Lead PALOMA-2 Author Says Results Will Boost Global Use of Palbociclib

Richard Finn, MD

Results from the phase III PALOMA-2 study—which demonstrated a significant progression-free survival (PFS) advantage with palbociclib (Ibrance) plus letrozole compared with letrozole alone in ER-positive, HER2-negative metastatic breast cancer—were recently published in The New England Journal of Medicine.

The use of palbociclib, the first CDK4/6 inhibitor approved in this setting, will only continue to rise following these published findings, said lead study author Richard Finn, MD, an associate professor of Medicine at the UCLA David Geffen School of Medicine.

“The uptake has been very brisk in the United States, and that is really driven by the compelling efficacy data and the fact that it is well tolerated,” he said. “PALOMA-2 will just continue to boost that, not only in the United States, but globally.”

The double-blind, placebo-controlled trial found that the addition of the CDK4/6 inhibitor increased median PFS from 14.5 months to 24.8 months versus letrozole alone. The treatment was also well tolerated.

These findings confirm the results of the phase II PALOMA-1 study, which led to the February 2015 FDA accelerated approval of palbociclib as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

OncLive: What led to the development of palbociclib?

In an interview with OncLive, Finn discussed the clinical impact of PALOMA-2 and palbociclib in ER-positive breast cancer and the reason CDK4/6 inhibition is effective in this patient population.Finn: The development of palbociclib goes back several years. It was a drug that was really looking for an indication and there was a collaboration between myself, Dr Dennis Slamon, and others at UCLA Jonsson Comprehensive Cancer Center and Pfizer. We received this compound—which didn’t have a name at the time, it was called PD-0332991—and we did a preclinical evaluation to try and identify an indication for this CDK4/6 inhibitor. The biology of CDK4/6 had been around for a long time, but no one really had a good CDK4/6 inhibitor, and the companies that did were still looking for an indication of where to develop them.

In the preclinical findings, which were published in 2009 and referenced in The New England Journal of Medicine article, we identified that the ER-positive subtype of breast cancer is very sensitive to inhibition in the lab and that there was synergy between CDK4/6 inhibition with palbociclib and antiestrogens.

How did PALOMA-2 compare with previous findings?

What impact has palbociclib had for patients with ER-positive breast cancer?

The phase II study, PALOMA-1, looked at 165 patients who received palbociclib and letrozole versus letrozole alone to see if the laboratory data held up in the clinic. That study was impressive. We saw a more than 10-month improvement in PFS, and it turned out to be very well tolerated. This was the basis for an accelerated approval by the FDA in 2015. There was always a commitment to do a real phase III registration study—not only for the FDA—but because several global registration authorities would not accept a phase II study.PALOMA-2 was a large phase III study, which had over 600 patients and was blinded and placebo-controlled with palbociclib and letrozole versus placebo and letrozole. The goal of the study was to serve as confirmation of PALOMA-1. Remarkably, the results were exactly like the phase II study. We went from a small, open-label phase II trial to a large randomized phase III trial, and we still saw the same increase of over 10 months improved PFS. The safety profile was also very much the same, as fewer than 2% of patients had neutropenic fever and it was very well tolerated.There has been a lot of effort to improve on single-agent endocrine therapy in metastatic breast cancer. For decades in frontline therapy, we only had endocrine therapy, and that’s not because other things weren’t looked at, but because nothing tended to be positive in randomized studies.

Is there any understanding of why CDK4/6 inhibition is effective in this space?

PALOMA-1 was the first, very positive randomized study—which has now been confirmed in PALOMA-2—that showed that combining endocrine therapy with another targeted agent could improve PFS in the frontline setting. The efficacy is significant, with a hazard ratio of 0.58, which is consistent across pretty much all of the clinical subgroups that we have looked at. They are very compelling data. It should become standard of care for these patients. This is the only CDK4/6 inhibitor approved in this space.There are a few reasons. One, breast cancer is driven by steroid hormones and peptide hormones. Those growth factors signal through cyclin D1, CDK4/6, and the Rb pathway. Endocrine therapy works through that pathway, and palbociclib and other drugs in that class work through that pathway. I would hypothesize that a lot of the resistance mechanisms signal through that pathway.

Therefore, we are picking up on a common pathway for normal growth control, but also some resistance mechanisms. There are tons of data that show that EGFR mechanisms are important to endocrine therapy resistance.

Are there any challenges with palbociclib oncologists should be aware of?

However, all of the studies with EGFR inhibitors have failed. The question becomes, “Have they failed because the biology is bad, the drugs are bad, or because the right groups of patients were not selected?” I would argue to a large extent that it is because they can’t identify the right group of patients. With a mechanism of action such as CDK4/6 inhibition, regardless of the specific mechanism of resistance, a lot of them still signal through CDK4/6.The neutropenia is real. The label indicates how to watch for that in each cycle. Obviously, the cost issue is also real, but we understand that there is a commitment from industry that every patient who needs it should get it. Over time, doctors will see that it is very well tolerated, it has side effects but ones that are manageable, and many patients just go on with their normal lives.

Finn R, Martin M, Rugo H, et al. Palbociclib and letrozole in advanced breast cancer. N Eng J Med. 2016; 375:1925-1936.