CDK 4/6 Inhibition: The Next Big Thing in ER+ Breast Cancer Impresses at SABCS 2012
| Dec 6, 2012
Co-authored by Josh Garcia, Associate Consultant
It was a little over one year ago that Novartis presented data showing that adding a targeted agent, the mTOR inhibitor Afinitor® (everolimus), to hormone therapy could significantly and dramatically prolong progression-free survival (PFS) in relapsed hormone receptor-positive post-menopausal breast cancer. With PFS nearly tripling (11.0 versus 4.1 months; HR 0.36, p<0.0001), the results were immediately regarded as practice-changing, and questions began to arise about the potential of adding targeted agents to earlier lines of hormone therapy and the toxicity costs of these combinations.
Enter the CDK 4/6 (cyclin-dependent kinase 4 and 6) inhibitor, PD 0332991 (Pfizer/Onyx). The inhibitor is designed to shut down retinoblastoma (Rb) phosphorylation, which drives cell division. With very favorable preclinical activity, CDK inhibitors have been on key opinion leaders’ radars recently as very promising agents, and the results from the randomized Phase II combining PD 0332991 with Femara® (letrozole, Novartis) did not disappoint (Finn, Abstract S1-6, SABCS 2012). The study enrolled 165 first-line post-menopausal estrogen receptor (ER) positive breast cancer patients who had not been previously treated for advanced or metastatic disease. It is important to note that ER positivity was the specific biomarker for sensitive patients; this was independent of progesterone receptor (PR) status. As part of the trial design, CCND-1 amplification and p16 were prospectively evaluated as potential biomarkers, but only ER status was predictive of activity. At this interim analysis the addition of PD 0332991 to Femara compared with Femara alone increased median PFS from 7.5 months to 26.1 months (HR=0.37, p=<0.001)! The control arm underperformed somewhat in this study (historical PFS rates for first-line aromatase inhibitors are still in the nine- to 10-month range), but this still represents a significant improvement with PD 0332991. It’s notable that the majority of enrolled patients had rather aggressive disease (de novo metastatic disease or a short disease-free interval following adjuvant therapy), which may explain the underperformance of the control arm and further raise the meaningfulness of the PD 0332991 arm’s performance. A benefit in objective response rate (ORR) was also observed, but the magnitude did not approach the same levels as PFS benefit — ORR was 34% in the PD 0332991-containing arm and 26% in the Femara monotherapy arm. The discordance in ORR benefit and PFS benefit may be explained by CDK 4/6’s role in regulating mitotic progression, but not in mediating cell death. The mechanism may also explain why the clinical benefit rate in this breast cancer study was dramatically improved (CBR = 70% with PD 0332991+Femara versus 44% with Femara alone).
The caveat to all the fantastic efficacy data is that the CDK inhibitor did add some significant hematologic toxicity. Rates of Grade 3/4 neutropenia were increased from 1% to 51% and leukopenia from 0% to 14%. On study, 71% of patients required a dose interruption and 35% required a dose reduction; adverse events led to 10% of the discontinuations. However, the author noted that there were no cases of febrile neutropenia, and no administration of growth factors was required. It would appear that the hematologic toxicity could be considered significant but manageable. Ultimately, if the dramatic PFS benefit holds up in the Phase III study, physicians may be willing to deal with the toxicity.
Physicians’ perception of toxicity in first-line hormone therapy will be a key point to be understood going forward. Hormone therapy has always been considered a relatively benign treatment, and physicians usually try to keep women on hormone therapy as long as possible before switching to chemotherapy. While the addition of targeted therapy to hormone therapy is reducing that toxicity benefit, it seems as though the efficacy benefits are likely to outweigh toxicity when it comes to PD 0332991. Pfizer has announced plans for a Phase II/III study (NCT01740427) in the same patient population and anticipates initiation in February 2013. With Afinitor recently approved in combination with hormone therapy and pursuing development in the adjuvant setting, and PD 0332991 now demonstrating highly meaningful clinical activity in ER+ patients, we are at the dawn of a new era in breast cancer treatment that could have significant impact on the future course of the disease.