ASCO 2013

Ganetespib inhibits Hsp90 with docetaxel for advanced lung cancer

Dr Suresh S. Ramalingam - Emory University, Atlanta, USA

Heat shock protein 90 (Hsp90) is a unique target because by inhibiting Hsp90 you can actually get to a number of key oncoproteins that are critical for the cancer cell. So inhibiting heat shock protein has been an on-going effort for two decades but now we finally have a drug that has shown in a randomised trial to improve the efficacy of chemotherapy in advanced stage lung cancer.

What does this drug do?

So when a protein is newly synthesised in the cell it’s almost like coming out of an assembly line. It has to associate itself with Hsp90 and then it undergoes the activation process. There are more than 200 proteins that have been described in the literature that are dependent on Hsp90 activation in the interaction. So by blocking Hsp90 you are able to knock out the oncogenic functions of many of these oncoproteins.

Is this what the chaperone is called?

Yes, that is exactly right. Heat shock protein is known as the chaperone and we refer to proteins like EGFR, ALK, HER2 as client proteins of Hsp90.

Is it a master modulator?

It plays a very critical role; it accounts for almost 1-2% of all cellular proteins are heat shock proteins.

Can you tell me about the drug you have been using?

Ganetespib belongs to what we refer to now as a second generation of Hsp90 inhibitors. It is administered intravenously - we give it once on day 1 and day 15 of every three week cycle in this particular trial. It’s tolerated well, the most common toxicity you see is diarrhoea which is about 2-3 days from the time of infusion, readily manageable with appropriate agents that are available over the counter. So it’s a drug that affects a number of key proteins and has shown activity as a single agent in specific molecular subsets of non-small cell lung cancer.

Can you tell me specifically about the study you are reporting?

The study that we did was a randomised phase II trial. The goal was to see which subgroup of patients benefit from a combination of ganetespib with docetaxel. So this was for patients with advanced stage lung adenocarcinoma. We randomised them to the combination or control arm of docetaxel. 250 patients were enrolled and it was one to one randomisation. What we saw was that patients who got the combination had an improved progression free survival and improved overall survival. Even more important and interesting was the fact that patients who came in with greater than six months from the time of diagnosis had almost a hazard ratio of 0.6 for PFS and overall survival with very significant p-values and these were 70% of all patients enrolled to the trial suggesting that this group derived the maximal benefit from the combination therapy.

How many patients were you looking at and what stage are we at?

This is a large phase II trial, randomised phase II trial, and these exciting observations have now prompted a phase III trial and this phase III trial will test the regimen against the same control arm, the main difference is going to be we will enrol only patients greater than six months from the time of diagnosis.

This started with 250 patients, are you now moving into the thousands?

500 patients will be in the randomised phase III trial, approximately.

What do you think could come out of it?

Well we hope to show that the combination extends survival for patients with lung adenocarcinoma.

What are the clinical implications of this?

If you look at the patient landscape for lung cancer in the salvage therapy setting in nearly ten years there has not been a single drug approved and we’ve reached a plateau for those patients. Having a combination or a drug that extends survival would be a breakthrough for this patient subgroup.

What about up front therapy?

If we show that the salvage therapy setting is associated with improved survival then clearly we are thinking about how this can be moved to the up-front setting using ganetespib as part of combinations. So that would be the next step as our research extends.

What about toxicity?

We have seen very good tolerability of the combination, we are encouraged by what we see. There was nothing unanticipated that we saw in this randomised phase II trial and given that we now have experience in a large group of patients with the combination, nearly 125 patients, we feel good about the tolerance.

How do you think this targeted agent fits in with the others?

We now have lung adenocarcinoma being viewed as distinct molecular subsets. You have EGFR mutation that accounts for 15%, ALK translocation accounts for 5% and a slew of other abnormalities that are seen in 1% or less of patients. So for specific subgroups if you can have a targeted agent we treat them, but that’s only about 15-20% of lung adenocarcinomas right now. We still have 80% of lung adenocarcinoma patients for whom there is no proven targeted agent. So if we have a drug that broadly affects patients I think it’s going to be very impactful in lung cancer.

Is adeno cell carcinoma leaving behind squamous cell carcinoma?

Squamous cell carcinoma is a subset that’s decreasing, fortunately, in incidence in the United States and certainly we’re seeing trends in Europe. We are now beginning to understand the genomic drivers in squamous cell carcinoma and there are targeted agents being developed. It’s following the same paradigm that we’ve used for adenocarcinoma but I anticipate that we’re going to have targeted agents for squamous as well, just not this particular drug.

What is your take home message?

Brief practical take home message for doctors is that the combination of ganetespib and docetaxel appears promising and if you have the trial please enrol patients so we can get this phase III trial completed quickly.