NorthWest Biotherapeutics Inc (NWBO)

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RECIST (that again!?) and ORR, and other Important Thoughts on these Issues.

When considering the recent abstract on Direct that will be the subject of AACR, I think it’s important to consider some of the criteria that’s been under discussion both here and on YMB.

Some posters such as Pyrr, and others that have somewhat agreed with him, are voicing concerns about RECIST, ORR (Overall Response Rate) and how the market and investment funds may view that, given the recent AACR abstract posted last week.

Some of you may even remember back (how can we forget?) to when Adam Feuerstein posted his 10th 2014 bash piece entitled, “Cancer Patients Aren’t Responding to Northwest Bio’s DCVax-Direct” on May 27.

I remember that there had been some very insightful, well researched discussion on that topic at that time so I wanted I just wanted to feature below some of the posts that I found to be valuable, insightful and definitive thoughts posted here on I-Hub from May 27, 2014.

#11537 - Regarding RECIST and ORR

Let’s remember, “RECIST can be used (and is in this case) as a way of to determine (among other methods) whether or not an IND has the potential to show effect in a larger trial when it is used in an early stage trial (such as this one).

In summary, this trial is NOT using ORR as the primary endpoint with RECIST criteria to verify benefit. But even if it WAS, it would still be approved on that basis, if by the end it showed ANY improvement in the disease and quality of life of these terminally ill patients, for whom no therapeutic treatment options are available (and stable disease certainly would be basis to show DCVax-Direct is effective).

To say that 28% shrinkage of tumors, with no adverse side-effects, no dose limiting toxicities, no duration of treatment limitations due to toxicity, an improvement in QoL, probable improvement in PFS, and improvement in immune system functioning, in terminally ill patients with no other therapeutic options and massive 15cm-17cm tumors is in any way a FAILURE is... well, the epitome of ignorance.

If they keep on this track in later stage trials, they'll be approved with flying colors--especially if the far more important endpoints (than ORR) show benefit--namely, PFS and OS. And I think they will.

Of course, we are still early into this trial. Many have only received half of their treatments. None have received all 6 shots. And the RECIST is being confounded by various inflammatory responses to treatment. These will subside with time. We will need a good year behind all of these patients to get an accurate view of things. That's a ways off...

It would be easy to envision a protocol for a future, larger Ph IIb or Ph III trial with PFS as a primary ep, ORR using Choi criteria and OS as secondary endpoints. This Ph I/II is a test for possible effectiveness relative to toxicity (risk-benefit), while taking into account the severity of disease and alternative treatment options (in this case, worst, and none, respectively). So far it's passing with flying colors.”

#11497 - ORR may not be as Important a Measurement - see Choi Criteria

So I don’t think ORR is as important a measurement as some may think at this point. In fact, ”that's why ORR is typically only a surrogate endpoint. This doesn't apply to immunotherapies like DCVax-Direct. For one, the cancer cannot mutate and escape. Full biomarkers and cytokine response remove that tumor-surviving "ability." And two, you do not need to cease treatment due to toxicity, because it is ENDOGENOUS to the host.

[Here’s] An example of how chemo and high RECIST response rates fail:

imr.sagepub.com/content/42/3/737.abstract

You see here an example of an effective chemo that induced a remarkable (60%) RECIST response rate (the sum of complete and partial responses) in 18/30 patients. This occurred in only 21 days. Yet, because it's so toxic, you cannot continue on this therapy very long. You must cease or get deathly ill from the toxic treatment. Well, what happens after you cease this chemo? Of course the cancer comes roaring right back...

The OS rate despite such great ORR for this indication:

Quote:

Overall outlook

Of all those with stomach cancer, about 42 out of every 100 people (42%) will live for at least a year after they are diagnosed. About 19 out of every 100 people (19%) will live for at least 5 years. And about 15 out of every 100 people (15%) will live for at least 10 years.

As with many other types of cancer, the outcome of stomach cancer depends on how advanced it is when it is diagnosed (the stage of your cancer). Most stomach cancers are advanced when they are diagnosed. Only about 20 out of 100 people (20%) are able to have surgery to try to cure their cancer.

from http://www.cancerresearchuk.org/cancer-help/type/stomach-cancer/treatment/statistics-and-outlook-for-stomach-cancer

#11537 - At least 18 months are required to fully vet results.

“Btw, number of patients with tumor response is given an 18 months time frame on clinicaltrials.gov. That means each patient analyzed over an 18 month window for this criteria. Most of those 19 patients with available data are only some 3-6 months into treatment. Given the crescendo ability of immunotherapies, we will likely see a much greater response rate (tumor shrinkage, among other things) the closer to 18 months out for each patient we get. As well as confounded RECIST due to inflammation subsiding.”

I know this has already been said, but to punctuate it once more, the AACR abstract was written and submitted by December 3. By that time, by 8 days prior to submission of this abstract, only 9 people had received their 6th injection. NINE. That means that NO ONE had reached 18 months by December 3. NO ONE.

So if one accepts that it takes at least 18 months to see a greater response, I’d say that showing an immunological response of 62% and a 55% of increasing necrosis with only 9 patients having received their 6th dose is phenomenal. By the time the ASCO abstract was submitted (Feb 2), up to 11 more patients had JUST received their 6th injection. And by the way, ONLY ONE (Allan) had reached 18 months by that time.

