After writing the first two posts in the series, I was much amused to see this tweet in my Twitter stream from one of buddies:
When you've been blogging on science, marketing, PR and cancer topics for several years you begin to wonder if it actually beneficial to anyone, so today's post is dedicated to Miguel in Barcelona for making me smile :-). If you're on Twitter, please do follow him because he's a great guy and shares a lot of very interesting pharma related links. Give him some Twitter love!
Today's topic is about a new generation flavanoid, ASA-404, from Novartis. Of course, under FTC guidelines, I should disclose that as many of you know, I'm a former employee and have also done consulting work for the company, but not on this particular product.
ASA-404 is an interesting agent in phase III development. It's a vascular disrupting agent (VDA) with a tubulin dependent mechanism of agent. Unlike taxanes, which target the microtubulin in DNA, this agent is also part anti-angiogenic agent because it selectively disrupts the tumour vasculature with both direct and indirect effects. In simple terms, I think of it as a kind of hybrid cross between an anti-angiogenic such as bevacizumab (Avastin) and a taxane such as paclitaxel or docetaxel.
Dr Mark McKeage presentation at the AACR lung cancer meeting was focused on the phase II that has been published to date, including a publication in the British Journal of Cancer (see bottom of article).
The drug was well tolerated in phase I trials, achieving an MTD of 3700 mg/m2.
In a phase II trial, paclitaxel and carboplatin (pc) therapy was used as the reference arm, and ASA-404 added to the standard chemotherapy in the other arm to determine if the agent added any extra benefit for newly diagnosed patients with non-small cell lung cancer (NSCLC) with either a squamous or non-squamous histology. They looked at 2 different doses of ASA-404 - 1200mg/m2 was used in the randomised comparison with carbo-tax and 1800mg/m2 with out the comparator arm but in combination as before. 36 patients were accrued into the reference pc arm, 37 in the lower dose ASA-404 arm and 31 in the higher dose ASA-404 arm. This gave a total of 104 patients in the pooled phase II study.
Overall, similar rates of adverse events (AE's) were seen in the squamous and non-squamous patients, except for a slight increase in AE's related to blood/lymphatic effects. No serious AE's associated with vascular effects of bleeding, hemorrhage or hemoptysis were seen. There was an increase in hematologic toxicities (anemia, neutropenia and thrombocytopenia) but these were not significant and none rose above 20%. There was no apparent increase in neutropenia related sepsis.
In terms of efficacy and median overall survival, McKey reported:
PCA vs. PC
14.0 vs. 8.8 mos for 1200mg/m2
14.9 for 1800mg/m2
Thus we can clearly see that adding ASA-404 to standard carboplatin-paclitaxel therapy improved median overall in frontline NSCLC by 5 months.
Recently, the FDA has approved several therapies in NSCLC in different histologies, due to either issues with side effects (bevacizumab and bleeding issues) or lack of efficacy (pemetrexed), while others such as erlotinib have been shown to be particularly effective in non-smoking female asians with an adenocarcinoma histology, although the approval is not based on histology.
Let's take a look at the ASA-404 histology data:
Squamous: Non-Squamous: Overall:
PCA PC PCA PC PCA PC
ORR (%) 40.0 14.3 31.7 25.0 34.4 22.2
One third of the patients had a squamous histology, but experienced no bleeding issues seen with VEGF agents.
While the results are higher for those with a squamous histology, there was also a trend towards higher efficacy in the non-squamous patients. The positive results provided support and evidence for the drug's effectiveness and rationale for beginning the phase III triala, ATTRACT-1 in first line and ATTRACT-2 in second line NSCLC without restriction on histology.
To put the 5 months improvement in median OS with ASA-404 in context, I checked out the PI for other therapies. Bevacizumab was approved on the basis of 12.3 months vs. 10.3 months, ie a 2 month improvement, while pemetrexed was approved on the basis of non-inferiority when comparing pemetrexed plus cisplatin to gemcitabine plus cisplatin (ie 10.3 months of overall survival in each arm).
The front-line trial has completed accrual and is ongoing, but the ATTRACT-2 trial for patients who have had prior chemotherapy is still enrolling. You can find it here: ATTRACT-2.
Of course, these are early days yet and positive phase II data does not always translate to phase III success, but they are a hopeful sign of good things to come. If the data are repeated, it will be good news for patients with NSCLC.
McKeage, M., Von Pawel, J., Reck, M., Jameson, M., Rosenthal, M., Sullivan, R., Gibbs, D., Mainwaring, P., Serke, M., Lafitte, J., Chouaid, C., Freitag, L., & Quoix, E. (2008). Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer British Journal of Cancer, 99 (12), 2006-2012 DOI: 10.1038/sj.bjc.6604808
