Sunday, July 13, 2014

Nivo/ipi combo, Nivo vs Pembro, PD-L1: SugarCone and 2014 ASCO data

B found two posts from SugarCone Biotech Blog, June 12, 2014. The author was apparently at ASCO scoping things out; taking screen shots from the presentations.  Good stuff.  My synopsis:

...PD-1 appears to be a central control point for curtailing T cell responses...similar to the role CTLA4 plays in regulating initial T cell activation...Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed that the PD-1 pathway was used by tumor cells as a shield against immune system attack.  It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers.  Less clear is...why certain patients respond or don't, what biomarkers might predict response, how to increase response..., how to..measure response, and how to safely combine anti-PD-1 with other therapies.

This table lists PD-1 therapies in development, for various tumor types [side highlight...not mine]:

 This table defines response parameters and their abbreviations:

Background note:  The very first trials of [anti] PD-1 began with...Nivolumab in metastatic melanoma.  [For comparison] ipilimumab (Yervoy) an anti-CTLA1 approved for treatment of metastatic melanoma....In a Phase 3 trial....of Stage IV melanoma patients who had failed prior therapy (chemo), the trial compared ipi to a tumor vaccine targeting the melanoma antigen gp100.  Ipi treatment = OS of 10 months vs 6 months with vaccine.  1 year survival = 45%.  ORR was only 10%.  AEs (adverse events) were autoimmune issues (colitis, pituitary inflammation) and 2% of patients had treatment related deaths.  In separate study of treatment naive Stage IV mel patients:  Ipi = OS of 11.2 months, 1 year survival = 47%, falling to 21% by year 3.  Patients were given ipi or placebo plus dacarbazine, then moved to ipi or placebo alone if there was a response measured or if the initial therapy caused toxicity.  AEs went up, with 38% of patients experiencing Grade 3/4 SAEs (severe AEs).

Nivolumab (Anti-PD1 by BMS)...provides median OS of 17 months, 1 and 2 year survival rates of 62% and 43%.  ORR = 33%.  AEs less significant than ipi.  Immune-related events occurred in 54% of patients (skin, GI, endocrine problems), but only 5% of patients had Grade 3/4 events and there were no drug related deaths.

So....when you combine ipi and Nivo:  At ASCO last year....trial data reported 4 cohorts of patients given different doses of nivo and ipi in combination.  ORR across cohorts = 40% and 1 year survival was 82%.  Median OS had not been reached.  SAE across cohorts = 53%.  Slide describing cohorts:

In trial update by Sznol this year (Table below) optimal dose rates of 1+3 and 3+1. ORR = 43-53%.  "Aggregate Clinical Activity Rate" = 81-83% in cohorts 3 and 4. (Note that Cohort 4 was the maximum tolerated dose due to SAEs and will no longer be used.) The percent of patients whose tumor burden was reduced by more than or equal to 80% at 36 weeks was 42% across the cohorts.  In patients who responded the median DOR in cohorts 1-3 and cohort 8 has not yet been reached.  In cohorts 2-3 the 1 year OS = 94%, 2 year OS = 88%.  Median OS in cohorts 1-3 = 40 months.

These data are best-in-class for treating advanced outstanding issue remains that of toxicity...23% of patients had to discontinue therapy due to toxicity, and one died of complications of treatment....Sznol...pointed out that...toxicities are controlled by standard intervention...but that includes cessation of therapy.  We have already learned from ipi...that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1-2 doses....time may not be kind.

....The activity of pembrolizumab, formerly MK-3475 (Merck's anti-PD1) in melanoma is very similar to that of nivo...and closely resembles nivo except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating.  Slide comparing pembro and nivo:

...the pembro data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma...Merck...made a strategic decision to stratify patients by prior exposure to ipi...This gave [Merck] a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients. the toxicity profile of ipi, there are a lot of these patients....  If we focus on the ipi-naive ORR and 1 year survival data...we have to conclude that these drugs are pretty comparable...To differentiate will have to come from longer duration...ongoing trials....In the nivo trial...half of the responding patients stopped therapy for reasons other than disease progression, most likely...due to AEs.  [Though] 3/4 of nivo patients stopping therapy maintained a response, some for extended periods.  In pembro...the SAE rate was 12% but only 4% of patients discontinued therapy.  The catch is that in order to move ORR higher than 40%, combination therapy may be needed.  But..the ipi/nivo combo comes with much higher toxicity and drop-out rates.

Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway...PD-L1 is also important in...predicting response to therapy...the utility of this marker...was subject of considerable discussion.  When ORR is 40% it is helpful to select patients prospectively.  In a study of responsiveness to pembro, Kefford, used an analysis of PD-L1 expression to demonstrate a remarkable difference in...response between patients with greater or = 1% PD-L1 expression vs patients who were PD-L1 negative.  Biopsy 2 months before pembro determined PD-L1 expression.  Patients were given Pembro at either 10mg/kg q2wk, 10mg/kg q3wk, or 2mg/kg q 3 wk with median treatment of 23 weeks and 13 month follow-up.  ORR = 41%.  Median PFS = 31 weeks and median OS was not reached.  1 year survival = 81%.  So this was a terrific cohort within the larger pembro study, likely due to the higher dose used.  PD-L1 expression was associated with improved ORR by 51% vs 6%, PFS = median 12 vs 3 months, and 1 year survival = 84% vs 69%.  No treatment related deaths, 14% experienced SAEs, again reflecting the aggressive dosing schedule.

In the larger trial of ipi naive patients treated with Nivo, PD-L1 tumor staining was associated with ORR, but only weakly with PFS and OS.  Why the data are less robust than the Kefford study is unclear.  What is abundantly clear however is that there were profound responses in patients scored as PD-P1 negative, as shown in the screen grab from Dr. Weber's review:

Not exactly new information from posts I made in June 2013 or within more recent ones...but some interesting view points and nice access to slides.  You can check out the posts themselves via the link below.  Best - c

PS...I couldn't get the address to work as a link...but if you copy/paste the address below and then search....the information will come up.  C

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