When to stop immunos

Thanks for posting Eric and Celeste thanks for putting together the blog page. Some thoughts and some questions for the two of you, first the thoughts. Keynote 006 had 811 patients in a three arm trial with two arms pembro (keytruda) with two different schedules of 10mg/kg either two weeks or three weeks. 383 out of the 811 had died by the 2year mark (melanoma just sucks) so we are left with 528 patients. The data that is now being followed from this study is the 103 patients that made it to 2 years on treatment. 28 complete responders, 65 partial responders and 10 stable disease. Now fast forward 2 years from them stopping so 4 years in total and 14 of the 103 showed progressive disease after stopping, around 85% have no progression, great # and of those 8 of the 14 go back on treatment and are doing well. First question is why not include the data on all the 528 that were alive at 2 years and how they are doing as well. Second question is in this study 80.6 % of patients were Pd-L1 positive and I know it is not a great biomarker but patients with positive Pd-L1 staining do better on different immunotherapy trials than Pd-L1 negative patients. Third question is why not look at more patients than 103, there are now thousands of melanoma patients that have had nivo or pembro, I would think that there would be some way to share the survival data and how long they were on treatment. Last thought is checkmate 067, 4 year survival data was published at ESMO and if my memory is working 52% of the combination of ipi+ nivo and 48% of the nivo monotherapy patients are alive at 4 years, each arm had 315 patients at the start. I think I am reaching the rambling point now so I will stop, but one last thought about socialized medicine and how it makes stopping a more difficult choice. In Canada, it has been great to get access to trials like checkmate 067, it saved my life. I have been having conversations lately about stopping Nivo with my Oncologist but the sticking point is that I don't know if I stop and then progress if I will be offered any treatments or access to nivo again!!! Coming up on 5 years of treatments every two weeks and as much fun as that sounds, stopping is starting to sound like the right move!!! Best Wishes!!! From a tired little Canadian mouse.

Hello my tired, brave, awesome mouseketeer!!!  All good points…that honestly….I don't have good answers to.  I am not in Weber's head…but I suspect that he reviewed many more studies than Keynote 006…given how he put that sentence…but used it as the prime example.  The sad other point (I was trying to be my "BUBBLY" self in my post) is that the plan for stopping and the data he was describing regarding that decision was dealing ONLY with the peeps who had a complete, partial, or LONG TERM (and I think you may well be in this group!!!) stable response to immunotherapy.  Unfortunately, we know that somewhere between 30-40% of peeps don't get there.  So this rationale, and data that supports stopping with good outcomes, applies only to those who responded well to their immunotherapy treatment.

Looking back on trials like this, in order to draw meaningful and super important conclusions, that affect life and death decisions for mice and ratties, proves the necessity of good, common sense, CONSISTENT trial design.  We cannot attain meaningful data for all with:  Trials that compare the latest and greatest new treatment to treatments we KNOW do NOT WORK (like dacarbazine in melanoma).  Trials that do NOT include wide swaths of peeps (as so many melanoma trials did…and some continue to do….excluding folks with CNS disease, mucosal mel, etc).  Trials that do NOT follow patients the requisite years in order to determine what really happened to those peeps who participated.  Trial design and the SHARING OF THE INFO between researchers matters!!  And that SHARING should start from design forward. 

And finally, I hear you.  When I completed the 2 1/2 years of nivo that my trial dictated, I asked Weber (this was June of 2013) what he would recommend should I recur.  He told me then that he would suggest I repeat nivo.  Luckily, I have not been faced with that.  However, I always wondered how I would get it if I needed it.  Would my insurance company pay for it?  I imagined they could argue, "No, man.  You already did that and now you're back to melanoma.  Clearly, that's not for you."  Trials I looked at for others, that offered anti-PD-1 in some form, often excluded those who had been administered anti-PD-1 already.  Now….we've come a long way since then.  And internationally respected melanoma researchers like Weber coming out with these statements in this way, helps us ratties make the argument for additional immuunotherapy to the powers that be, should we recur and need to dip back into these treatments again.  That's not a guarantee….but it is more than we have had in the recent past.

Probably doesn't help you much.  But, that's what I've got.  Love you bunches!  – c

 

This other bit by Weber may help you and others trying to graple with this further:

https://www.facebook.com/OncLive/videos/vb.132307776836828/343580312872591/?type=2&theater  

Here Weber speaks further on the topic of stopping immunotherapy based on scan results – saying:

"[…for melanoma patients on immunotherapy at one year] who then had a PET/CT scan or PET/CT scan and biopsy – those who were metabolically or histologically negative and stopped at one year – even if they didn't have a complete response by CT scanning – did very well and had a 90% plus chance of remaining in remission.  So, what that does for me is, in melanoma – I would feel comfortable treating for no less than one year, no more than two years, and at one year, if a patient has had a stable response or has been stable over at least 2 scans – I would be very comfortable telling them to get a PET/CT scan and if there's complete metabolic regression on the PET, no matter what you see anatomically on the CT – I would say you can safely stop.  I might say – Oh, we'll go one more cycle and then stop.  And in those patients, I think they can be safely observed, knowing their likelihood of relapse is really low."

