Replies to post #306577 on NorthWest Biotherapeutics Inc (NWBO)

[highwayman4life]

Alpha~

I appreciate all the work and data gathering you have done! I am with you on the anticipated results of the trial.

As to Reefrad's question and your response, there were so many unknowns in immunotherapy when this trial was originally designed. Aside from the Psuedoprogression issue and "possible" mishandling of info by DMC head Dr. Furberg there were other parameters that LP et all had to contend with to try and give this trial the best possible chance of approval.

This is all well known but I find these particular statement resonates very well regarding the DCVaxL trial:

The patterns of response to treatment with immuno-oncology agents differ from those seen with conventional therapies [3]. Long-term survival and delayed clinical benefit are common outcomes. Stable disease or responses can occur after conventional progressive disease owing to clinically insignificant new lesions in the presence of other responsive lesions and to a reduction in total tumor burden. As such, discontinuation of immuno-oncology therapies at the first sign of progressive disease might not always be appropriate [4]. In addition, durable stable disease might represent meaningful antitumor activity in patients who do not meet the criteria for an objective response [3]. Because the clinical benefit of immuno-oncology agents might extend beyond that of traditional cytotoxic agents, alternative statistical methods should be considered to allow treatment efficacy of immuno-oncology therapies to be assessed appropriately [3,5].

Standard group sequential designs and interim analyses have been used in Phase III studies to allow early study termination for success or futility. Standard designs and response criteria should be reassessed when considering immuno-oncology studies [4]. Early interim analysis should be approached carefully because a drug with delayed separation of the survival curves might confer a misleadingly negative early result. In a Phase III trial of tremelimumab in metastatic melanoma, an early interim analysis showed no survival benefit and the study was terminated; however, extended follow-up showed delayed separation of the survival curves [46].

I wonder why so much work went into the revised SAP?:-)
Lastly:

Immuno-oncology therapies that harness the patient's immune system to target cancer cells are likely to have a significant impact on the treatment of MM, with improved clinical outcomes and changing treatment paradigms. Appropriate study designs, end points and statistical methods are essential for evaluating immuno-oncology therapies to achieve more favorable treatment outcomes. Currently, much focus is placed on median time-to-event end points, such as OS and PFS. As clinical benefit with immuno-oncology therapies is often delayed, a long-term approach to the assessment of immuno-oncology data should be taken, including assessment of HRs over time (which assess benefit across the entire course of a study and include all patients) and milestone PFS/OS analyses, as clinical trial results can be misleading if analyzed too early. In addition to the conventional efficacy end points, we propose selecting appropriate immune end points to determine early signs of an immune response, and adapting currently accepted end points to ensure the long-term evaluation of clinical benefit with immuno-oncology agents.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705823/

We will all know soon enough the details for the "delay" in ending the trial and if the extension of it was well worth the wait!! As painful as it has been, I believe NWBO has given themselves the best possible chance for approval.

GLTA