Anatomy of a Failure.
The discussions about phase 3 NSCLC trials that have failed even though the previous phase 2 NSCLC trial(s) were seemingly positive led me to a little more study. There is a message here. I had a look at the recent failure of the FORTIS-M trial evaluating talactoferrin in NSCLC.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
"Planegg/Munich (Germany), Princeton, NJ and Houston, TX, August 6, 2012 – Agennix AG (Frankfurt Stock Exchange: AGX) today announced that the FORTIS-M Phase III trial with talactoferrin alfa (talactoferrin) did not meet its primary endpoint of improving overall survival."
"The FORTIS-M trial is a randomized, double-blind, placebo-controlled Phase III trial evaluating talactoferrin plus best supportive care compared to placebo plus best supportive care in Stage IIIb/IV NSCLC patients whose disease has progressed following two or more prior treatment regimens. There were 742 patients enrolled in the trial from over 160 clinical sites in North America, Europe and the Asia/Pacific region."
"Median overall survival in the talactoferrin arm was 7.5 months compared to 7.7 months for placebo (hazard ratio 1.04, p-value 0.66)."
Rajesh Malik, M.D., Chief Medical Officer and Member of the Management Board, said: “We are extremely disappointed and surprised with today’s results, especially considering the earlier promising results we had seen in two randomized Phase II trials with talactoferrin alfa in non-small cell lung cancer."
Note that this phase 3 trial was for third-line, or fourth-line patients.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Now let's look at the "promising" results from the two previous phase 2 trials. I am just going to look at the overall survival results, since that is what we are interested in.
Trial 1:
Journal of Thoracic Oncology, Volume 6, Number 6, June 2011. Digumarti et al.
A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral Talactoferrin in Combination with
Carboplatin and Paclitaxel in Previously Untreated Locally Advanced or Metastatic Non-small Cell Lung Cancer
N = 55 in the TLF arm, and N = 55 in the placebo arm. 100% Asian (Indian) patients.
In the ITT population, median OS increased from 8.5 months in the placebo arm to 10.4 months in the TLF arm (HR = 0.87; p = 0.26)
Note that this trial was for first-line NSCLC.
Trial 2:
Journal of Clinical Oncology, Volume 29, Number 31, November 1, 2011. Parikh et al.
Randomized, Double-Blind, Placebo-Controlled Phase II Study of Single-Agent Oral Talactoferrin in Patients With
Locally Advanced or Metastatic Non–Small-Cell Lung Cancer That Progressed After Chemotherapy
N = 47 in the TLF arm, and N = 53 in the placebo arm. 100% Asian (Indian) patients.
Both arms had about 75% second-line patients, and 25% third-line or more.
The median OS in the ITT population was 3.7 months (90% CI, 2.8 to 4.9 months) in the placebo arm and 6.1 months (90% CI, 4.7 to
8.4 months) in the TLF arm (HR, 0.68; 90% CI, 0.47 to 0.98). The one-tailed P = 0.04 by log-rank test met the primary end point with
the prospectively targeted level of statistical significance.
Note this trial was for second-line, or third-line patients
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------
So why was there surprise that the phase 3 trial failed when all three trials evaluated different patient groups?
Why didn't they do a phase 3 trial that duplicated the phase 2 trial that was a success?
When you hear about a phase 3 trial that failed, even though the phase 2 trial was supposedly a success, it pays to look a little more closely at the facts.
Here is the message to take from this:
Robert Garnick, PhD, Head of Regulatory Affairs at Peregrine. "A global Phase III trial designed very similarly to the robust design of this Phase II trial greatly increases bavituximab's likelihood of success."