See The Follower's chart that he was kind enough to post here:

http://investorshub.advfn.com/boards/read_msg.aspx?message_id=111934296

Still, if by early December, MDA was willing to include 29 patients in their AACR abstract, we should see an even more pronounced improvement in those measures presented in the ASCO abstract.


#11480 - More About Choi Criteria as opposed to RECIST

“A more recently developed standard, called the Choi criteria, appears to better predict survival in a small series of patients than RECIST, said Robert S. Benjamin, M.D., chair of sarcoma medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston, at the ASCO meeting. A good response by the Choi criteria is defined as a 10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced computed tomography (CT) scan.

The benefit of using the Choi criteria was confirmed in a second series of GIST patients, Benjamin reported. By RECIST, 28 (48%) of patients showed response and 30 (52%) were nonresponders. Yet there was no statistical difference in time to progression between the two groups (P = .2). By the Choi criteria, however, 49 (84%) were good responders and 9 (16%) were not. The good responders had a longer time to progression than the poor responders (P = .0002). The Choi criteria also more accurately predicted disease-specific overall survival than the RECIST criteria.

“RECIST did not predict for survival in any way. Choi criteria did,” Benjamin said.

Although the Choi criteria were developed to evaluate GIST patients, Benjamin showed that the criteria potentially have value in other diseases by reanalyzing previously published clinical trial data testing sorafenib in renal cell cancer patients.

“By using 10% rather than 30% as a cutoff for response, the Choi criteria really does allow for a more sensitive assessment,” said Richard Pazdur, M.D., head of the Office of Oncology Drug Products at the FDA's Center for Drug Evaluation and Research. “Also, the criteria aim to rectify the incorrect premise of response rate, as defined by RECIST, that tumor size is directly proportional to the number of tumor cells. … The Choi criteria try to take this into account.”

The Choi Criteria fit the response requirements set forth by David A. Karnofsky in his 1961 paper in Clinical Pharmacology and Therapeutics. It is objective, quantifiable, reproducible, and a surrogate marker for survival. Also, response—or progression—could be detected early and help direct treatment.

“I think we need to start employing multiple modalities” for detecting response, Benjamin said. “Based on CT [scans], the Choi criteria are very effective, but I would add in PET or whatever else you have. If you see evidence of response by any criteria, that trumps nonresponse. And more likely, unless there is evidence that the tumor is growing when you take it out, I would call these patients responders.”

jnci.oxfordjournals.org/content/98/18/1272.full

Again, stopping tumor progression, or regression of ANY KIND is a success for this therapy. In other words, the treatment is already showing all it would need to in order to be approved if they stopped the study today (obviously you need much more data from many more patients for this--but in terms of efficacy that would certainly do it).

Let me further clarify--in the end even a 10% reduction in some 30% of patients over a period of 10 months (8 weeks after final dose) would increase survival and QoL and would get this therapy approved in a larger trial. There is no effective therapy for these patients. The bar is very low.

Immunotherapies continue to work after treatment. Chemos on the other hand do their damage quickly and then must cease from use or kill the patient--and then these tumors nearly always grows back, absent the chemo. Direct retrains your immune system to continue to barrage the tumor and the surrounding area with t-cells, and can be administered continually without toxicological affects. Apples and oranges... Don't think FDA doesn't FULLY understand that.

Btw, it matters how far along a cancer is. LP mentioned some of these tumors being 15cm (massive). Even a strong chemo with proven tumor reduction capability can't touch these behemoths (otherwise these patients wouldn't be terminal, would they?).

It also depends on indication. Some have very few effective therapies that can shrink tumors. Such as liver cancer: http://www.sirweb.org/patients/liver-cancer/

But I don't think other than a few scared after hours traders that hardly anyone would possibly be duped by what he said.

That same day, one of our valued posters said when the subject of RECIST first came up...

#11539 - Let the fearful drop out

Let the fearful drop out while new funds come in and take their shares. There is much validation for NW's tech from their recent release of data. Select hedge funds looking to add will get that, even as some retail investors and day traders don’t.

I'm sure many of you will find those quotes to be quite helpful, as I certainly did. I had never even heard of the criteria called RECIST before Adam brought it up so I appreciated learning that as a criteria for Direct, it may not be the monster Adam purported it to be, but yet another straw man argument by him.

If you were long, and recently sold or considered selling because you feared for the overall success of Direct due to the challenges RECIST might present, please go back to 5/27/14 and read through some of these posts I've featured above.

Interestingly, each and every one of these quotes were voiced by the same person. Can you guess? Yes, it was Pyrr who wrote every one of these insightful, well researched comments on the subject. And for myself, he helped to assuage many of my fears at that time due to his thorough and compelling presentations (as you all have read above).

Should we just...

https://www.youtube.com/watch?v=V3FnpaWQJO0&list=PL3Pnazt6x_6f2Y677i6ASIIqbvFVL2gdv&index=5

these current concerns and stick with the prior premises? And thanks to Pyrr for these very helpful posts.