ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Survival, biomarker, and toxicity analysis of Nivolumab (NIVO) in patients that progressed on ipi.  ASCO J Clin Oncol 33, 2015. Weber, Gibney, Yu, et al.

PD-1 antibody, nivolumab was administered to 126 patients with unresectable melanoma that failed at least one regimen and were ipi naive (34) or progressed on ipi (92).  Patients refractory to ipi were given Nivo at 3 mg/kg. 2 cohorts were HLA 0201 positive: N = 10 had grade 2 or less ipi related AE's.  N = 21 had dose limiting grade 3/4 ipi related AE's.  A third cohort (N = 61) was not HLA restricted and had experienced grade 2 or less ipi related AE's.  RESULTS:  Median f/u for ipi refractory pts was 18.7 months. Response rate was 29%.  44% had clinical benefit with confirmed partial and complete response or stable disease at 24 weeks.  Median duration of response was 14.3 months.  Median progression free survival was 5.4 months and median overall survival was 20.1 months with 1 and 2 year OS of 69.2% and 39.1%.  Of 14 patients that have completed all therapy or stopped due to toxicity while stable or in response, all remain in remission. Of 21 patients with prior ipi induced grade 3/4 AE's, only 2 had subsequent dose limiting (and different) AE's with nivo, with 8 PR and 5 SD seen.  All 8 PR and 3 SD are without progression.  Biomarker studies showed that circulating MDSC (myeloid derived suppressor cells) were associated with progression and worse OS.  CONCLUSION:  Prior ipi related AE's were not replicated by NIVO.

Safety of pembrolizumab in patients who stopped ipilimumab due to immune-related adverse events.  ASCO J Clin Oncol 33, 2015.  Shoushtari, Postow, Horvat, Chapman, et al.

Pembro which blocks programmed death-1 was recently FDA approved (as was Nivo) for the treatment of patients with advanced melanoma after progression on ipi.  Ipi is associated with immune mediated adverse events which can lead to treatment cessation.  Researchers collected date on patients with melanoma who received pembro at Sloan Kettering and had received less that 4 doses of ipi due to AE's grade 2 or higher requiring steroids.  RESULTS:  N= 10.  12 AE's contributed to ipi cessation:  colitis, neuropathy, ALT elevation (increased liver enzymes), rash.  All were given steroids and 3 required infliximab.  Median pembro doses given = 5.  7/10 patients are still getting treatment.  2/10 had treatment with pembro interrupted due to AE's that required steroids.  Neither were the AE seen when on ipi.  CONCLUSION:  Patients who stop ipi due to AE's may have different AE's on pembro.  Severe AE's on ipi does not preclude a patient from taking pembro.


Efficacy and toxicity of treatment with the anti-CTLA4 antibody Ipilimumab in patients with metastatic melanoma who have progressed on anti-PD1 therapy.  ASCO J Clin Oncol 33, 2015.  Prithviraj, McArthur, Atkinson, et al.

Immunotherapy with anti-CTLA4 (ipi) and anti-PD1 antibodies has demonstrated overall survival benefits in patients with metastatic melanoma compared to standard therapy.  Early clinical trails suggests that combination therapy with ipi and anti-PD1 increases the response rate sompared to single agent treatment however is associated with increased toxicity.  Anti-PD1 therapy demonstrated equal efficacy and toxicity in patients that progressed on or were naive to treatment with the anti-CTLA-4 antibody Ipilimumab.  So far, only very limited evidence exists regarding efficacy and toxicity of ipi in pateints that have progressed on treatment with an anti-PD1 agent.  Study:  N= 10 patients who had received Nivo/Pembro in a clinical trial and were subsequently treated with ipi.  Ipi was given at 3mg/kg every 3 wks for 4 cycles and response was assesses by CT scan 4-6 wks after last dose.  Results:  Median time between last dose of anti-PD1 and ipi was 7 months.  4/10 patients had increased LDH on commencement of ipi therapy.  1/10 patients achieved a partial remission as their best response to anti-PD1 therapy with an additional 5/10 having stable disease. 4/10 were given all 4 doses of ipi.  F/U after last dose of ipi has been more than 3 months.  1/10 patients achieved a response to ipi with another 1/10 having prolonged stable disease.  3/10 experienced grade 3/4 immune related AE.  Conclusion: Ipi can induce responses in patients who have failed anti-PD1.  The response rate appears similar compared to patients who have not received prior anti-PD1 therapy.  AE's were observed.  Significance of these observation remains to be seen.

The first two reports are not really news.  Patients who had to stop taking ipi due to side effects can take anti-PD1 (Nivo OR Pembro) without being cursed with their prior side effects from ipi and gain a response.  Additionally, and this is newer as fewer patients have reached this position, you can get a response from ipi after having taken anti-PD1. And ~ myeloid derived suppressor cells need to get out of our way!!! Hang in there ratties.  Sometimes it's a long ride! - c