Checkpoint Inhibitor Combination Strategies

Celeste– thanks for sharing this experience.  This is the boat I think I may be in.  Nearing two years on the Ipi-Nivo combo, and amid  all the good news (stable and shrinking tumors) up pipes something in the lungs that can either be a) melanomia b) pneumonitis or c) an accumulation of immuno-cells (gunk).  The Drs. opted to cancel a treatment and have an unscheduled CT scan in 4 weeks.   I  was surprised it wasn't treated as a reaction (I suppose they didn't want to dampen the ongoing beneficial reaction to the drug?). I'm hoping it just goes away– like yours.  Curious as to how long it took for your body to get on top of the adverse reaction?

Thanks

Celeste– thanks for sharing this experience.  This is the boat I think I may be in.  Nearing two years on the Ipi-Nivo combo, and amid  all the good news (stable and shrinking tumors) up pipes something in the lungs that can either be a) melanomia b) pneumonitis or c) an accumulation of immuno-cells (gunk).  The Drs. opted to cancel a treatment and have an unscheduled CT scan in 4 weeks.   I  was surprised it wasn't treated as a reaction (I suppose they didn't want to dampen the ongoing beneficial reaction to the drug?). I'm hoping it just goes away– like yours.  Curious as to how long it took for your body to get on top of the adverse reaction?

Thanks

Celeste– thanks for sharing this experience.  This is the boat I think I may be in.  Nearing two years on the Ipi-Nivo combo, and amid  all the good news (stable and shrinking tumors) up pipes something in the lungs that can either be a) melanomia b) pneumonitis or c) an accumulation of immuno-cells (gunk).  The Drs. opted to cancel a treatment and have an unscheduled CT scan in 4 weeks.   I  was surprised it wasn't treated as a reaction (I suppose they didn't want to dampen the ongoing beneficial reaction to the drug?). I'm hoping it just goes away– like yours.  Curious as to how long it took for your body to get on top of the adverse reaction?

Thanks

G-Sama,

When I was first diagnosed as Stage IV in 2010, the source of that diagnosis had been sitting in my lungs for more than 6 months, unchanged.  It was an plug of gunk sitting IN my bronchus (a tube) of my right lung….not spots within the lung tissue itself…a more common presentation of melanoma lung mets. Given my condition as a known asthmatic…the bronchoscopy that told the tale was put off to see if it was just gunk that asthmatics occasionally collect.  At any rate, a bronch and pathology on a piece of the gunk proved it was melanoma afterall.  So….

I am not sure what your CT is looking like, but….  Pneumonitis, basically a diffuse inflammatory process, is usually a very vague sort of haziness…most classically described as a "ground glass appearance" throughout at least some portion of the lung tissue itself.  Obviously, the more of the lung involved – the more serious the condition, symptoms and risk, as lung tissue that is affected that way does not work very well.

Here is an excerpt of a post I made when I reviewed the side effects I had with Nivo and when they occurred:

Dose 7 = 3/25/2011
   My scans at the 3 Month evaluation showed "ground glass appearance" in the right lower lobe of my lung.  I was also having wheezing at the time.  Scans were reviewed by the tumor board at Moffitt and determined to be related to my asthma or an inflammatory process that Weber had seen before in patients on ipi.  Wheezing gradually improved on albuterol and inhaled corticosteroid; symbicort. Perhaps most importantly, the 3mm something???? in my brain on my MRI when I started is GONE!

For that whole (have to say…rather long and boring) post where I reviewed my symptoms and when they started and ended here's the link:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabmy-story.html

You have to keep in mind, of course that I was only taking nivo.  The anti-PD1 products tend to produce fewer and less detrimental side effects than ipi alone.  However, you can see that Weber acknowledged seeing pneumonitis that looked much like mine did in his ipi patients.  Obviously, (Weber and Ribas addressed this in their "chat"…see blog post on 6/13/14) while results are better than anti-PD1 alone when it is combined with ipi…the side effect profile is much increased and causes patients much more concern.  Still, now that providers know what these drugs can do, they are much more aware and vigilent when the patients demonstrates the beginning signs of any of them….therefore fewer patients die and all suffer less.

