Triple Negative Breast Cancer: Worse or Just Different?

[gdpawel]

Palbociclib doubled the average amount of progression-free survival (PFS) time among patients with advanced breast cancer. But in the first detailed glimpse of its impact on overall survival (OS) - a key feature to the future prospects of this flagship program - the therapy has failed to demonstrate a statistically significant improvement in extending patients' lives after an initial assessment. Palbociclib is on of the cyclin-dependent kinase inhibitors.

Patients with hormone receptor-positive metastatic breast cancer enjoyed a median PFS rate of 20.2 months when taking a combination of palbociclib and the antiestrogen drug Femara (letrozole), compared to 10.2 months for letrozole alone, according to researchers presenting the latest data at the American Association for Cancer Research (AACR)meeting in San Diego. The OS rate, though, was 37.5 months for the combo versus 33.3 months for the solo therapy. That was an improvement, but not a big enough one to qualify as significant enough to meet the secondary endpoint.

Investigators were quick to note that there haven't been enough patient deaths in the study to firm up the OS numbers, happy at this stage to point to a trend in the drug's favor. But investors were left feeling somewhat deflated over the shortfall on OS, especially after seeing signs of a dramatic improvement in PFS earlier on. At the interim point, patients taking palbociclib saw a delay in disease progression of 26.1 months, compared to only 7.5 months in the control arm.

Financial analysts had expected the PFS rate over the letrozole arm to balance out a bit in the follow-up. And they expect the results are sufficient for a regulatory application soon, which is what investors have been gambling on. Pfizer (the drug's manufacturer), though, hasn't come right out and said whether they're going for an early approval.

Palbociclib is a CDK-4/6 inhibitor. And it's not alone. Last December, Novartis pushed its rival program for LEE011 into Phase III, setting up a showdown over a market that could deliver billions in potential revenue. Both therapies target a pair of cyclin dependent kinases that play a role in cancer. Eli Lilly also has a contender in the pipeline, LY2835219. But the pharma giant is well behind the leaders in this race, and Lilly suffers from a reputation for carefully regimented development programs that often lag well behind those of rivals.

Lilly's investigators reported at AACR that of the 47 patients with metastatic breast cancer in the study, 9, or 19%, had a partial response while 24, 51%, had stable disease. "Disease progressed despite treatment in 11 patients," according to a release from Lilly. "All of the nine patients who had a partial response, and 20 of the 24 patients who had stable disease, had HR-positive disease, which meant that the partial response and stable disease rates for patients with HR-positive disease were 25 percent and 55 percent, respectively."

Schoenebaum takes a positive view on Lilly's come-from-behind position in the race for an approval. "Overall, these data seem to indicate that (Lilly's) drug is clearly active," he wrote. "Whether it's actually MORE active than Pfizer's palbociclib remains an open question as you must be very careful when comparing across different trials with small patient numbers. As a reminder, Lilly has argued that their drug might work better because it can be dosed continuously (vs palbociclib's 3 weeks on; 1 week off regimen) due to less severe neutropenia. Lilly plans on announcing next steps later in the first half of 2014 - we believe it's possible that a phase 3 could begin by year 2014's end or in early 2015. There is very little, if anything, in Lilly consensus estimates for this drug - so in theory, at least, it represents all upside."

The view from Pfizer's investigators remained upbeat, despite the setback on OS rates.

"This is an exciting data set that shows a major clinical benefit for patients who have hormone receptor-positive, metastatic breast cancer," said UCLA Professor Dennis Slamon. "The potential impact of this study could be huge. We are doing further Phase III work with the drug, but the current data are as exciting as the initial studies we were involved in when testing Herceptin for HER2-positive breast cancers."

Source: FierceBiotech

[gdpawel]

In an early trial, an experimental breast cancer drug stopped disease growth and shrank tumors by more than 30 percent in some patients.

The pill, bemaciclib, was safe and well-tolerated by women with breast cancer that had spread, or metastasized, to other parts of the body, according to the results of this phase 1 trial.

