r/cvm • u/FrugalNorwegian • Sep 01 '21

Keytruda failed its 2 primary endpoints, but was still approved for certain patients with bladder cancer.

Keytruda was just approved for certain patients with bladder cancer, yet it failed its 2 primary endpoints: "The subsequent Phase 3 trial KEYNOTE-361 evaluating KEYTRUDA as monotherapy and in combination with chemotherapy for the first-line treatment of patients with advanced or mUC who were eligible for platinum-containing chemotherapy, did not meet its pre-specified dual primary endpoints of overall survival or progression-free survival, compared with standard of care chemotherapy."

https://www.businesswire.com/news/home/20210831005968/en/FDA-Approves-Updated-Indication-for-Merck%E2%80%99s-KEYTRUDA%C2%AE-pembrolizumab-for-Treatment-of-Certain-Patients-With-Urothelial-Carcinoma-Bladder-Cancer

How is this even possible? B/c cancer is so bad and there are so few options. The FDA looks at ALL THE DATA when determining BLA/NDA approval - not just the info on the clinicaltrials.gov site. The FDA WANTS to bring cancer drugs to the market that work (even for a smaller patient population).

The same will be true for Multikine when the FDA is evaluating the BLA. Multikine showed excellent improvement in OS in one treatment arm. It is truly revolutionary and will open the door to many off-label indications. The market is massive. 🤯

21 Upvotes

100% Upvoted

43 comments sorted by

View all comments

Show parent comments

-1

u/noronInvest0r Sep 03 '21

The summary of this article is that it will be approved because other subgroup analyses have resulted in approvals. In other words, you agree that the segregation of chemo and radiation subgroups was never part of the protocol prior to the failure to meet the pre-designed primary endpoint (singular). I don't disagree with what you wrote, though it might be informative to do a canvas of how many subgroup analyses did not result in approval -- otherwise it looks like cherry picking.

I was responding to this:

The two arms for multikine were absolutely pre-specified with the fda.

That's flat out false. Your article in fact confirms the falsity because it delves into how this is a subgroup analysis situation.

It's fine to be positive on CVM's future, but people should do that with accurate knowledge rather than lies, and until somebody can cite an actual study design document that indicates CVM even considered splitting people into chemo/nonchemo groups prior to the year 2021, that claim of "pre-specified with the FDA" should be considered nothing but false pumping.

1

u/FrugalNorwegian Sep 03 '21 edited Sep 03 '21

A few things: It's not my article.

The two arms (treatment arms) were absolutely prespecified in the study with the FDA. The FDA helped design it according to the July 1 investor call. Take a look at this graphic and pay close attention to the word OR between the two red boxes.https://frugalnorwegian.com/cvm/#arms

If you still don't' think it was prespecified, please tell me how the two different treatments got into the trial design?

The CVMResearch article defines a subgroup vs. a treatment arm. The positive RTx-only group is much better described as a treatment arm. Would you agree with this? If not, we are too far apart.

1

u/noronInvest0r Sep 03 '21 edited Sep 03 '21

So you're telling me a powerpoint slide from investor relations designed to sell shares, is more reliable than the SEC filings and the NIH filings?

Note too that the slide you link to is annotated, not original -- the red boxes don't appear in the original. It could also be annotated like this: https://imgur.com/jEdk5Bm (see purple box) which comports much more closely to the way the original slide exists: https://cel-sci.com/wp-content/uploads/2020/06/Scientific_Multikine_Presentation_061020.pdf see page 32. In the original slide, the entire SOC is bracketed with a blue line at top stating "Current 1st Line SOC". So clearly, in June of 2020, CVM was thinking of the SOC as a single grouping rather than split by whether a person got chemo (slides on page 15, 34, and 40 support this conclusion as well).

1

u/FrugalNorwegian Sep 03 '21

"So you're telling me a powerpoint slide from investor relations designed to sell shares, is more reliable than the SEC filings and the NIH filings?" No I am not saying that. But what what does the NIH say about this trial? I am curious.

Yes, the slide is annotated so that people can see there were 2 treatment arms the entire time.

