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Exelixis, Inc. Message Board

  • wildbiftek wildbiftek Sep 12, 2013 1:38 PM Flag

    Ipilimumab misses stat-sig OS target in prostate cancer...

    ... but just barely:

    "The ipilimumab arm demonstrated a median OS of 11.2 months compared with 10 months with placebo (HR=0.85; 95% CI, 0.72–1.00; P = 0.053"

    An inclusion criterion for the population of this study is:

    "Prior treatment with docetaxel"

    And an exclusion criterion is:

    "More than 2 prior systemic anticancer regimens for prostate cancer"

    I'm thinking this may preclude abiraterone and enzalutamide pre-treated patients from this population. Compare this to COMET-1 which has an inclusion criterion:

    "Received prior docetaxel (minimum cumulative dose of 225 mg/m2) and either abiraterone or MDV3100 treatment and has evidence of prostate cancer progression on each agent independently."

    The phase two result for Cabo of 10.8 months OS in PC had substantial pre-treatment so it's not looking too bad.

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    • "I'm thinking this may preclude abiraterone and enzalutamide pre-treated patients from this population. Compare this to COMET-1 which has an inclusion criterion:"

      This trial started around March 2009, and Abiraterone approved in April 2011. I think recruitment for the trial was 2 years, so I don't think many had Abiraterone or Enzalutamide for that matter.

      "The one- and two-year survival rates for Yervoy versus placebo were 47% versus 40%, and 26% versus 15%, respectively."

      The tail separates a bit over time, but not a very large difference.---I'm guessing that tail helped get helped get Ipi so close to stat sig with little difference in median OS between treatment arms.

      That 10 month OS in placebo arm does give me a little more confidence in Cabo COMET trials, but that Ipi trial had 48% with BPI 4 pain score. This has me believing the placebo arm was still pretty advanced.

      I'm still curious about what the delta is between soft tissue RECIST and bone scan PFS for Cabo? The PFS(combination of bone and RECIST progression) wasn't much different from Abiraterone pretreated and those who were not pretreated with Abiraterone in NRE.---This is the only data set that has me worried about Cabo's duration of response, particularly between early and later stage disease in prostate cancer.

      I will throw these comments out there to digest. Remember PFS and duration of response have different meanings

      "On the cabo arm, we had from the NRE, we had several metrics of durability of response. The bone scan response had about a 5.5-month duration of response, which I think we are very pleased to see. Again, what would be the argument, it could be seen at the sub-optimal dose in terms of the 100 mg does. So we see that being longer with the lower more stable dose, number one.

      The PFS for this late population, for both the overall group, as well as the abi preceded group was about 4.4, 4.5 months."

      These are similar to Abiraterone in CRPC so doesn't concern me in late

      • 2 Replies to hbomb57108
      • Thanks for that analysis regarding pre-treatment and quote. You're right, dosing looks to be important to the Cabo trial in light of the NRE and MTC OS data; having correct dosing does seem very important both to avoiding AE related death and prolonging dosing duration.

        I was expecting that there'd a lower OS time in the COMET placebo group than the Ipi placebo group due to disease rebound for those patients who discontinued abiraterone or enzalutamide treatment (survival curves seemed to meet for both anti androgens). Never the less, this placebo group seems closer to COMET-1's compared to say Alpharadin's (11.2 months median trial: "[HR] = 0.70; 95% CI, 0.55-0.88; two-sided P = .002.") which had specific exclusion requirements for visceral metastases or Abiraterone's prednisone control group which may not have been as advanced (10.9 months OS, trial: "hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P less than 0.001.")

        Looks like an ideal future course of treatment could center around immuno-therapy first with either Ipi or Provenge, then simultaneous abiraterone and ezalutamide, and finally Cabo. Combinations are a wild card as Cabo might fruitfully be combined with any of the above or combined with a cytotoxic agent if it's tolerated (Cabo seems to reduce tumor's resistance to cytotoxic agents as seen in pancreatic cancer).

      • "I'm still curious about what the delta is between soft tissue RECIST and bone scan PFS for Cabo?"

        On second thought, if duration of response by bone scan is only 1 month difference from pfs, the delta can't be too large.

    • Also from Onclive:

      "A pre-specified subset analysis suggests that patients with lower disease burden experience the most benefit with ipilimumab."

      Prostate cancer is becoming quite a crowded space, but I think Cabo maintains some advantages and 10.8 months looks good when you consider the heavy pre-treatment.

      • 2 Replies to wildbiftek
      • $$$$
        At this point in the process of data maturing toward a commercial prospect, I feel this is very good news. Ipilimumab being noted as most efficacious in patients pops with a lesser disease burden places an imperative to gather Cabo data in earlier settings than we've seen. Future data from the Cabo/Abi combination trial may further tease out some earlier stage trial planning - or (and I consider this more likely) - Cabo treatment will remain relegated to advanced patient groups where metastasis is imminent, particularly in those with known familial history of predisposition towards bone mets.

        OT-FWIW ... SNTA got walloped today on news that Ganetespib has received FT designation, and has traded over a 20% range. I must be stupid, I bought more in the $6.50's.
        It's developing huge SI, and it's a bit like having a second EXEL in my portfolio...

      • I own BMY, up today,

6.12+0.24(+3.92%)Aug 3 4:00 PMEDT