"This is a novel oral treatment for patients with metastatic breast cancer," said lead researcher Dr. Amita Patnaik, the associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio.

If these results are replicated in future trials, it's conceivable that the pill might extend survival for women with terminal breast cancer, experts suggested.

The drug was particularly effective for the most common type of breast cancer, called hormone receptor-positive breast cancer. In this type of cancer, cancer cells grow in response to signals from the hormones estrogen and/or progesterone.

The study included more than 130 women. Overall, Patnaik said half of them had cancer growth controlled and 25 percent had shrinkage of their tumors.

Unlike standard cancer drugs, this is a twice-daily pill that allows women to go on with their daily lives. In contrast, other cancer drugs are given intravenously at a hospital or doctor's office. Another difference, Patnaik said, is that bemaciclib is a targeted therapy, a newer type of drug that is better able to identify and attack specific cells.

"Our results show that it can be given safely over a long period of time, and patients are able to go on with their routine activities and have a good quality of life," she said.

Side effects of the drug include diarrhea, nausea and vomiting. For study participants, most of these problems were mild or moderate, Patnaik said.

The trial results were presentated on Sunday at the annual meeting of the American Association for Cancer Research (AACR) in San Diego. The study was funded by Eli Lilly and Co., the maker of bemaciclib.

"It is important to remember that this is a first-time evaluation of the drug and these results will have to be confirmed in later studies," Patnaik cautioned. More trials are being planned, she said.

Dr. Neelima Denduluri, a medical oncologist at Virginia Cancer Specialists in Arlington, pointed out that metastatic breast cancer is generally incurable. "Goals of therapy include maintaining quality of life while administering effective therapy," said Denduluri, who was not involved in the study.

She said she hopes bemaciclib and other new drugs will make a difference in the treatment of advanced breast cancer.

For hormone receptor-positive breast cancer, doctors often use anti-estrogen therapies. However, tumor cells stop responding to these drugs, so alternatives are often needed, Denduluri said.

"Bemaciclib's trial results are very exciting and confirm that developing this class of drugs is very promising for patients with advanced breast cancer," Denduluri added.

For the study, Patnaik's team tested the drug on 132 women with breast cancer. Forty-seven of them with metastatic cancer had tried as many as seven other drugs before bemaciclib.

The women took bemaciclib pills twice daily for 28 days.

Thirty-six of the 47 patients with metastatic breast cancer had hormone receptor-positive disease, the researchers noted. Nine of the 47 patients had a partial response, and 24 of the 47 patients saw the growth of their cancer stopped.

Among the metastatic breast cancer group, 11 patients had their cancer progress despite treatment, the researchers said.

Among women with hormone receptor-positive breast cancer, 81 percent had a complete response, partial response or stable disease, and their cancer didn't progress for an average of nine months, the study found. For study participants overall, progression-free survival was nearly 6 months.

The trial lasted 28 days, but women who benefited from the drug could continue on it in 28 day cycles as long as they continued to benefit. Eighteen of the hormone receptor-positive breast cancer patients are still being treated with bemaciclib, said Patnaik.

Dr. Myra Barginear, an oncologist at North Shore-LIJ Cancer Institute in Lake Success, N.Y., is also excited about the potential of this drug and others like it.

"As a breast cancer doctor, I am thrilled to potentially have a new agent for my patients with advanced hormone receptor-positive breast cancer. This is the most common type of breast cancer -- representing approximately 80 percent of all cases," she said.

Data and conclusions presented at meetings are typically considered preliminary until published in a peer-reviewed medical journal.

Source: HealthDayNews

[gdpawel]

These kinase inhibitors can work across various types of cancer, but often only extend life by around three to six months. However, researchers believe they can unlock the true potential of these drugs by changing the way they are used, after uncovering a hidden way that they work. Those researchers had planned to conduct clinical trials using kinase inhibitors at higher doses, but with rest periods to take advantage of the new mechanism, and believe the new method has the potential to keep cancers at bay for much longer.