Here's a break down of the side effects of nivo in particular…but immunotherapy in general and why it happens:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumab.html

Here is a short synopsis of the side effects I knew of in my cohort at the time:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabfinal-thoughts.html

As more and more patients have been given ipi…more than just the classic side effects have been noted…here are a couple of articles that speak to that…but you will also see that docs are better able to deal with these things now because they learned to watch for them!!!  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/03/melanoma-patients-teach-us-more-about.html

I hope this helps and I wish you my best and prompt resolution of whatever is in your lung!!!  Yours, C

G-Sama,

When I was first diagnosed as Stage IV in 2010, the source of that diagnosis had been sitting in my lungs for more than 6 months, unchanged.  It was an plug of gunk sitting IN my bronchus (a tube) of my right lung….not spots within the lung tissue itself…a more common presentation of melanoma lung mets. Given my condition as a known asthmatic…the bronchoscopy that told the tale was put off to see if it was just gunk that asthmatics occasionally collect.  At any rate, a bronch and pathology on a piece of the gunk proved it was melanoma afterall.  So….

I am not sure what your CT is looking like, but….  Pneumonitis, basically a diffuse inflammatory process, is usually a very vague sort of haziness…most classically described as a "ground glass appearance" throughout at least some portion of the lung tissue itself.  Obviously, the more of the lung involved – the more serious the condition, symptoms and risk, as lung tissue that is affected that way does not work very well.

Here is an excerpt of a post I made when I reviewed the side effects I had with Nivo and when they occurred:

Dose 7 = 3/25/2011
   My scans at the 3 Month evaluation showed "ground glass appearance" in the right lower lobe of my lung.  I was also having wheezing at the time.  Scans were reviewed by the tumor board at Moffitt and determined to be related to my asthma or an inflammatory process that Weber had seen before in patients on ipi.  Wheezing gradually improved on albuterol and inhaled corticosteroid; symbicort. Perhaps most importantly, the 3mm something???? in my brain on my MRI when I started is GONE!

For that whole (have to say…rather long and boring) post where I reviewed my symptoms and when they started and ended here's the link:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabmy-story.html

You have to keep in mind, of course that I was only taking nivo.  The anti-PD1 products tend to produce fewer and less detrimental side effects than ipi alone.  However, you can see that Weber acknowledged seeing pneumonitis that looked much like mine did in his ipi patients.  Obviously, (Weber and Ribas addressed this in their "chat"…see blog post on 6/13/14) while results are better than anti-PD1 alone when it is combined with ipi…the side effect profile is much increased and causes patients much more concern.  Still, now that providers know what these drugs can do, they are much more aware and vigilent when the patients demonstrates the beginning signs of any of them….therefore fewer patients die and all suffer less.

Here's a break down of the side effects of nivo in particular…but immunotherapy in general and why it happens:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumab.html

Here is a short synopsis of the side effects I knew of in my cohort at the time:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabfinal-thoughts.html

As more and more patients have been given ipi…more than just the classic side effects have been noted…here are a couple of articles that speak to that…but you will also see that docs are better able to deal with these things now because they learned to watch for them!!!  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/03/melanoma-patients-teach-us-more-about.html

I hope this helps and I wish you my best and prompt resolution of whatever is in your lung!!!  Yours, C

G-Sama,

When I was first diagnosed as Stage IV in 2010, the source of that diagnosis had been sitting in my lungs for more than 6 months, unchanged.  It was an plug of gunk sitting IN my bronchus (a tube) of my right lung….not spots within the lung tissue itself…a more common presentation of melanoma lung mets. Given my condition as a known asthmatic…the bronchoscopy that told the tale was put off to see if it was just gunk that asthmatics occasionally collect.  At any rate, a bronch and pathology on a piece of the gunk proved it was melanoma afterall.  So….

I am not sure what your CT is looking like, but….  Pneumonitis, basically a diffuse inflammatory process, is usually a very vague sort of haziness…most classically described as a "ground glass appearance" throughout at least some portion of the lung tissue itself.  Obviously, the more of the lung involved – the more serious the condition, symptoms and risk, as lung tissue that is affected that way does not work very well.

Here is an excerpt of a post I made when I reviewed the side effects I had with Nivo and when they occurred:

Dose 7 = 3/25/2011
   My scans at the 3 Month evaluation showed "ground glass appearance" in the right lower lobe of my lung.  I was also having wheezing at the time.  Scans were reviewed by the tumor board at Moffitt and determined to be related to my asthma or an inflammatory process that Weber had seen before in patients on ipi.  Wheezing gradually improved on albuterol and inhaled corticosteroid; symbicort. Perhaps most importantly, the 3mm something???? in my brain on my MRI when I started is GONE!

