Results of a randomised phase 2 study of PD 0332991

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Published: 17 Dec 2012
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Dr Richard Finn - Universtity of California, Los Angeles, USA

Dr Richard Finn talks to ecancer at SABCS 2012 about the cyclin-dependent kinase 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer.

 

Dr Finn explains that PD 0332991 prevents cellular DNA synthesis by blocking cell cycle progression.

 

Preclinical studies in a breast cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 

SABCS 2012

Results of a randomised phase 2 study of PD 0332991

Dr Richard Finn – University of California, Los Angeles, USA



We presented some very exciting data, randomised phase II data, of an investigational compound, PD 0332991 or PD 991. This is a novel agent against a novel target which is cyclin-dependent kinases 4/6 with letrozole versus letrozole alone as the first line therapy for ER+ post-menopausal advanced breast cancer. This study came out of some strong laboratory work done by ourselves at UCLA which identified that ER+/HER2-, as well as HER2 amplified models, tended to be more dependent on CDK 4/6 inhibition by PD 991 than other subtypes of breast cancer. With that in mind we did other studies which determined that there was a very strong synergistic interaction in inhibiting cell growth between anti-oestrogen agents and PD 991 in ER+ models and used that data to generate a hypothesis to be tested in this randomised phase II study. By way of background, cyclin-dependent kinases are a new target in breast cancer, really in oncology. They play a critical role in regulating cell cycle progression. This is achieved by interacting with various cyclins throughout the cell cycle; specifically here we’re speaking about cyclin-dependent kinases 4/6 and the molecule that inhibits them, PD 991. Cyclin-independent kinases 4/6 interact with cyclin D during G1, which is the first part of the cell cycle, and are responsible for hyper-phosphorylating the retinoblastoma gene product or RB. RB normally functions as a brake point on progression of the cell cycle. When RB is hyper-phosphorylated that brake is released and cell cycle progression is allowed to continue. The idea here is that by blocking CDK 4/6 with PD991 we’re subsequently blocking the RB hyper-phosphorylation and therefore inducing a G1 arrest. That’s what we’ve seen in preclinical models and now is bearing out in clinical data that cyclin-dependent kinase inhibition, CDK 4/6 inhibition, is showing a signal of clinical activity.

Are you reinstalling the tumour suppression?

We’re adding an extra brake. As it turns out, the reason we think ER+ breast cancer is more sensitive to CDK 4/6 inhibition as compared to triple negative breast cancer, this hypothesis is based on the fact that we think in ER+ breast cancer the RB pathway is important. If you don’t have the RB gene product, if you’re not making the protein, it would be hard to conceive how CDK 4/6 inhibition would work. From what we understand about ER+ breast cancer is that RB loss is an uncommon event and it’s quite possible that’s why we’re seeing this profound activity with PD991.

Results were quite astounding. When we’re looking at efficacy endpoints, our primary endpoint was progression free survival. This was an interim analysis. I should comment on study design that it was a two part study; part one accrued 66 patients that were selected for being ER+/HER2- and randomised to PD 991 125mg daily, three weeks on, one week off, with daily letrozole 2.5mg versus letrozole alone. We presented the initial efficacy data from this study at the IMPAKT meeting in May of this year and at that time we saw a very impressive hazard ratio of about 0.35 with an improvement in median PFS from 5.7 months to over eighteen months. That was very encouraging but obviously not a huge number of patients, 66 patients randomised.

The second part of the study accrued 99 patients and all these patients were similar, ER+/HER2-, but we also prospectively selected patients that had genomic changes in cyclin D1 or p16, that is to say, cyclin D1 amplification by FSH or p16 loss by FSH. The analysis we presented was a combined analysis of both parts of that study given that they were both an ER+/HER2- population. The tolerability of the drug was remarkably similar to what we saw in the smaller population. Now we have over 160 patients and the most common toxicity has been leukopenia and neutropenia, though very manageable. There was no neturopenic fever and this was a very self-limited event, it’s not cumulative. The efficacy was similarly as impressive, if not more so, than with what we saw at the IMPAKT meeting. If we look at response rates for patients who had bone only disease or patients who had only measurable disease, there was significant improvement in response rates and the clinical benefit rate, if we include responses as well as those patients who had prolonged stabilisation of disease, was increased significantly as well. When we consider a clinical benefit rate which includes response rate as well as those patients who had stable disease for more than six months, we saw an improvement from letrozole alone, a clinical benefit rate of 44% to a clinical benefit rate of 70% for the combination of PD 991 and letrozole. This was very encouraging. What really caught our eye was the progression free survival data. Here we saw a dramatic improvement in PFS; the PFS for the control group was 7.5 months, progression free survival for the study arm was over 26 months. This magnitude of benefit, I think, is unprecedented in breast cancer studies and probably almost all the tumour oncology studies. The hazard ratio was 0.37 and it was not only statistically significant but very clinically significant. Then this is balanced against what we interpret as a very manageable toxicity profile.

The role of progression free survival as an endpoint in front line breast cancer studies is felt to be meaningful. How PFS will translate into overall survival at this point it’s too early to tell. Given the magnitude of benefit that we see in PFS we should hope and can assume that if you can see an improvement in overall survival after seeing an improvement in PFS, if you can’t see it with this magnitude of benefit I don’t know what kind of magnitude of benefit you will see it with. But it’s just too early to see those events.

So this randomised phase II study validated laboratory hypotheses and was proof of concept for CDK 4/6 inhibition in breast cancer. With this in mind we’re very anxious to conduct a randomised phase III study for registration and the plan is to move ahead with that next year.