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Replies to post #514180 on NorthWest Biotherapeutics Inc (NWBO)
09/15/22 2:32 PM
09/15/22 3:54 PM
“Let's see, first NWBO chose PFS as their primary endpoint. Dr. Liau, the lead clinician, reconfirmed PFS as the primary endpoint again in her 2018 journal publication. Also outlined the process to deal with pseudo-progression. Then NWBO failed to meet the PFS primary endpoint and suddenly NWBO redid the whole trial.”
“Results: For the intent-to treat (ITT) population (n=331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)- derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.
Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.”
…
“Statistical analyses
The study’s primary endpoint is PFS, and the secondary endpoint is OS. PFS has not yet been evaluated for this publication and will be the subject of later analyses to allow for central, multi-factorial assessment by an expert panel, using criteria currently emerging as appropriate for immune therapy in this patient population where progression can be complex to determine and pseudo-progression is a known confounding phenomenon. Analysis of the blinded interim data on OS of the ITT population (using SAS version 9.4) was performed 34 months after the midpoint of patient enrollment, and 16 months after the last patient was enrolled and randomized.
General descriptive statistics include the number of observed values, mean, standard deviation, median, and range values for continuous measures. For categorical variables, the number and percentage of subjects with a specific level of the variable are reported. For survival analyses, Kaplan–Meier (KM) curves were generated, yielding estimates of median survival times, along with the two-sided confidence intervals (95% CIs) and estimates of survival at specific time points.”
“Dr. Liau chose PFS as the lead efficacy endpoint for the NCI SPORE Keytruda combination trial. She seems ok with it as does NCI and Merck, the leader in oncology treatment revenue having done dozens and dozens of oncology trials.”
“Outcome Measures
Primary Outcome Measures :
1. Cell cycle-related signature [ Time Frame: Up to 6 years ]
2. Expansion of T cell receptor (TCR) clones [ Time Frame: Up to 6 years ]Two-sample T-test with Bonferroni adjustment will be used to compare the increase number of expanded TCR clones after dendritic cell (DC) vaccination with PD-1 blockade in Group A versus (vs) DC vaccination with a placebo in Group B.
3. Incidence of adverse events (AEs) [ Time Frame: Up to 30 days post treatment ]Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who receive any amount of pembrolizumab/placebo or ATL-DC vaccination will be evaluable for toxicity, serious adverse events (SAEs), and events of clinical interest (ECIs).
Secondary Outcome Measures:
1. 6 month progression-free survival (PFS6) [ Time Frame: At 6 months ]Efficacy will be measured by percent PFS6 as defined by Response Assessment in Neuro-Oncology (RANO) criteria. Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Percent PFS6 will be estimated from the KM curves and compared to historical controls.
2. Overall survival (OS) [ Time Frame: Up to 6 years ]OS will be compared using log rank test.?
Other Outcome Measures:
1. Biomarker analysis [ Time Frame: Up to 6 years ]The association between biomarkers and clinical outcomes (PFS and OS) will be evaluated using Cox regression. Changes in markers pre- and post- treatment will be assessed using paired t-tests.
2. TIL (tumor infiltrating lymphocyte) density and TCR (T cell receptor) Clonality in the tumor quantitatively measured by next generation TCR sequencing [Time Frame: from baseline to surgery ]The differences of TIL density and TCR Clonality between the archival tumor (pre-treatment) and protocol tumor (post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.
3. TIL density and TCR Clonality in the peripheral blood quantitatively measured by next generation TCR sequencing [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]The changes of TIL density and TCR Clonality in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in TIL density and TCR Clonality and clinical outcome (PFS and OS) will be evaluated using Cox regression.
4. gene expression signature and somatic mutations in the tumor measured by RNA Seq and nano string IO360 [ Time Frame: from baseline to surgery ]The differences of gene expression signature and somatic mutations between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the cell cycle related gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.
5. gene expression signature from peripheral blood measured by RNA seq and nano string IO360 [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]The changes of gene expression signature in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in gene expression signature and clinical outcome (PFS and OS) will be evaluated using Cox regression.
6. T cell subset and activation markers within peripheral blood measured by flow cytometry [ Time Frame: from baseline to surgery and post surgery treatment period, up to 24 months ]The changes of T cell subset and activation markers in the peripheral blood from samples collected prior to neoadjuvant treatment and samples collected post-neoadjuvant treatment at each MRI visit will be assessed using paired T-test, and the association between the changes in T cell subset/activation markers and clinical outcome (PFS and OS) will be evaluated using Cox regression.
7. TIL quantification including tumor quantification of PD-1, PD-L1, CD3, CD4, CD8, Iba-I, Ki-67 measured by immunohistochemistry of FFPE tissue [ Time Frame: from baseline to surgery ]The differences of PD-1, PD-L1, CD3, CD4, CD8, Iba-I, Ki-67 protein expression level between the archival tumor (collected pre-treatment) and protocol tumor (collected post-neoadjuvant treatment) will be assessed using paired T-test, and the association between the changes in the protein expression level and clinical outcome (PFS and OS) will be evaluated using Cox regression.”
“FDA accepts PFS as one of the 6 tumor cancer endpoints for approval consideration. If you reviewed any of the ASCO clinical data presentations many used PFS. Dismiss it all you want. but PFS is a valid endpoint -- except if you are NWBO and you fail to meet you primary endpoint."
“And NWBO has repeatedly reported that the naive OS data was confounded which raises questions as to the validity of the data It is certainly not "gold standard" when the data is confounded. Don't hear NWBO report that in their TLD presentation did you?? It's just buried on page 16 of their SEC 10K filing.”
09/15/22 5:38 PM
09/15/22 5:38 PM
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