Weber and Sznol chat about ipi and anti-PD1

Immunotherapies
Interview by Jeffrey Weber, MD, PhD (Moffitt Cancer Center, Tampa, Florida) of Mario Sznol, MD (Yale Cancer Center, New Haven, Conneticut).  Published October 31, 2012:  Medscape.

Annotated but direct quotes:

Sznol:  The most important data from the abstracts relate to long-term survival with ipilimumab....  Those studies have consistently shown a flattening of the curves at 3 years. So, the survival at 3 years, at 4 years, and at 5 years is very similar, suggesting that you are getting long-term durable responses in these patients.

Weber:  It sounds like we could possibly even use the phrase functional cure for some of these patients. Do you think that is realistic possibility?

Sznol:  ...for our own patients and for some of the patients treated in the phase 2 trials, we have had follow-up going beyond 5, 6, or 7 years that shows no evidence of relapse.  You can actually start using the word cure for some of these patients.  Of course, one never knows whether they might relapse at 10 or 15 years, but still, 8 to 10 years without any evidence of progression would functionally translate into cure.

Weber:  Michele Del Vecchio [reported] a significant number of patients who received reinduction therapy.  We don't have a lot of data about the outcome for those patients, but what do we see here?

Sznol:  ...their data is impressive and are consistent with data that were presented by...Hodi.  [Patients with an initial response to ipi...stable disease or some evidence of clinical regression....were allowed to receive another 4 induction doses of ipi if they had disease relapse or progression after 24 weeks.]  It really suggests and it has actually been true in our own anecdotal experience that patients who have an initial response to ipilimumab or prolonged stable disease followed by disease progression can get additional benefit from another 4 doses of treatment.

Weber:  Let's talk about that PD-1 abstract [by Sosman].

Sznol: ....This is probably the most active melanoma drug we have ever administered and one of the best tolerated.... The overall response rates went up a bit since the ASCO presentation and are now around 31%.  The durability of these responses are impressive.  When I looked at the data recently, I believe they showed that 70% of the patients still have ongoing responses, and several of these patients have responses out beyond 2 years.....This is probably the best drug that we have for melanoma.  I myself have treated 16 patients in that trial with metastatic melanoma; 5 of those patients have near-complete responses, and none of them have relapsed.  One patient is now at 4 years without progression....

Weber:  Data I presented at ESMO suggest that it may be useful to sequence PD-1 and ipi.... People who fail to rspond to PD-1, which is still 70% of patients given the drug, up-regulate CTLA-4 on the CD4 and CD8 cells; this suggests that if you are given PD-1 first and do not respond, you might subsequently respond to ipilimumab.  That might push the response rate up to very high level indeed.

Sznol:  Your data actually provide a strong rationale for combining these agents; that is based on important clinical correlative data.... Even if you sequence them, because of the long half-life of the antibodies, you may well see more autoimmune toxicity.  The question is whether that toxicity will be manageable, whether the risk-benefit ratio will be acceptable.  But my own guess is that this will be a more active combination and I believe the toxicities will be acceptable and manageable.

My take:

Brent was very sad that my first comment was:  70% of people with melanoma are still totally F%#K@$!!!!!!

This is the first time I have ever heard the word "cure" come out of the mouths of these babes!!!

A 10 year "CURE" is only awesome when you are a melanoma patient.

FIVE of SIXTEEN???????????!!!!!!!!

Go Alan K!!!!  I know your numbers are represented here.  Keep on keeping on!!!!

Yeah, buddy.  Bout to go get some more bug juice and have currently been experiencing skin flares like nobody's business for the past couple of weeks.  But, compared to dead.....bring it on.

I am lucky smart guys keep working on these things.

I am glad I have a SUPER smart guy in my corner.  Thanks Bent.

Best to all. - c