ASCO 2015: IL2 followed by anti-PD1 = GOOD!!!!

Overall survival of metastatic melanoma treated with high dose IL-2 followed by ipi.  J CLin Oncol 33, 2015.  Wong, Morse, McDermott, Kaufman, et al.

PROCLAIM is an IL-2 observational registry with over 40 participating sites consisting of a retrospective (n=70, locked) and prospective cohort (n greater than 343, ongoing). Previously, we reported a median overall survival of 20 months with a median f/u of 37 months in melanoma patients treated with HD IL-2 between 2007 and 2012 from a retrospective cohort (ASCO 2014).  We report this time,  analysis of 240 prospective patients. Patients must have received at least one dose of HD IL-2 prior to 2014.  Survival is current to Jan 2015.

For the 240 prospective patients, the median overall survival is 17.9 months and overall response rate is 15.2% at a median f/u of 20.1 months.  The 1 year survival rate of patients receiving anti-PD1 or ipi after HD IL-2 is 100% and 68% respectively, compared to 58% in IL-2 only group.  The median overall survival for these patients is 25.1 (n=20), 18.4 (n=75), and 14 months (n=112), and the median f/u is 24.2, 20.6, and 17.4 months respectively.  Of the 20 anti-PD1 patients, 12 received ipi first, 4 anti-PD1 first, and 4 anti-PD1 only.  The median time between the last IL-2 dose and start of ipi/anti-PD1 is 3.8 months.  There were no differences in IL-2 treatment intensity between these 3 groups.  Ten of 73 ipi patients suffered treatment-related autoimmune disease in post treatment f/u compared to 0 in the 20 anti-PD1patients.  There were no treatment-related deaths in the combined retrospective and prospective cohorts (n=578).

Conclusion:  The median overall survival for melanoma patients receiving anti-PD1 after HD IL-2 is significantly prolonged over either treatment with IL-2 only, or ipi therapy following IL-2.  The small 'n' for anti-PD1 group and intrinsic shortcomings of registries limits a definitive conclusion about the optimal sequencing of immunotherapies.  Checkpoint therapy after IL-2 appears to be well tolerated, does not impact therapeutic activity and provides a path forward for trials designed to enhance durable, unmaintained IL-2 responses.

Thoughts:
1.  Most researchers feel that combination therapy will hold the key to improved response rates for melanoma patients in the future.  Clearly the Ipi/Nivo combo is demonstrating that, albeit with increased rates of side effects.
2.  Here too, when IL-2 is followed by either ipi or anti-PD1, 1 year survival hits 68% after ipi and 100% after anti-PD1 vs 58% in patients given IL-2 alone. 
3.  Ipi remains the tricky component regarding side effects here...much as it is in the ipi/nivo combo.
4.  That 100% 1 year survival stat in patients having had IL-2 followed by anti-PD1 is AMAZING!!! 
5.  But....so far, that is in small numbers.
6.  And...patients selected for IL2 tend to be in pretty good health in order to be allowed to take the harsh regimen that it is.
7.  Will these numbers for the IL2/anti-PD1 combo end up beating the results for the ipi/nivo combo?
8.  Given the side effect profile and requirement for hospitalization with IL-2 administration...will the results be sufficient to make it worth the difficulty as a first line therapy?
9.  Will these results hold true for patients given anti-PD1 first....and IL-2 later?

Very interesting.  Keep up the good work, ratties.  Best - c