Originally published April 8.
Palbociclib, Pfizer's drug for estrogen receptor-positive, HER2-negative locally advanced breast cancer, nearly doubled the time patients lived without tumor progression when administered in combination with the anti-estrogen drug letrozole, compared to letrozole alone, according to the results of the Phase II study PALOMA-1.
However, since the combination regimen wasn't statistically significant for improving overall survival in patients compared to the standard arm, the latest data — presented this week at the American Association of Cancer Research annual meeting in San Diego — raised questions from industry observers about how the findings would impact palbociclib's regulatory path.
Garry Nicholson, president of Pfizer Oncology, told investors and Wall Street analysts during a call following the AACR presentation that the firm is in discussions with the US Food and Drug Administration regarding palbociclib, which garnered breakthrough designation from the agency a year ago.
"We're not able to confirm today the exact regulatory strategy," Nicholson said. "We do expect a path to filing based on PALOMA-1 data that was presented [at AACR] … but at a future point the FDA will have seen what they need to see in the way of information and we will clarify the next steps."
The randomized, Phase II PALOMA-1 trial was designed to assess whether palbociclib plus letrozole compared to just letrozole significantly improved progression-free survival in ER-positive, HER2-negative patients with locally advanced or metastatic breast cancer. At AACR, Richard Finn, associate professor of medicine at the University of California, Los Angeles and one of the study investigators, reported that patients in the palbociclib/letrozole combination arm had a median progression-free survival of 20.2 months compared to 10.2 months for those receiving just letrozole.
"The hazard ratio for progression was 0.488, representing a more than 50 percent reduction in risk of progression for the combination arm," Mace Rothenberg, chief medical officer of Pfizer Oncology, told analysts during the call. "This is statistically significant and an important median progression-free survival result in the context of current therapies. What I mean by that is this is the longest median progression-free survival ever reported in a randomized trial in first-line, ER-positive breast cancer."
PALOMA-1 was split into two parts, wherein the first part included 66 patients with ER-positive, HER2-negative advanced breast cancer and the second part examining 99 patients with ER-positive, HER2-negative disease and specific biomarkers, including cyclin D1 amplification, p16 loss, or both. The difference in PFS between the two treatment arms was statistically significant in both parts.
Although preclinical data had suggested that ER-positive patients with cyclin D1 amplification and p16 loss might be best responders, this didn't bear out in PALOMA-1, the researchers reported. In part one, PFS was 26.7 months versus 5.7 months for the palbociclib/letrozole-versus-letrozole-only arm, respectively, and in part two PFS was 18.1 months versus 11 months, respectively. Even though the PFS for those receiving standard letrozole therapy doubled when patients were selected according to biomarkers, the investigators don't believe these markers are predictive for palbociclib benefit. Given that Pfizer is developing palbociclib in a molecularly defined subset – ER-positive, HER2-negative patients – the drug developer isn't planning to further home in on a stratified patient population for palbociclib based on these results.
"We are not selecting patients [by biomarkers] because we didn't find that any of the biomarkers used in part two improved our ability to detect women who will benefit from palbociclib any better than women with ER-positive breast cancer," Rothenberg said. "So, that's what we're using for our selection criteria for PALOMA-2 and PALOMA-3."
Another secondary endpoint in PALOMA-1 was objective response rate, which was also increased in the palbociclib-containing arm, 43 percent compared to 33 percent in the letrozole-only arm. The clinical benefit rate, including those who had stable disease for 24 weeks or more, was 81 percent for the combination treatment versus 58 percent for letrozole alone.
However, in the trial, median overall survival in the palbociclib/letrozole arm was 37.5 months compared to 33.3 months for letrozole-only treated patients, not a statistically significant improvement. "[The data] highlights the potential for palbociclib to be a new standard of care for ER-positive breast cancer patients," Nicholson said during the call, adding that Pfizer was pleased with the magnitude of PFS benefit seen with the palbociclib regimen and the "consistency" of the overall survival benefit. "The adverse event profile is entirely consistent with what we've seen previously," he added.
Rothenberg emphasized during the call that the primary endpoint of PALOMA-1 was progression-free survival, not overall survival.
"This overall survival analysis was triggered not by the number of events but the timing of the final analysis for the primary endpoint [of] progression-free survival," he noted, suggesting that showing a significant improvement in PFS has been sufficient for regulatory approval of aromatase inhibitors and other drugs for ER-positive, HER2-negative advanced breast cancer. At the time of the final PFS analysis in PALOMA-1, 37 percent of the study participants had passed away.