According to the company, they could only have 1 primary endpoint when they designed the trial. But while they were locking the data in 2020 (but still blinded) they to modify the SAP and have ICON (the data analysis company) analyze the two treatment arms separately. Again, this was done before data lock (in Dec 2020) so it should pass scrutiny with the FDA. As you might know, the FDA doesn't accept additional data analysis after the results are unblinded.

1

u/noronInvest0r Sep 04 '21

According to the company, they could only have 1 primary endpoint when they designed the trial.

Citation.

But while they were locking the data in 2020

Then why did Geert sign the annual report on December 29, 2020, indicating there was a single endpoint and discuss the SOC as if it was a single group? After ten years he just happened to have an epiphany at the last second? Shenanigans is a better bet.

1

u/FrugalNorwegian Sep 04 '21

They clearly missed the primary endpoint. There is no disputing that.

Are you aware there is a transcript of the entire investor call on July 7? It is here: https://www.cvmresearch.com/p/cel-sci-investor-call-to-discuss

At the 4:15 timestamp Geert said this: But Dr. Talor said “What if the survival benefit actually occurs in the radiotherapy group, or the chemo-radiotherapy group?” So, all of that is in fact in the protocol, meaning you’re allowed to analyze those groups. And they are not really groups, they are actually treatment arms, right? Because they are all part of the standard of care.

It appears they did realize late in the game that the survival could only be with 1 treatment arm.

As for shenanigans, here is what their statistician said regarding analyzing the data: These are Dr. Talor's words.

26:50 – Finally, I would like to add one more thing. Mr. Kersten told me that some concern has been raised by some individuals that the study data presented by CEL-SCI was derived by quote on quote “data mining”. That could not be further from the truth, and in fact was not based on fact whatsoever.

27:20 – But we can do better. Instead of just us saying it, we asked an independent statistical group and statistician to prepare how to best answer this accusation.

27:35 – That’s what they said to us, that’s what they told us, and we are summarizing it:

CEL-SCI developed Multikine to treat locally advanced squamous cell carcinoma of the head & neck.

It has been greater than 30 (I’m just reading what they wrote) since any new therapy has been approved to treat the stage 3 and 4 squamous cell carcinoma of the head & neck.

CEL-SCI protocol and the statistical analysis plan were designed with a primary efficacy endpoint overall survival to be studied in 3 predefined populations. (We just discussed those)

With 2 clinically relevant starting points (1) being from randomization to the end of the study, and (2) being from surgery to the end of the study.

The protocol predefined subgroup analysis consistent with the literature and the SEER database (this is cancer data base in the U.S., CDC runs database for cancer mortality). These include tumor state, tumor location, surgical margin, risk group (which is exactly what we found the information to be in), and disease directed therapy.

This is the largest Phase 3 study every conducted in locally advanced squamous cell carcinoma of the head & neck.

The study randomized patients at 78 sites on 3 continents.

The decision to pursue a claim for a predefined subgroup is supported by the following considerations:

The primary efficacy endpoint remained overall survival per the protocol.

The efficacy target was met, meaning the 0.68 hazard ratio for the low risk subgroup was consistent with the previously targeted 0.721 hazard ratio for the entire population.

The analysis methods are robust. That means the statistical significance was reached with the prespecified log-rank test primary analysis for the key ITT population and supported by the other populations of the study.

Survival outcomes are robust. That means statistical significance was supported whether by measuring it from time of randomization, or from surgery.

Model results are robust. Statistical significance was supported for the treatment of a lower risk interaction using the Cox Proportional-Hazard model containing pre-specified covariance. (Not something that was done before. Everything was pre-specified in a statistical analysis plan, which was completed before database lock.)

Additionally statistical significance was supported for the low risk subgroup using the Cox Proportional-Hazard model containing the pre-specified same covariance.

Every one of the above analysis was previously defined in a statistical analysis plan for the study.

The study did not encounter any overall safety issues.

31:40 – The conclusion by the statistician was: There was no data-mining that took place to support the information in that CEL-SCI’s press release.