Do melanoma peeps with side effects to immunotherapy have a better response? - Side effects of immunotherapy - Part 10!!!

I've been posting data and case studies of  Side Effects of Immunotherapy - Part 9! forever!!!

Here are two articles that address side effects with the ipi/nivo combo specifically:

Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. Callahan, Kluger, Postow, et al.  J Clin Oncol. 2017 Oct 17.

The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). 

Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. 

Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. 

This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

OK.  Here 94 peeps took the ipi/nivo combo in several different ways.  For all of them, the 3 year overall survival rate was 63% with the median rate not yet reached after f/u for 30-55 months.  This is significant evidence pointing toward the durability of a response to this combo.  Objective response rates were 42%, with a median duration of response at 22.3 months.  More than half of the patients experienced Grade 3 and 4 side effects.  Understand that these are things that are much greater than fatigue, rash, and mild to moderate joint pain.  Of the Grade 3/4 side effects the most common one was elevated liver and pancreatic enzymes.  One patient died from multi-system failure 70 days AFTER their last dose.

Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. Sznol, Ferrucci, Hogg, et al.  J Clin Oncol. 2017 Sep 15. 

The addition of nivolumab (anti-programmed death-1 antibody) to ipilimumab (anti-cytotoxic T-cell lymphocyte-associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. 

This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. 

Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four on-study deaths were attributed to therapy. 

Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

This study looked back on 448 patients who had been treated with the ipi/nivo combo in a traditional manner.  Again, more than 50% of the patients had Grade 3/4 side effects with more than 30% of those having to stop treatment.  Most common side effects generally, were related to skin and GI issues.  When looking at Grade 3/4 side effects, the most common ones affected the liver and GI tract (much like the prior study).  Onset of Grade 3/4 side effects took only 3 weeks for skin and 16 weeks for renal problems.  With endocrine side effects excluded, the average time it took for side effects to resolve was about 2 weeks for renal and 4+ weeks for pulmonary issues.  Resolution rates were between 79 and 100% with immune-modulating agents {read:  steroids or medicines like remicaid/infliximab and others}.  I suspect that side effects in the endocrine system, given the nature of that beast and the fact that they were "excluded" here, were NOT "resolved" with such immune-modulation, but rather required therapy for the duration of the patient's life, as treatment for diabetes and hypothyroidism is expected to be.

Three new cases of bullous pemphigoid during anti-PD-1 antibody therapy. Le Naour, Peuvrel, Saint-Jean, et al.  J Eur Acad Dermatol Venereol. 2017 Sep 2. 

Anti-programmed death 1 (PD-1) antibodies are revolutionizing the treatment of many cancers, including melanoma . Cutaneous adverse events (AE) of anti-PD-1 antibodies are common (20%) and mainly non-specific. Bullous pemphigoids (BP) are very rare immune-related AEs induced by anti-PD-1 antibodies, with only 12 cases previously published. We report here three new cases of BP during anti PD-1 therapy with nivolumab. 

So....one more lovely thing that can develop with immunotherapy, which I've reported on before in these posts:  immunotherapy and bullous skin eruptions

We already know that vitiligo, as a response to immunotherapy, is a good prognostic sign.  But, what do other toxic reactions mean in regard to response rates?  Below ~ an article that begins to address that issue:

Correlation between toxicity and outcome in melanoma patients treated with ipilimumab plus nivoumab (ipi/nivo).  Cohen, Jilaveanu...Sznol, et al.  Society for Melanoma Research 2016 Congress.  Published 29 January 2017.

Immune checkpoint inhibitors have become the standard of care for treatment of metastatic melanoma. However immune-related adverse events (irAEs) remain a serious concern. We report our experience investigating the potential correlation between degree of toxicity and progression-free survival (PFS). 74 pts were treated with the combination of ipi/nivo as part of the phase I trial, [NCT01024231], an expanded access protocol [NCT02186249] or with commercially available drugs from Dec. 2009 to Oct. 2015. irAEs were graded according to the CTCAE v4.0 and steroid use was studied as a surrogate for overall toxicity. 69 (93%) pts experienced an irAE of any grade. 39 pts (53%) had a grade 3 irAE and 4 (5%) had a grade 4 irAE. Pts often experienced greater than1 irAE. Females tended to get more toxicities than males. The median PFS in the patient population was 9 months (range 0–65). The median OS was 16 months (range 3–65). The objective response rate was 55%. 70 pts survived greater than 6 months. There was a statistically significant difference in the PFS in pts who experienced no irAEs when compared with those who had any irAEs. Similar findings were seen in the analysis of OS. PFS and OS were also stratified by length of time on steroids. Any steroid requirement at all was associated with a reduced risk of disease progression but the number of days on steroids above the median (23 days) corresponded with an increased risk of progression. Pts treated with the combination of ipi/nivo who received steroids to treat autoimmune toxicity had improved outcomes when compared with those pts who received no steroids, suggesting that pts who have some irAEs from immunotherapy may have improved outcomes. However, a fine balance between autoimmunity and anti-tumor response may be necessary for optimal long-term outcomes.

Here, of 74 patients treated with ipi/nivo, 93% had some level of side effects and 39 (once again, more than 50%) experienced Grade 3/4 side effects.  PFS was 9 months.  OS was 16 months.  Objective response rate was 55%.  70 of the 74 lived more than 6 months.  OKAY...but to the point of the current question:  "There was a statistically significant difference between the PFS in patients"  with NO side effects when compared to those who had ANY.  This was true of overall survival as well.  Furthermore, "Any steroid requirement at all was associated with a reduced risk of disease progression." However, the authors go on to employ a caveat, noting that if steroid use was prolonged (beyond the average 23 days) there was a corresponding "increased risk of progression."  Now...what is unclear about that statement to me is this:  Did prolonged steroid use actually account for the increased risk of progression?  OR...  Were these patients so badly affected by their adverse reactions to the treatment that they were unable to continue therapy and in the absence of treatment progressed?  Especially if side effects occurred early and the amount of immunotherapy they had received was minimal????  There is some data already addressing that point as is evidenced in these posts: 

Feb 2016: Time to Response...Ipi vs Nivo and ipi

ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!

Aug 2017: 40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!

All of these posts include data which demonstrated that patients who stopped treatment due to side effects, had about the same outcomes as those who completed treatment.  (There are many implications in that fact.... Are we simply treating folks too long?  Should we decrease the dosage of ipi, as it is the bad boy of side effects, when we combine it with nivo - as some current/on-going studies are doing?)

While it is far from absolute or simple...among these patients, it is looking as though side effects to immunotherapy are demonstrable proof of the immune reaction we are seeking to get rid of our melanoma and, within limits, those ratties have better outcomes than those with lesser or no side effects.  If nothing else, this data is certainly a testament to the truth in my 9 million rants that side effects to immunotherapy CAN and SHOULD be treated, even with immunosuppressive drugs, as patients will: A) survive their adverse event, and B) still attain a response to the treatment! 

My yelling from as far back as 2015:
Immune related side effects from immunotherapy can and SHOULD be treated!!!!

Side effects and how to manage them in targeted and immunotherapy for melanoma

To more recently:  Patients with preexisting immune disease, melanoma, and treatment with Anti-PD-1? Yes, this can be done. Yes, autoimmune flares should be treated with immunosuppressive therapy while on immunotherapy. And YES!!!! These patients can still attain a response!

As ever, ain't noth'n simple in melanoma!  Hang in there ratties!!! - c