"We are encouraged by this [overall survival] trend at this early point in time," Rothenberg said. Researchers are planning to conduct a follow-up analysis of the secondary overall survival endpoint after additional events occur in the study.
Women diagnosed with advanced or metastatic, ER-positive breast cancer generally have long survival rates of three years or more. "We'll have to wait quite a long time … before we know more about this," he added. "We also recognize that regulators have looked for consistency in measures of efficacy and when you line all these up between the primary endpoint of progression-free survival, the objective response rate, the clinical benefit response rate, and overall survival, they're all consistent and heading in the right direction for the combination."
At AACR, following presentation of the study results, discussants raised concerns about whether the open-label design of PALOMA-1 may have introduced bias in favor of or against keeping patients on a particular arm in the study. But Rothenberg dismissed these concerns during the call with investors, noting that "when you look at the magnitude of the difference in progression-free survival of 10 months between the investigational arm and the standard arm, any bias that may have led to one arm being prematurely terminated in a particular patient or the other arm being continued is really trivial."
In PALOMA-1, the palbociclib/letrozole combination was well tolerated and the safety information tracked with previously reported findings. The most common adverse reactions with the combination, according to researchers, were decreases in total neuotrophil count (neutropenia) and total white blood cell count, as well as fatigue and anemia. The cases of neutropenia were manageable, the researchers said, and Rothenberg highlighted during the call that the neutropenia experienced by PALOMA-1 participants didn't progress to infection or fever. Palbociclib is an inhibitor of kinases CD4 and CD6 and the neutropenia experienced by patients treated with the drug is due to the drug's blockage of CD4 and its impact on the bone marrow.
"When you take the neutropenia and even the thrombocytopenia out of the picture, there's no grade 3 or 4 adverse event that occurs with a greater than 4 percent incidence," Rothenberg noted. "So, the side effects are very well understood, very specific primarily to the bone marrow."
Researchers from Pfizer conducted PALOMA-1 at more than 100 participating sites globally in partnership with the Jonsson Cancer Center’s Revlon/UCLA Women’s Cancer Research Program. The study was led by Dennis Slamon, chief of the division of hematology and oncology at UCLA.
Pfizer is evaluating palbociclib in four Phase III advanced breast cancer trials: PALOMA-2, PALOMA-3, PEARL, and PENELOPE-B. Like PALOMA-1, the randomized, double-blind, Phase III PALOMA-2 study compares palbociclib/letrozole against just letrozole as a first-line option for ER-positive, HER2-negative metastatic breast cancer patients. In PALOMA-3, Pfizer is investigating palbociclib in combination with the estrogen receptor downregulator fulvestrant versus just fulvestrant in women with hormone receptor-positive, HER2-negative advanced breast cancer who have progressed despite endocrine therapy.
Pfizer is then studying palbociclib in combination with exemestane versus capecitabine in post-menopausal women with ER-positive, HER2-negative metastatic breast cancer patients who are refractory to the non-steroidal aromatase inhibitors letrozole or anastrozole. The drug developer is conducting this study, called PEARL, with support from GEICAM (Grupo Español de Investigación del Cáncer de Mama) and in collaboration with the Central European Cooperative Oncology Group. Finally, the randomized, double-blind PENELOPE-B study, sponsored by the German Breast Group, will compare palbociclib plus standard endocrine therapy against just endocrine therapy in around 800 women with hormone receptor-positive, HER2-negative early-stage breast cancer, whose disease features suggest they might be at increased risk for recurrence after chemotherapy and surgery.
Rothenberg also highlighted that Pfizer is evaluating whether palbociclib in combination with GlaxoSmithKline's Mekinist (trametinib) will benefit melanoma patients with BRAF and NRAS mutations. Pfizer is working with the Dana Farber Cancer Institute to investigate palbociclib in KRAS mutant non-small cell lung cancer and squamous cell lung cancer, and with the Friends of Cancer Research to look at the drug in squamous cell lung cancer patients with certain tumor-specific genetic features.
Separate from the development program for palbociclib, Nicholson noted during the same call that an investigational ROS1/ALK inhibitor calledPF03446962 has yielded promising preclinical results and will be advanced in clinical development.