Some private laboratory oncologists have found that high-dose kinase inhibitors can be effective for central nervous system (CNS) disease, so long as resistance has not developed. It may have something to do with entry into the cell; efflux out of the cells; inactivation, or whatever. They have often recommend higher dose, pulse/intermittent therapy, in combination with other agents. Palbociclib is being looked at right now, because of its advancement in clinical trials, but I'm sure they will be ready for Bemaciclib when it becomes available.

One of those private laboratory oncologists, Dr. Robert A. Nagourney, will be attending the upcoming American Society of Clinical Oncology trade show in Chicago, where he will present early studies on Cyclin-dependent kinases as therapeutic targets: examination of palbociclib (PD0332991) and flavopiridol in human tumor primary culture microspheroids.

[dawny]

Thank you gdpawel, as always for your informative posts!

Dawn

[gdpawel]

Treatment with palbociclib combined with letrozole resulted in significantly improved progression-free survival (PFS) compared with letrozole alone in patients with hormone receptor-positive metastatic breast cancer, according to a phase 2 trial presented at the American Association of Cancer Research Annual Meeting in San Diego, CA, on April 6, 2014.

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6.

The study design comprised 2 parts. In part 1, researchers recruited 66 postmenopausal patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and, in part 2, they recruited 99 postmenopausal patients with the same diagnosis who had been found to have CCND1 amplification and/or loss of p16, which are markers of sensitivity to palbociclib. Patients continued to receive medication until disease progression, unacceptable toxicity, or withdrawal from the study, and their tumors were assessed every 2 months.1

PFS in patients treated with palbociclib plus letrozole was almost double that of patients treated with letrozole alone: 20.2 versus 10.2 months (P=0.0004). There was a 51% reduction in the risk of disease progression in patients who received palbociclib.1

“This study grew out of a strong initial preclinical observation made a few years ago that hormone receptor-positive breast cancer cells are dependent on CDK-4/CDK-6 for their growth, and that these cancers are sensitive to inhibition of CDK-4/CDK-6,” said lead researcher Richard S. Finn, MD, associate professor of medicine at the University of California in Los Angeles.

The risk for disease progression did not decrease further in patients who were recruited in part 2 of the study, whose tumors had the molecular targets specific for the drug: risk decreased by 70% for those in part 1, compared with 49% for those in part 2. “The challenge with any targeted drug is identifying patients who are dependent on the target,” said Dr. Finn. “Having an intact Rb pathway seems to be the most critical factor for this drug to be effective, because most hormone-positive tumors are dependent on this pathway.”

Overall survival was 37.5 months in patients treated with palbociclib and letrozole and 33.3 months in patients treated with letrozole alone, a difference that was not significant.1

“A small lead-in phase 1 study conducted prior to this phase 2 trial showed that palbociclib and the antiestrogen drug letrozole could be given safely as a combination, with manageable side effects,” said Dr. Finn. The most common adverse events associated with palbociclib treatment were neutropenia, leukopenia, fatigue, and anemia. “It is important that we not only improve the efficacy of the compound, but also that we do not add an undue burden in toxicity, and we are happy that the drug was well tolerated overall.”

Two important reasons for the success of this trial, Dr. Finn explained, were that hormone receptor-positive/HER2-negative patients are more likely than other patients to benefit from palbociclib and that the compound is highly specific in its ability to block CDK-4 and CDK-6, leading to less toxicity.

Palbociclib is being tested in phase 3 trials in combination with letrozole (PALOMA-2) and fulvestrant (PALOMA-3) for late-stage, metastatic breast cancers, and in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.

Reference

Finn RS, Crown JP, Lang I, et al. Final results of a randomized phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18) [Abstract CT101]. Presented at the American Association for Cancer Research, San Diego, CA, April 6, 2014.

Source: Chemotherapy Advisor