For that whole (have to say…rather long and boring) post where I reviewed my symptoms and when they started and ended here's the link:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabmy-story.html

You have to keep in mind, of course that I was only taking nivo.  The anti-PD1 products tend to produce fewer and less detrimental side effects than ipi alone.  However, you can see that Weber acknowledged seeing pneumonitis that looked much like mine did in his ipi patients.  Obviously, (Weber and Ribas addressed this in their "chat"…see blog post on 6/13/14) while results are better than anti-PD1 alone when it is combined with ipi…the side effect profile is much increased and causes patients much more concern.  Still, now that providers know what these drugs can do, they are much more aware and vigilent when the patients demonstrates the beginning signs of any of them….therefore fewer patients die and all suffer less.

Here's a break down of the side effects of nivo in particular…but immunotherapy in general and why it happens:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumab.html

Here is a short synopsis of the side effects I knew of in my cohort at the time:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2013/10/side-effects-of-nivolumabfinal-thoughts.html

As more and more patients have been given ipi…more than just the classic side effects have been noted…here are a couple of articles that speak to that…but you will also see that docs are better able to deal with these things now because they learned to watch for them!!!  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/03/melanoma-patients-teach-us-more-about.html

I hope this helps and I wish you my best and prompt resolution of whatever is in your lung!!!  Yours, C

Joe, I will try to answer one of the 20 questions. I am on the BMS trial of Nivolumab and Ipi monotherapy or both together. The PD-1 drug (Nivolumab) schedule is every two weeks for 2 years. There are three arms to the trial with 2 arms having the PD-1 drug. The literature that I read from Dr. Ribas(UCLA) suggested that PD-1 drugs tend to work as show results on Ct- scans as early as 8 weeks. The trial scaned at 12 weeks and I was lucky enough to be a responder with reduction to my 2 lung mets.  Dr. Ribas also talks about the fact that patients in earlier Pd-1 trials continue to respond even after treatments stop. I find it very interesting that the big names in Melanoma still describe what is happening in the field of immunotherapy as, we think that this or that is going on. I really like watching presentations from  Dr. Charles Drake ( mouse research guy), I think he is at John Hopkin's. He gets into the mouse research side of things and is very good at explaining what the research field is doing in immunotherapy. My thinking for Pd-1 schedule once approved for Nivolumab will be every two weeks for two years unless the Melanoma progresses. My thinking on this is that the phase 3 trial which has 1000 patients in it is using this protocal. The $ crunchers could shorten this time frame. Ed

My Drs may be overly optimistic–but there is believe out there that immuno-therapy, particularly when it involves the Ipi/pd1 combo contributes to the long term memory of the body– and that once the immune system has picked up the scent and is responding it will continue to fight the Mel.  When I expressed fear of being turned out onto the ice at the end of the trial it was metaphorically described: if we give you more after this it's like turning the ignition with your engine already running.   ( it may be what they tell all old Eskimos) 

Yeah, I hear the same things from my doctors, always qualified with, "but we just don't know for sure or for how long."  It would make sense, even given my limited knowledge of the immune system, that there is a memory built as part of the adaptive immune system — there are "memory T-cells" that are supposed to serve this purpose, with the question being do these immunotherapies, be they ipi, PD-1, or TIL, have an effect on the memory T-cells.  My medical oncologist also likes to remind me that my immune system has already been "primed", with the implication that multiple immunotherapies should theoretically have a cumulative affect.  Again, it makes sense when you consider that the combination trials are looking at both parallel and sequential uses of multiple agents.  So when I had ipi in 2013, the thinking was that since I'd already had IL-2 in 2010 and TIL in 2011, that ipi would be that much more effective having already seen these two previous therapies.

I do find it interesting the difference in ipi and PD-1 as far as the dosing schedule.  I don't know what protocol the ipi trials followed as far as number of doses, and I don't know how they arrived at 4 for the standard treatment regimen.  I know there is an option for one or more "maintenance doses" every twelve weeks after finishing the course of 4, but my understanding is that the insurance companies often balk at the maintenance doses.  There may be studies that show that the maintenance doses don't influence OS, PFS, or whatever metric they want to use.  So Ed, yes, the bureaucrats may unfortunately end up playing a role in dosing protocol.

