This work is focussed on small cell lung cancer. Small cell lung cancer accounts for about 15-20% of all lung cancers worldwide, of which there are 1.6 million cases annually. It’s a disease for which the standard therapies have been largely unchanged for the last thirty years and there’s a tremendous need for improved therapies in this disease.
We developed a phase I/II trial looking at combination olaparib tablets and temozolomide in small cell lung cancer. The work that I’m presenting here is specifically focussed on the phase I portion of that study. Olaparib is a PARP inhibitor and an interesting new drug in small cell lung cancer because PARP1 has been found to be highly expressed in small cell lung cancer cell lines compared to other cell lines. There are some preclinical analyses emerging and other clinical data showing some activity of PARP inhibitors in small cell lung cancer.
Temozolomide is an alkylating agent that causes single strand DNA breaks and we think that there is potential synergy between the DNA damage induced by temozolomide and the subsequent response of the PARP complex and PARP trapping by the PARP inhibitor olaparib.
So the trial that we designed is a 3 3 dose escalation trial in patients with small cell lung cancer who have received at least one prior line of therapy including a platinum based chemotherapy. We escalated patients through four dose levels of combination olaparib and temozolomide and assessed the safety profile of this combination. We found that the combination was generally well tolerated at the doses that we tested.
When we looked at the thirteen patients treated on this phase I trial we found that six of those patients had objective responses that were all confirmed for an overall response rate of 46% in this small population. It’s a small trial but I think that’s an encouraging result. We found that the median progression free survival among these patients was 5.6 months; the median duration of treatment was 5.0 months, again encouraging results in this early phase trial.
Through several collaborations at Mass. General we’ve been able to develop PDX models from small cell lung cancer patients, both from biopsies as well as from circulating tumour cells with very high efficiency. Our efficiency of generating CTC derived PDXs is 35% overall and that now starts to afford us the power to generate models from patients at multiple time points over the course of their treatment. So, for example, on this trial we’ve had several patients where we’ve been able to develop patient derived xenograft models both before treatment with olaparib and temozolomide and after treatment with olaparib and temozolomide. What’s striking is that we find that those mouse models respond to the drug or are resistant to the drug in the same way that the patient was at the time point at which the model was derived. So we think that these models can be a very useful tool in starting to pick apart some of the mechanisms underlying why some patients are sensitive to this combination and then why patients are either primarily resistant or become resistant over time to this combination.
What are the next steps?
The trial itself is moving ahead to a phase II portion. It’s a small phase II expansion to twenty patients at a recommended phase II dose that we have determined from the earlier portion of the trial. That’s enrolling currently and we hope to have results from that within the next 6-12 months. In addition to that we’re also working in great detail with these PDX models that we have developed. We’re looking both at the models developed directly from the patients who are on the trial as well as looking at models developed from other patients to try to better understand markers of sensitivity and markers of resistance to this combination and also other drugs that we’re looking at in the laboratory setting.
