Colitis after 1 treatment of IPI and NIVO

Hello Anon… and Celeste;

A first post from me on this forum… been reading/lurking for a while!

First, Anon, back in November I was in precisely the same position as you – but also had extreme pain in both feet akin to gout. I was hospitalized for two weeks, and put on high dose steroids with both Colitis and Thyroiditis, and to this day I am still in the steroid tapering phase. No fun but in a weird way somewhat relieved that my oncologist has indicated I am not going back on Ipi/Nivo. The severity of the side effects [Grade 3] would suggest my immune system clearly did have a massive boost – and both CT and MRI in early Feb confirmed no disease progression. Recent clinical trial results (which Celeste pointed to) back up both of our Oncologists' advice – that is, even with one cycle, this single combination infusion may have the same efficacy as compared to someone who goes through the entire treatment cycle.

The story is of course ongoing – I have follow up scans end March/April…. So will be monitoring closely to ensure that single Ipi/Nivo infusion I received back in October continues to ‘work’.

But, like you, Anon, I worry about the “what if?” and what treatment alternatives might be available if the CT/MRI shows disease progression.

And so a follow up query for Celeste (or anybody else who might be able to offer insights) :
Celeste, you state that “Most folks with side effects to the ipi/nivo combo, can proceed to nivo alone…as ipi is the bad boy of side effects in this treatment… once they have had their side effects treated and resolved…with no significant problems.” During my most recent consultation with my oncologist I also suggested this on the basis that Nivo could be considered as a treatment ‘fall-back’ option for continued immunotherapy treatment. His response, as I recall, was that in his opinion Nivo was equally responsible for adverse side effects but he also made the point that my body’s reaction to Nivo would be such that it would in any case *see* Nivo as a combination treatment, and that I would therefore likely have the same adverse reaction to it as I had following the first cycle.

What might be the conditions that I could ‘safely’ continue with Nivo? [Colitis/Thyroiditis are being treated but are still an issue] Are there any clinical trials that show an extended benefit using Nivo only after having had an adverse reaction to the combination treatment? And are there other treatment alternatives [other than going back on Dafranib/Trimitineb]?

If only life was simpler!! Any experience from others that might provide further insight most gratefully received!

Many thanks,
David M

Hi David,

While the side effect profile is the same for all immunotherapy, the data is very clear that ipi causes more of those side effects, more often, and in more people.  It is also clear that side effects to the ipi/nivo combo are often worse and more frequent than with either agent alone.  It is also very clear that most of those side effects occur within the induction phase (ie. 1-16 weeks into therapy).  That is not to say that someone can't take nivo (or keytruda) alone and suffer delbilitating side effects.  Sadly, many people have.  Still, the fact remains that many who have suffered side effects to the combo can go on to tolerate anti-PD-1 alone.  Here is a very recent discussion of this very topic on this forum, with the patient reporting that despite side effects her docs were going to try to continue her treatment:  https://www.melanoma.org/find-support/patient-community/mpip-melanoma-patients-information-page/colitis-nivo  

Here is just one article that notes patients with pre-existing immune disease or immune side effects to ipi can go on to tolerate anti-PD-1:

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI).  ASCO 2016. #9515.  J Clin Oncol 2016.  Menzies, Johnson, Ramanujam, et al.

Background: Anti-PD1-antibodies (PD1) have activity in many cancers, and are standard care for melanoma, lung and renal cancer. All trials excluded patients (pts) with significant preexisting AD or major immune-related adverse events (irAEs) with IPI. We sought to explore the safety and efficacy of PD1 in such pts. Methods: Pts with advanced melanoma and preexisting AD and/or major irAEs with prior IPI (requiring systemic immunosuppression, [IS]) treated with PD1 were retrospectively identified. Data regarding AD, IPI and PD1 treatments, toxicity and outcome were examined. Results: 119 pts were included, 95 with prior IPI. 109 received pembrolizumab, 10 nivolumab. 86 (72%) had greater or = to, 3 months follow-up, median (med) 4.6 mo, with med PFS 6.8 mo. 31 (26%) had died. Of 52 pts with preexisting AD, 15 (29%) had active symptoms at PD1 start and 16 (31%) were on IS. The ORR was 33%. 20 (38%) flared with PD1 after a med 1.3 mo, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren’s syndrome, 1/2 with scleroderma, 2/2 with immune thrombocytopaenic purpura, 3/8 with psoriasis, 1/4 with Graves’ disease, 0/6 with gastrointestinal (GI) (including 3 Crohn’s disease) and 0/5 with neurological disorders. 3 (6%) had grade (G) 3 flare, and 2 (4%) discontinued PD1 for flare. 15 (29%) developed other irAEs (5 G3), 3 (6%) discontinued PD1. 67 pts had irAEs requiring IS with prior IPI (9 G2, 51 G3, 7 G4), including 47 with greater than or = to, G3 colitis (15 had infliximab), 2 with G4 hepatitis (1 had antithymocyte globulin), and 9 with hypophysitis. All irAEs except hypophysitis had resolved at PD1 start except in 1 pt (arthritis), 5 were on IS at PD1 start. The ORR was 40%. 2 (3%) had recurrence of IPI irAEs with PD1 (arthritis, colitis), but 23 (34%) developed new irAEs (13, 19% greater than or = to, G3), and 11 (16%) discontinued PD1. There were no treatment related deaths. Conclusions: PD1 have efficacy in pts with preexisting AD and/or major irAEs with IPI. PD1 may flare preexisting AD, particularly rheumatologic, but GI and neurological disorders may flare less. In pts with prior major irAEs with IPI recurrence of the same irAE is rare, but new irAEs occur. The rate of irAEs in these pts appears higher than in clinical trial pts.

It is also true that if a side effect occurs…it is imperative to treat it…often with steriods and give the patient a break from treatment.  Some docs think that if the level of the side effect was Grade 3/4 that the treatment cannot be resumed.  Others do not see it that way.  So…it is tricky to say the least.

On a positive note…there is this:  http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2017/08/40-of-melanoma-patients-stop-ipinivo.html
Which in sum, says this: "Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy."

Hope I have not made things more confusing.  I wish you my best.  Celeste

I am currently setting in the hospital with colitis on high dose steroids from Nivo alone.  As soon as cardiologist clears me for possible pulmonary issues they will  begin tapering steroids and start Remecade. Once colitis clears up and steroids removed the plan is to restart treatment with Nivo again. I expect my labs and doc visits will be closely scrutinized before each treatment  to avoid this again.  Melanoma docs are pushing cardiologist to expedite tests to get the ball back in their court.  I am stage 3C and NED after surgery and they want to restart my treatment, l would expect stage 4 would almost guarantee continuing treatment.