Joe

Yeah, I hear the same things from my doctors, always qualified with, "but we just don't know for sure or for how long."  It would make sense, even given my limited knowledge of the immune system, that there is a memory built as part of the adaptive immune system — there are "memory T-cells" that are supposed to serve this purpose, with the question being do these immunotherapies, be they ipi, PD-1, or TIL, have an effect on the memory T-cells.  My medical oncologist also likes to remind me that my immune system has already been "primed", with the implication that multiple immunotherapies should theoretically have a cumulative affect.  Again, it makes sense when you consider that the combination trials are looking at both parallel and sequential uses of multiple agents.  So when I had ipi in 2013, the thinking was that since I'd already had IL-2 in 2010 and TIL in 2011, that ipi would be that much more effective having already seen these two previous therapies.

I do find it interesting the difference in ipi and PD-1 as far as the dosing schedule.  I don't know what protocol the ipi trials followed as far as number of doses, and I don't know how they arrived at 4 for the standard treatment regimen.  I know there is an option for one or more "maintenance doses" every twelve weeks after finishing the course of 4, but my understanding is that the insurance companies often balk at the maintenance doses.  There may be studies that show that the maintenance doses don't influence OS, PFS, or whatever metric they want to use.  So Ed, yes, the bureaucrats may unfortunately end up playing a role in dosing protocol.

Joe

Yeah, I hear the same things from my doctors, always qualified with, "but we just don't know for sure or for how long."  It would make sense, even given my limited knowledge of the immune system, that there is a memory built as part of the adaptive immune system — there are "memory T-cells" that are supposed to serve this purpose, with the question being do these immunotherapies, be they ipi, PD-1, or TIL, have an effect on the memory T-cells.  My medical oncologist also likes to remind me that my immune system has already been "primed", with the implication that multiple immunotherapies should theoretically have a cumulative affect.  Again, it makes sense when you consider that the combination trials are looking at both parallel and sequential uses of multiple agents.  So when I had ipi in 2013, the thinking was that since I'd already had IL-2 in 2010 and TIL in 2011, that ipi would be that much more effective having already seen these two previous therapies.

I do find it interesting the difference in ipi and PD-1 as far as the dosing schedule.  I don't know what protocol the ipi trials followed as far as number of doses, and I don't know how they arrived at 4 for the standard treatment regimen.  I know there is an option for one or more "maintenance doses" every twelve weeks after finishing the course of 4, but my understanding is that the insurance companies often balk at the maintenance doses.  There may be studies that show that the maintenance doses don't influence OS, PFS, or whatever metric they want to use.  So Ed, yes, the bureaucrats may unfortunately end up playing a role in dosing protocol.

Joe

My Drs may be overly optimistic–but there is believe out there that immuno-therapy, particularly when it involves the Ipi/pd1 combo contributes to the long term memory of the body– and that once the immune system has picked up the scent and is responding it will continue to fight the Mel.  When I expressed fear of being turned out onto the ice at the end of the trial it was metaphorically described: if we give you more after this it's like turning the ignition with your engine already running.   ( it may be what they tell all old Eskimos) 

My Drs may be overly optimistic–but there is believe out there that immuno-therapy, particularly when it involves the Ipi/pd1 combo contributes to the long term memory of the body– and that once the immune system has picked up the scent and is responding it will continue to fight the Mel.  When I expressed fear of being turned out onto the ice at the end of the trial it was metaphorically described: if we give you more after this it's like turning the ignition with your engine already running.   ( it may be what they tell all old Eskimos) 

I agree with you about Dr. Charles Drake, Ed.  That guy is amazing!!!  Posted one of his videos here:

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/06/how-to-make-anti-pd1-work-better-with.html

I think his discussion regarding getting the immune system to refire after a relapse in melanoma (as well as other cancers and diseases) is fasinating and critical.  So many studies have taught us that while folks who have already taken and responded to everything from ipi, to BRAFi, to anti-PD1~ can, sometimes, though with fewer numbers, get yet another response if they relapse.  Just as we've learned that ipi naive patients respond in greater numbers to anti-PD1 than patients who have failed or relapsed on ipi.  (That's why I so hate the requirement of failing ipi before being allowed to have anti-PD1!!!!)  Figuring out how to create a better response from the immune system "second time round" is so important for so many.  Of course, figuring out how to never have to deal with melanoma after initial treatment would be fab, too!!!

