re telk
>1) ASSIST-1: survival endpt, 3rd line ovarian, telcyta mono vs doxil...phase II data is 15% response rate in tel and 12% historically for doxil...my bet - under 30% chance of success<
ASSIST-1 is in 3rd line ovarian. So a patient must fail a platinum compound in the first line, then fail one of doxil or hycamtin as second line treatment. Such patients are then randomized to either telcyta, or one of doxil or hycamtin, whichever it was that they have not yet taken. So a patient that failed doxil in second line could be randomized to either telcyta or hycamtin; one that failed hycamtin can be randomized to telcyta or doxil.
In this respect, the two independent phase II trials for telcyta are difficult to compare to the 16% for doxil in platinum refractory patients (Gordon, 2001). The patients in the pivotal Gordon study were ineligible if they had previously received Doxil or Hycamtin. So in effect, the 16% response rate for doxil in this study was strictly for patients that are one line of therapy ahead of the patient population in ASSIST-1. Those patients in the gordon trial would have to fail doxil or hycamtin, and only then would they be eligible to enter ASSIST-1.
The reported response rate of 15% in the published telcyta trial, where all had failed plat and 61% had failed either doxil or hycamtin prior to entry, is numerically similar to doxil in the second line, but the patients are farther along the disease progression path. The same is true for the other confirmatory phase II that showed an 18% response rate in a similar patient population having received 3 prior median therapies. Some suggest that the response rate percentages will creep up as you go higher up in the treatment ladder, but I don't want to make such extrapolations.
For patients with platinum refractory disease in the gordon paper, doxil provided a median survival of ~42 weeks. It was 60 weeks for patients in the telcyta study. This increase in survival was preserved for the 1 year and the 18 month time points as well. Hardly a rigorous mathematical comparison given the small number of patients in the telcyta trial (36), but that's what we have right now.
>2) ASSIST-2: survival endpt, 3rd line NSCLC, telycta vs Iressa...completely meaningless regardless of outcome because Iressa has no survival benefit...so at best is tel is another tarceva, which is not seeing much growth in sales in 2nd/3rd nsclc markets..<
This trial has excluded a subset of adenocarcinoma that tends to respond better to EGF-R inhibitors. So the control arm in this trial is likely to show a median survival a shade less than 5 months. Your friend is correct that in the absence of a survival benefit for Iressa, interpretation from this trial could be problematic. However, it appears that there was some foresight by management, as they stated on numerous occasions that the SPA covering this trial specifically addresses the use of Iressa in the control arm. The other potential problem for this trial is that it does have foreign enrollment centers; if not well policed, those can occasionally cause problems so that is another potential pitfall.
I think this trial is a case where the actual magnitude of the treatment benefit, rather than simply a stat sig difference, will determine approvability. Without a stat sig difference, there is obviously no hope. But a stat sig difference with only a modest reduction in the risk of death (20-25%) would not be clinically meaningful. The modeling assumptions for this trial have not been disclosed, but from speculation on this board, it is pretty likely that they're targeting at least a >30% reduction in the risk of death (i think dew suggested that it may be pushing 40%.. or that it should). If they show that magnitude of difference, i don't think it will matter that the comparator arm was no better than BSC.
>3) ASSIST-3: response rate endpt, 2nd line ovarian, telcyta plus carbo vs doxil alone...highest chance of success, but again meaningless in the approval path because if ASSIST-1 is a bomb, odds for the agency to let a RR surrogate endpt to go thru in light of a negative survival study (with the same drug and similar indication) are poor<
Generally agreed. If ASSIST-1 fails to show a survival benefit, then it will be an uphill battle to convince the FDA that an incremental increase in response rate for ASSIST-3 is a predictable surrogate for survival. However, PFS is also an endpoint in this study, so they do have the chance to demonstrate significance in a better surrogate to go along with a possible increase in response rates. If the response rate of ~50% holds up versus ~15% for doxil in this trial, that already tilts the scales in favor of telcyta insofar as surrogates that depend on disease progression (PFS / TTP).
I'd be fully agreed with your friend if PFS wasn't an endpoint in ASSIST-3.
>also, one has to question why in 3rd line ovarian, the response rate of tel mono vs doxil mono is not that big of a difference..(phase II tel plus carbo RR was 56%...recall the doxil RR is about 12%)...so could the real benefactor is carbo instead of tel..<
Again, this comparison of doxil's mono response rate to telcyta's mono response rate isn't the best one, since the doxil patients were only plat refractory (2nd line), whereas the telcyta patients, in addition to being plat refractory, had failed additional therapies including doxil or hycamtin (as stated above).
As for the real "benefactor" being carbo rather than telcyta... i guess that is possible if the docs have done a shoddy job of sticking to the enrollment criteria which requires plat refractory / resistant patients.
One preclinical explanation for the synergistic combination of carbo and telcyta may be related to the inhibition of gst p1-1.
>telk also running trials of tel plus cisplatin in frontline nsclc...this is another trial that ignores the landscape of nsclc options...cisplatin now used in combo with gemzar as a standard...along with paclitaxel and carboplatin...these two are the gold standards...few folks use cisplatin alone these days...throw in the avastin monkey wrench in frontline setting..people will use pac/carbo/avas before anything else...i just dont see telcyta will work in the frontline space with the trials onging..<
The tel + cisplatin trial seems to be one that is being run just to have the data in hand as they think out a way to enter the european treatment market. However, management has been more aggressive for the pac + carbo + telcyta triplet (pac + carbo is first line in US), and they've previously announced that they're expanding the numbers for this trial. A registration strategy for lung cancer has not yet been described, so it is difficult to criticize companies for running exploratory phase I/II trials.
And Avastin is a legitimate threat. It is a monkey wrench for basically all competing oncology drugs right now. So our choices are to throw our hands up in the air and invest solely in DNA, or take our chances with other companies if we think the conditions are appropriate.
>900 Million mkt cap for a refractory ovarian indication at best is a very very very very veryexpensive proposition.<
True.
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