Depending on which publication you read, up to 70% of oncology phase III studies fail the primary endpoint when they all had positive phase II results. As this product failed in several other phase II trials for different indications what are the chances that this will work out?
A cancer treatment from Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals Inc. failed to meet its main, late-stage study goal of improving overall survival in patients with advanced cases of lung cancer.
The companies said Tuesday they studied Nexavar in patients with advanced relapsed or refractory non-squamous non-small cell lung cancer whose disease had progressed after previous treatments.
The international study involving more than 700 patients compared the performance of Nexavar, or sorafenib, tablets to a placebo.
This only happens when the PhII was poorly designed.
Currently, there is not a biomarker linked to Nexavar therapy, so we don't know why the drug failed in this new tumor-type...
This is exactly what most oncology drugs are now being developed with a companion Dx... to enrich a "target" population, so they can significantly improve response rates to the drug... and therefore, significantly increase chances of approval...
In addition, if biomarkers are used to enrich the target population and improve response rates, that should also significantly decrease the time it takes to complete a clinical trial... because it will take a significantly smalller number of patients to reach their endpoint(s) and statistical significance... and compress overll time to approval...
You also need to put the historical phase 3 failure rates into perspective... Given our new knowledge of the humane genome and our understanding of the complex signal transduction network within the cancer cell, these new targeted drugs have a much better chance of working (with less side effect and toxcity) because of the rational design of these new agents...
Since specific genes are being targeted on the front end, and the appropriate patient populations are being pre-selected for those genetic abnoralities (based on the gene target), the treatment arms are being enriched with the "right" patients, which significantly increase the odds of the drug working....
Look at the response rates for the targeted drugs versus non-targeted drugs:
1. Tarceva & Iressa (based on EGFR mutations
2. Xalori (EML4-ALK)
3. Gleevec (BCR-ABL)
4. Affinator (mTOR)
5. Herceptin & Tykerb (HER2)
6. Many other in development
All of these are examples of "targeting" specific signaling pathways...
Now that we have the molecular Dx testing technoogy to ideentify and detect these genetic abnomalities, we're seeing an explosion in drug development with respect to targeted therapies.... which will yield many new drug to treat cancer... anfd c-MET is just one of thoise targets..,
I predict that we will start seeing more and more targeted drugs approved after Phase 2 (like Pfizer's Drug Xalori)...
Historically, we needed Phase 3 randomized controlled trials to "tease out" and prove efficacy" (given the typical low response rates). However, with this new targeted approach, when you see HUGE response rates in phase 2, the question now becomes, is a Phase 3 study really necessary...
<I predict that we will start seeing more and more targeted drugs approved after Phase 2>
You cannot grant drug approval based on 10-20 patients many PhII are. There will not be any reliable data either for efficacy or side-effects. These vital info must be available prior to marketing approvals.
Granted, some PhII trial are good and an a conditional approval makes sense.
The reason why some of these targeted drugs don't work in other indications is because that particular pathway is probably not active in that particular tumor-type... In other words, if c-MET is not active in a particular cancer, then the drug has a higher liklihood of not being effective.
"As this product failed in several other phase II trials for different indications what are the chances that this will work out?"
First, no drug works in all indications.
Viagra was designed for cardiovascular applications where it has failed but it is a very successful drug for man sexual dysfunctions.
The best blockbuster selling cancer drugs work well at best in 2-3 very limited indications but were tested in at least dozen indications where they have failed. Cancer is a very poorly understood disease.
Usually, Ph III trials fail because Ph II trials were poorly designed and executed. Now, to your question: are there 100% guaranties for the ARQ 197 success in Ph III in NSCLC? No but its Ph II trail was very good. Consequently, there is a very good chance the Ph III will succeed.
ARQ 197 is a quite promising drug (based on clinical data) in NSCLC, 2nd-line HCC, and in NRAS-mutant melanoma. The drug did not work too well in a gastric indication.
Any suggestions for the coming AM questions?
ArQule announces ARQ 197 Phase 2 clinical trial results at ESMO annual meeting
Published on October 11, 2010 at 8:36 AM·No Comments
ArQule, Inc. today announced the presentation of final results from a Phase 2 clinical trial in non-small cell lung cancer (NSCLC) of ARQ 197 at the annual meeting of the European Society for Medical Oncology (ESMO).
The presentation included new exploratory data analyses related to the anti-metastatic effect of ARQ 197 observed in this trial.
Patients treated with ARQ 197 plus erlotinib had a median time to develop new metastases of 7.3 months, compared to 3.6 months for patients treated with erlotinib plus placebo. This effect was more pronounced among patients with non-squamous cell histology, among whom the median time to develop new metastases was 11.0 months for patients treated with ARQ 197 plus erlotinib, compared with 3.6 months for those treated with erlotinib plus placebo.
"The metastases-delaying data from this trial further strengthen our mechanistic understanding of the anti-cancer effect of ARQ 197," said Brian Schwartz, M.D., chief medical officer of ArQule. "We believe these findings are of clinical significance and reflect the biological involvement of c-MET in cancer cell metastasis and resistance to treatment with EGFR inhibitors such as erlotinib."
Source: ArQule, Inc.
Note that the median time to develop new metastases was 11.0 months for patients treated with ARQ 197 plus erlotinib.
The best NSCLC pts can hope being treated with present best chemo is ~ 14 months. Consequently, there is a good chance ARQ 197 can exceed 14 months.