the first randomized neoadjuvant trial of a CDK4/6 inhibitor in early-stage patients, twice-daily abemaciclib, either alone or in combination with anastrozole (Arimidex, AstraZeneca), significantly reduced Ki67 expression after 2 weeks of presurgery treatment in comparison with anastrozole alone. Thus, the three-arm, 161-patient study met its primary endpoint.
"Ki67 is a well-validated surrogate endpoint for disease-free survival," said lead study author Sara Hurvitz, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. She spoke at a press conference here at the San Antonio Breast Cancer Symposium (SABCS) 2016.
These new findings are akin to results from two earlier, single-arm neoadjuvant trials with palbociclib and ribociclib that also showed reductions Ki67 levels among patients with early-stage disease. Together, these results raise the question:
Is CDK4/6 inhibition well suited to be a curative therapy for early-stage disease?
Dr Hurwitz wants to find out: "We need to push this into early-stage disease," she told Medscape Medical News concerning adjuvant and neodadjuvant studies.
Echoing other experts, she said the results in metastatic disease are important and represent a new standard.
"It's the biggest thing that's happened in the last decade [in metastatic ER-positive disease]," said Dr Hurvitz, referring to the success of CDK4/6 inhibitors. "It's a very important class of drugs."
Tufia Haddad, MD, a medical oncologist at Mayo Clinic, in Rochester, Minnesota, who is not involved in these clinical trials, is looking forward to more results in early-stage disease.
"We are all very hopeful about this class of drugs in this setting," said Dr Haddad, adding that any improvement in overall survival and progression-free survival will be challenging because results with standard endocrine therapies are already good in these patients with early-stage disease.
The large international PALLAS study addresses this question, said Dr Haddad. Now enrolling patients, the adjuvant trial examines standard endocrine therapy alone or in combination with palbociclib for the treatment of pre- and postmenopausal women with stage II and stage III disease that is HR positive and HER2 negative.
Aditya Bardia, MBBS, MPH, a medical oncologist at the Massachusetts General Cancer Center in Boston, believes that CDK4/6 inhibitors will eventually be used in patients with early-stage disease.
"This is a bit speculative, but I think CDK4/6 inhibition would be effective in the right setting of early-stage disease," said Dr Bardia, who was not involved in this new study.
The right setting for curative use would "probably" be in higher-risk patients in whom endocrine therapy alone is unlikely to be sufficient, he told Medscape Medical News.
However, adverse events are a concern, because the adjuvant setting would involve longer-term use than the metastatic setting, Dr Bardia pointed out.
In the current study of abemaciclib, 55% of patients experienced some grade of diarrhea – and that occurred while the patients were receiving a prophylactic agent, per study design. Also, 37% experienced nausea (all grades). Notably, patients in the study were receiving twice-daily therapy only for up to 4 months. "Now imagine for 5 years, or even 1 year of daily therapy," said Dr Bardia. "This does impact the quality of life," he said.
"These are patients with early breast cancer ― the safety profile is very important," concluded Dr Bardia.
One of the selling points of abemaciclib is that it is associated with much less neutropenia than the other two CDK4 inhibitors, as reported in the literature.
In the current study, grade ≥3 neutropenia was reported in only 8.2% of patients, stated Dr Hurvitz. However, Dr Bardia pointed out that 66% of patients still experienced a decrease in neutrophil count.
At the SABCS press conference, Carlos Arteaga, MD, of the Ingram Cancer Center at Vanderbilt University in Nashville, Tennessee, said that abemaciclib was not just an imitation of the more extensively investigated palbociclib. "This is not like Pepsi-Cola and Coca-Cola," he said.
Dr Hurvitz explained that "this is a fairly unique drug in that it can be given continuously."
She said: "We do not need to take a 1-week or more break every month in order to allow neutrophil recovery," she added, referring to the higher rates of neutropenia seen with the other two agents, with their 3-week-off and 1-week-on regimens.
"During that 1 week off...there is this concern that there will be a rebound in [cancer] cell cycling that may actually promote resistance to this therapy," said Dr Hurvitz. "This is a theoretical benefit of abemaciclib."

- San Antonio Breast Cancer Symposium (SABCS) 2016. Abstract 24-06. Presented December 8, 2016.