Good News! Melanoma Patients who failed ipi had response rate of 30% to Nivo with no increased rate of side effects!!!

This data comes from an arm added to the Nivo/Opdivo trial I participated in.  When making my decision, in 2010, to participate or not, the two arms were - nivo with vaccines in NED Stage IV patients vs active/advanced disease Stage IV patients.  At that time, talk was that ipi would finally be FDA approved in spring of 2011 (It was approved for patients with advanced disease that March.) and it was anticipated that if you took ipi first, the FDA and the powers that 'WERE', would not ALLOW you to take anti-PD1 later as the accumulation of side effects, etc. would be too much! THEN, the powers that 'were' declared that NO WAY were side effects from immunotherapy cumulative...BUT, if you had had a bad experience due to side effects on ipi, NO WAY could you take anti-PD1.  Then, they made failing ipi a pre-req for taking anti-PD1!!!  Oh, my!  Well, today we KNOW that while on immunotherapy....side effects can indeed be cumulative (increasing and worsening over time) but now.....we also know this:

Phase I/II study of metastatic melanoma patients treated with nivolumab who had progressed after ipilimumab.  Weber, Gibney, Kudchadkar, et al. Cancer Immunol Res. 2016 Feb 12.

"The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30%. Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62%  having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab."

So....folks who had problems with side effects when taking ipi could still be managed well when placed on nivo.  And....patients in this study whose tumors had failed to respond to ipi, still gained a 30% response rate to nivo. (Here's a link to more data related to ipi/nivo sequential dosing: Sequential nivo then ipi - ORR of 41%. Ipi followed by nivo - ORR of 20% ) 

I think the connection between increased levels of MDSCs and poor outcomes is something that deserves additional research.  Here's a link to a post that speaks to what they are, what they do, and what could possibly be done to improve response rates in spite of the little suckers: Markers for response to immunotherapy

We've come a long way, ratties!!!  You are awesome!!! - c