Palbociclib exhibits antiproliferative activity in untreated early-stage breast cancer

Selina Chen-Kiang, PhD

The antiproliferative response to palbociclib in patients with newly diagnosed early-stage breast cancer suggests the use of palbociclib as a frontline treatment. It also confirms the mechanism of palbociclib action as a CDK4/6 inhibitor, first demonstrated in the phase 1 single-agent palbociclib clinical trial in mantle cell lymphoma. This finding was subsequently confirmed in a phase 2 clinical trial that combined palbociclib with letrozole in metastatic breast cancer. Results led to FDA approval of palbociclib for treatment of breast cancer in 2015.
The targets of palbociclib — CDK4 and CDK6 — are rarely mutated in human cancer. Therefore, it is not a surprise that palbociclib hits the intended target in all reported clinical trials as long as Rb, the substrate of CDK4 and CDK6, is expressed. Screening for Rb expression should be a requisite for palbociclib therapy. Beyond this, no other biomarkers for palbociclib have been identified. This is the most challenging and important question at hand.

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Leonard JP, et al. Blood. 2012;doi:10.1182/blood-2011-10-388298.

Andrew D. Seidman, MD & Maura N. Dickler, MD

Window-of-opportunity studies allow for serial assessment of biomarkers in the breast and serum in the context of a brief period of drug exposure before definitive, necessary curative surgery for early-stage breast cancer. Arnedos and colleagues performed such a trial in the PreOperative Palbociclib (POP) randomized trial comparing the cyclin-dependent kinase (CDK) 4/6 cell cycle inhibitor palbociclib (Ibrance, Pfizer) in a 125-mg oral daily dose for 14 days with placebo (3:1 randomization), in a largely ER–positive and HER-2–negative population. The primary endpoint of detecting a difference in cell proliferation as measured by Ki67 at day 15 was met, leading to a press release that stated, “palbociclib works in untreated early-stage breast cancer.”

Examining the impact of palbociclib on other indicators of antitumor activity, there was notably no increase in tumor necrosis or apoptosis and the trend, in fact, was in the direction of the placebo control arm. Given the known effects of CDK 4/6 inhibition on Rb protein, it was not surprising to see a decrease in phosphorylation of Rb (pRb) vs. placebo; pRb hypophosphorylation and decline in Ki67 were correlated, leading the authors to hypothesize that lack of Rb hypophosphorylation might represent primary resistance.

The study does not inform us regarding what the potential impact of aromatase inhibition (AI) or estrogen receptor downregulation (SERD) — the two current clinically relevant FDA–approved uses for palbociclib in ER–positive advanced breast cancer — in combination with CDK 4/6 inhibition might be. What does adding AI or SERD to CDK 4/6 inhibitor do? So, palbociclib monotherapy “works” in early-stage breast cancer?

In the Immediate Preoperative Anastrozole, Tamoxifen or Combined with Tamoxifen (IMPACT) trial, the 2-week Ki67 value after preoperative endocrine therapy for ER–positive breast cancer has been demonstrated to predict RFS. Does this hold true for any agent? What is the incremental advantage for the addition of palbociclib to endocrine therapy in this model — the seemingly more clinically relevant question not addressed by the POP trial? 

Words are important. To state, based on these data, that neoadjuvant palbociclib monotherapy “works” in early breast cancer has implications. Certainly, the randomized trial data from the PALOMA suite of trials support the investigation of CDK 4/6 inhibition in earlier stage ER–positive breast cancer. The ongoing PALLAS Trial is designed to determine benefit of palbociclib on invasive DFS in early breast cancer (NCT02513394).

The current biomarker data in POP — particularly the observation that PIK3CA mutational status was not associated with decline in Ki67, consistent with the observation that PIK3CA mutational status did not impact response to fulvestrant (Faslodex, AstraZeneca) plus palbociclib in PALOMA-3 — is useful in directing further drug and trial development. To be sure, the POP results afford a window into biology, not so much into efficacy.

As per the experience with preoperative metformin, where Ki67 decreased and apoptosis, in fact, increased (TUNEL), “evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical trial endpoints such as survival is needed.” POP goes the weasel.

References:

Cristofanilli M, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(15)00613-0.

Dowsett M, et al. J Natl Cancer Inst. 2007;99:167-770.

Klintman M and Dowsett M. J Natl Cancer Inst Monogr. 2015;doi:10.1093/jncimonographs/lgv002.

Niraula D, et al. Breast Cancer Res Treat. 2012;doi:10.1007/s10549-012-2223-1.