Again, while this whole ta dah is of limited usefulness to melanoma patients who do not gain a complete response, partial response, or lasting stable disease on immunotherapy – for those who do – this is at least a beginning of a road map showing how to proceed.  Hope this helps.  Love to all.  c

Celeste,

Saw this article after reading your response to Ed.  Little different angle but you aren't the only one who thinks we need to be doing better with trial design and analysis.  Makes me nervous though when I hear Dr. Luke say we are moving too fast.  Putting the brakes on isn't the answer IMO.  They just need to do better job in the areas you talked about in your post.

forgot article.

https://www.nature.com/articles/d41586-018-07445-3

Interesting read.  I'm with you.  I'm not about a slow down.  I'm about intelligence, organization, integrity, and yes…rigor is a good word!  Researchers can adopt those principles, share data, and move forward…ALL AT THE SAME TIME!!!  Another critical issue is making sure that the pharmaceutical company making the drug has a very clear and noted role in studies.  I get so tired of seeing folks new to melanoma getting all excited about a "new" drug (or lab test) that is amazing in melanoma patients, but the only data to be found is either from the company itself or an investment analysis.  

Oh well, if we ran the world!  Meanwhile, we'll just keep yelling!  c

Hi Ed! We too are in Canada and I have some of the same questions about the future. My husband Chris got his tage 4 diagnosis Jan 29 2018 after having a siezure cause by what we found out to be a brain met. PET scan revealed Mets in many more places. He was given 5 rounds of whole brain radiation (Feb 2018) in an attempt to control the big brain met and break the blood brain barrier to allow for the immunotherapy meds to get in there and do some work. We were signed up to the Access to hope program in which BMS would supply us with the Ipi/Nivo combo for 24 consecutive months from treatment initiation in March 2018. He received 2 doses of the combo but had a met in his intestine that was causing an intussusception and they were worried that the Ipi would thin his intestine to the point of breaking and cause a real mess. Between April and July he had quite a few long term hospital stays and had the palliative people bombarding us but he continued with Nivo maintenance on schedule. He had his last dose July 6th and his oncologist said his body needed a break. We did see the tumors shrinking at this point. In August it appeared his immune system went in to overdrive and he was in the hospital again unable to breathe or eat and hallucinating. He came out of it and on his next scans things looked even better. His October scans came back essentially NED. He has some clusters in his chest and abdomen that are likely lymph nodes, whether or not they are holding cancer we won’t know until his next PET scan. So treatment has stopped since July and now we know that the treatment works but the decision has been made to stop until there is progression. If that progression happens in our 2 year window we are covered but what if he makes it past then? Nobody knows. His oncologist likes to take things one step at a time. My understanding is that BMS is funding this in Canada in hopes that the data will show the fact that this is viable treatment and will cover it with pharmacare. So here we are 11 months after he was told he had 9 months to live, trying to catch our bearings on a world spinning too fast.
Next my Husband tells me to ask you “when does he start to feel better?”. He says he feels like a 90 year old man (He is 34). His joints ache to a level that completely debilitates his mobility. He is exhausted and sleeps but never for long periods of time. No apatite. Headache. The list goes on. Is there any wisdom you can impart?

Hi there, just came across your post and you sure have had an adventure. I have only had nivo so hard to compare the side effects that those that have had the combination of Ipi+nivo. Fatigue is my friend and has been with me at all times in this journey, now was it caused by SRS radiation to the brain or nivo or stress of treatments or combination of the three, kind of hard to tell but it is real!!! So joint pain go hand in hand for many, I know that arthrotec anti inflamatory NSAID drug has been helpful for me taken daily. I am glad to here that the treatment has worked that is half the battle. Best Wishes!!!Ed

Thanks for the post Eric and Celeste.  Special thanks to you Celeste for summing it up in your blog.  I hope the fact you put the summary together is an indication you feeling well and not entirely due to the other fact that you are Wonder Woman.

Brian

I am in cruising mode!  Ha!  Neither well nor Wonder Woman!  I am at the start of week 3, of my second (of 4) 3 week cycle of chemo.  The first week is the roughest….knocking me out 5 days the first round and 9 this last.  I "begin again" a week from today.  So, we'll see what happens then!  Thanks for the warm wishes!  They help!  Hope you and yours are well and Flo didn't cause you and your neighbors too much harm.  Love, c