Cancer compass review - PD-1 inhibitors

The following is what was said on the Cancer Compass cocktail thread about PD-1 inhibitors:

page 128:
A: "He mentioned Nivolumab, a PD-1 inhibitor, and essentially said that it would be possible to pay for it out of pocket. My girlfriend doesn't weigh much at this point, and he said paying for 3 administrations of the drug would probably be about $12,000 total. He said that, if he were choosing between Rindopepimut and Nivolumab, he would go for the Nivolumab."


A: "The Nivolumab idea has the potential to be a pretty effective addition at a rather reasonable cost (at least I consider 12k to be reasonable after getting quotes of 150k from the likes of DCVax and such). I'm going to be looking into it a lot now.

He essentially said that he was at a meeting where they were discussing very preliminary results of a study testing a PD-1 inhibitor vs. avastin in recurrent tumors. They were talking about how they were able to radiographically see increased inflammation from an immune response after the administration of a PD-1 inhibitor in a subset of the patients. This included some stable tumors and one that showed some regression."

SW: "I came across an interesting study showing that response to PD-1 inhibitors is correlated with mutational load. The study shows a graph which correlates response rate in various types of cancers to the median frequency of somatic mutations in those types of cancers. For example, melanoma has the highest response rate to PD-1 inhibitors, and also has the highest median number of somatic mutations.

Hypermutated tumors may have a better chance of response to these drugs, at least as single agents. Recurrent tumors previously treated with single agent TMZ are more likely to be hypermutated upon recurrence, but the only way to know if a tumor is hypermutated is with comprehensive genetic testing like FoundationOne. If there are a large number of mutations, plus a mutation in a DNA mismatch repair gene like MSH6, that would suggest a hypermutated tumor.

This is not to say that only hypermutated tumors would benefit from PD-1 inhibitors or CTLA-4 inhibitors, just that they might especially benefit.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937193/

In most cases newly diagnosed tumors won't be hypermutated. Mutations in mismatch repair genes (like MSH6) can be a resistance mechanism following single agent TMZ."

page 134:

A: "I've been doing some research, and some of the upcoming trials are combining Nivolumab with Ipilimumab (Opdivo and Yervoy). This is a PD-1 inhibitor combined with a CTLA-4 inhibitor. The toxicity seems rather large, with something like 50% of patients experiencing grades 3 and 4 adverse events. In melanoma, however, this combination has been very effective.

In mouse studies with glioblastoma, the results of combination PD-1 and CTLA-4 inhibition seems very promising.

What are your thoughts on this combination following 6 adjuvant chemo cycles? In theory, residual tumor burden would be low, and the cells that survived initial treatment might already be expressing a larger number of mutations.

Our NO is the one that initially suggested Nivolumab, which has a lower toxicity profile than Ipilimumab, so I'm not sure that he would even go for the combination. I've priced out 4 doses of the combination, which would be about $44,000. 4 doses of Nivolumab alone would be $16,000."

DS: "Dr. Conrad at MD Anderson (though he recently left MDA) told us that the Nivolumab with Ipilimumab trial had dropped the ipilimumab because it was too toxic and he signed my son up for the Nivolumab alone -- all the ipilimumab portions of the trial documentation were stricken through. We opted not to do the trial as it turned out."

A: "Thank you for that information! I'm surprised they dropped it, as they are combining the two for the treatment of advanced melanoma, and showing a lot of success.

They do note that the toxicity profile is high, but I wonder why they are OK with treating melanoma patients with that protocol and not GBM patients. I now see that the trial is being offered at UVA, so I'm guessing that is how our NO was able to hear preliminary information about some responses."

M: "from what i could determine about the nivo/ipi trial for gbm versus melanoma is this; the mechanism of action causes swelling. greater tumor burden correlates to greater swelling. there is no room for swelling in the brain as opposed to other organs of the body. melanoma patients may tolerate swelling whereas gbm patients would have to go on massive doses of steroids (which might not even help) and that would negate the workings of the immunotherapy."



Download the poster from the 2015 ASCO conference showing the first preliminary results of GBM patients treated with nivolumab alone or nivolumab plus ipilimumab (Yervoy).  Download here.