After the recent blog post on PI3-kinase inhibitors, I got a lot of emails asking for a specific update on the mTOR data, so here goes.
Firstly, there are 3 mTOR inhibitors already approved in the US, ie sirolimus (Rapamune), temsirolimus (Torisel) and everolimus (Afinitor) in that order. Another, ridaforolimus (formerly deforolimus) from Merck/Ariad is in phase III clinical trials. Sirolimus, also known as rapamycin, is manufactured in the US by Wyeth and is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants, although there has been some off-label use in oncology as the first rapalog approved. Given the order of FDA approval for the mTOR's, one might therefore expect there to be considerably more data available for temsirolimus compared with everolimus, which was only approved in advanced, relapsed renal cell cancer earlier this year.
Here's what a search of the 2009 ASCO abstracts produced:
If this list was an indication of future market share, I'd be a little worried if I were Wyeth. Oncology is very data driven, probably more so than any other therapeutic area I've worked in. Ultimately, it's like the middle linebacker position in American Football – hit early, hit hard and hit often – to ensure success. Novartis have shown that with a constant stream of new or updated data in different indications from Gleevec, for example, and Genentech/Roche followed a similar strategy with their four leading oncology products. This approach helps build organic awareness and reinforces the success of a brand in both existing and new indications. It is therefore a little surprising to see such paucity of data from Wyeth compared to Novartis who have the second to oncology market brand. Ultimately, being first to market isn't always a guarantee of success – in cancer, it's all about the data, baby!
Let's take another, more detailed look at the Torisel and Afinitor abstracts across tumour types. This is what we get:
Melanoma 1 1
Glioma 3 1
Adv solid tumours 2 4
Renal 4 3
TOTAL: 11 18
It's not just about the absolute numbers per se, but also the breadth of a program, because once you have 2 peer reviewed articles, Compendia listing is an option to enable doctors to treat patients once the drug is on the market, especially in situations were there are few or no options available with solid data.
What is interesting though, is not necessarily what was presented at the meeting, but a dramatic tweet I saw
in my Twitter stream afterwa
rds from my good buddy in Spain, Miguel, who alerted us all to a Reuters press release, which thankfully, I had bookmarked as a favourite for easy finding later:
Wow! On checking the Reuters press release Miguel linked to, it stated that Novartis reported Afinitor, "cut tumour size by 50 percent or more in a third of
patients with lymphoma in a mid-stage clinical trial."
The data was reported at the EHA meeting in Berlin, rather than ASCO. The actual Novartis press release observed:
"Results show that 33% of patients with relapsed NHL and Hodgkin's
disease treated with everolimus experienced a 50% or greater reduction
in tumor size…
The median time to disease progression for all 145 patients was 4.3
months (95% CI; 3.6-5.9 months) and the median duration of response for
the 48 responders was 6.8 months (95% CI; 5.4-11.0 months). Nineteen
responders remained progression free at 6 months."
A phase III trial in diffuce B-cell NHL has now begun. Confirmation of the phase II results may well lead to an approval in this indication. The PILLAR-2 (PIvotaL Lymphoma triAls of RAD001) trial will investigate adjuvant treatment with everolimus in poor-risk patients with DLBCL who achieved complete
remission with first-line rituximab combined with chemotherapy.
This study is important because the longer a patient with DLBCL is in remission, the more likely they remain disease-free. Currently, there is no approved therapy for the
approximately 50% of patients who will relapse after achieving a
complete response on initial treatment, demonstrating an important
unmet need that could be addressed.
What of the temsirolimus data in lymphoma? Well, the phase I trial reported at ASCO looked at patients with advanced solid tumours or lymphoma treated with a combination of ImClone's IGF-1R inhibitor, IMC-A12, with temsirolimus;
"Preliminary data suggest that the combination is well tolerated and that it warrants further investigation."
It is, however, too early to tell whether the responses seen to date will be meaningful or not. Phase II data will be eagerly awaited, because combination treatment with RTK's and mTOR's is likely to be the way to go in the future.