Best, Celeste

I agree with you about Dr. Charles Drake, Ed.  That guy is amazing!!!  Posted one of his videos here:

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/06/how-to-make-anti-pd1-work-better-with.html

I think his discussion regarding getting the immune system to refire after a relapse in melanoma (as well as other cancers and diseases) is fasinating and critical.  So many studies have taught us that while folks who have already taken and responded to everything from ipi, to BRAFi, to anti-PD1~ can, sometimes, though with fewer numbers, get yet another response if they relapse.  Just as we've learned that ipi naive patients respond in greater numbers to anti-PD1 than patients who have failed or relapsed on ipi.  (That's why I so hate the requirement of failing ipi before being allowed to have anti-PD1!!!!)  Figuring out how to create a better response from the immune system "second time round" is so important for so many.  Of course, figuring out how to never have to deal with melanoma after initial treatment would be fab, too!!!

Best, Celeste

I agree with you about Dr. Charles Drake, Ed.  That guy is amazing!!!  Posted one of his videos here:

http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/06/how-to-make-anti-pd1-work-better-with.html

I think his discussion regarding getting the immune system to refire after a relapse in melanoma (as well as other cancers and diseases) is fasinating and critical.  So many studies have taught us that while folks who have already taken and responded to everything from ipi, to BRAFi, to anti-PD1~ can, sometimes, though with fewer numbers, get yet another response if they relapse.  Just as we've learned that ipi naive patients respond in greater numbers to anti-PD1 than patients who have failed or relapsed on ipi.  (That's why I so hate the requirement of failing ipi before being allowed to have anti-PD1!!!!)  Figuring out how to create a better response from the immune system "second time round" is so important for so many.  Of course, figuring out how to never have to deal with melanoma after initial treatment would be fab, too!!!

Best, Celeste

Joe, I will try to answer one of the 20 questions. I am on the BMS trial of Nivolumab and Ipi monotherapy or both together. The PD-1 drug (Nivolumab) schedule is every two weeks for 2 years. There are three arms to the trial with 2 arms having the PD-1 drug. The literature that I read from Dr. Ribas(UCLA) suggested that PD-1 drugs tend to work as show results on Ct- scans as early as 8 weeks. The trial scaned at 12 weeks and I was lucky enough to be a responder with reduction to my 2 lung mets.  Dr. Ribas also talks about the fact that patients in earlier Pd-1 trials continue to respond even after treatments stop. I find it very interesting that the big names in Melanoma still describe what is happening in the field of immunotherapy as, we think that this or that is going on. I really like watching presentations from  Dr. Charles Drake ( mouse research guy), I think he is at John Hopkin's. He gets into the mouse research side of things and is very good at explaining what the research field is doing in immunotherapy. My thinking for Pd-1 schedule once approved for Nivolumab will be every two weeks for two years unless the Melanoma progresses. My thinking on this is that the phase 3 trial which has 1000 patients in it is using this protocal. The $ crunchers could shorten this time frame. Ed

Joe, I will try to answer one of the 20 questions. I am on the BMS trial of Nivolumab and Ipi monotherapy or both together. The PD-1 drug (Nivolumab) schedule is every two weeks for 2 years. There are three arms to the trial with 2 arms having the PD-1 drug. The literature that I read from Dr. Ribas(UCLA) suggested that PD-1 drugs tend to work as show results on Ct- scans as early as 8 weeks. The trial scaned at 12 weeks and I was lucky enough to be a responder with reduction to my 2 lung mets.  Dr. Ribas also talks about the fact that patients in earlier Pd-1 trials continue to respond even after treatments stop. I find it very interesting that the big names in Melanoma still describe what is happening in the field of immunotherapy as, we think that this or that is going on. I really like watching presentations from  Dr. Charles Drake ( mouse research guy), I think he is at John Hopkin's. He gets into the mouse research side of things and is very good at explaining what the research field is doing in immunotherapy. My thinking for Pd-1 schedule once approved for Nivolumab will be every two weeks for two years unless the Melanoma progresses. My thinking on this is that the phase 3 trial which has 1000 patients in it is using this protocal. The $ crunchers could shorten this time frame. Ed