Phase I/II trial of PD1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab

ASCO Abstract for 2013 annual meeting, J Clin Oncol 31, 2013, (9011)
Authors:  Weber, Kudchadkar, Gibney, et al.  Moffitt Cancer Center, Tampa, Florida

Nivolumab (new name for MDX 1106, then BMS 936558), an IgG4 human monoclonal antibody against checkpoint protein PD1, is active in metastatic melanoma, renal cell disease, and non-small cell lung cancer.  It was given with a multi-peptide vaccine to patients with unresectable melanoma who failed at least one regimen and were ipi naive or had failed ipi.

Three cohorts of 10 HLA A0201 positive, ipi - naive patients were given nivolumab at 1, 3, or 10mg/kg.  Three additional cohorts of patients who had failed prior ipi were given nivolumab at 3mg/kg:  2 of these cohorts with 10 patients each and were A0201 positive and had either grade 2 or less ipi toxicity, or grade 3 dose limiting ipi toxicity and were not HLA restricted.  Pretreatment archived tumor tissue, as well as pre and post-treatment peripheral blood cells were collected.

RESULTS:  Response rates by RECIST were 28% in 34 patients naive to and 32% for 46 patients who failed prior ipi.  Nivolumab did not induce the same irAEs (immune related adverse events) in patients with prior ipi induced toxicity. No cohort had more than one dose limiting toxicity. 2 patients had grade 3 pneumonitis.  Biomarker studies showed that elevated NY-ESO 1 and MART-1 specific CD8 T cells pre-treatment were associated with non-response, while CTLA-4 positive CD4T cells and T regulatory cells were elevated after treatment in non-responders.  Immunohistochemical analysis of pre-treatment tumors indicated that PD-L1 staining was associated with response, but responses were also observed in patients whose tumors did not stain.

CONCLUSIONS: Objective responses to nivolumab were observed after ipi and to ipi after failing nivolumab. Elevation of CTLA-4 after nivolumab in non-responders suggest that sequential therapy with the combination should be tested.  Tumor PD-L1 was associated with but not predictive of response.

MY THOUGHTS:
1.  This is my study...though my cohort...Stage IV NED metastatic melanoma patients...is not included in this data, though we were treated with the same vaccines and the same three dosing groups of 1, 3, or 10mg/kg doses of nivolumab.  (See my post from March 22, 2013.  Where I noted my best assessment of results for my cohort:  In my NED group:  N = 31. Seven patients progressed while in the trial. Two patients have passed.  One is probably going to pass soon. Of the 4 remaining that progressed, 2 are subsequently NED again (I cannot tell you if this is with additional treatment or without.  I know from past conversations one patient had become NED after initially progressing with NO treatment and I know that other patients had been "doing well" with subsequent treatment with ipi....however, I do not know what was done in these two cases in particular.)  THEREFORE....now, of the original 31 patients, 26 remain NED.  That demonstrates a clinical benefit of 83%.  Dr. Weber admitted that is was "much better" than he had ever thought we would do.  He said he was meeting with the folks at BMS to try to set up a trial with anti-PD1 as a real adjuvant treatment for melanoma patients with resected disease today...given these results.  Additionally, a proposal for publication of at least some of the data from my trial has been submitted for discussion/presentation at ASCO in June.  Whether either of these things will really happen remains to be seen.)  Apparently, the data from my cohort has been accepted for presentation at ASCO.  Hopefully, I will have more to report after my trip to Tampa in June.


2.  See my post on September 9, 2012 for my thoughts on testing our tumors for PD-L1 staining.  Wonder if any of us ratties will ever be privy to that intel or to the story our CD8 T cell pre and CD4 T and T reg cells post infusions told.

3.  See my more recent post, May 11, 2013, documenting the results of two studies which indicate that the peptide vaccines utilized in many of the patients in both the NED and unresectable groups DID ABSOLUTELY NOTHING OF BENEFIT!!!!!!!!!!!!! Though the requirement of HLA typing for A0201 did keep many patients OUT of the study!


4.  Nivolumab?  That's the name?  Really????????????????????  What the tub?

It's a mighty rattie world out there - c