Saturday, April 18, 2015

What to expect in Ipi vs Nivo Trial as adjuvant for resected melanoma???

The ipi vs nivo trial for resected Stage III and Stage IV melanoma is now recruiting!!!  Check out some info about adjuvant melanoma treatments and the trial reported here:  

New ipi vs nivo trial for resected melanoma

So what can patients expect?  These ratties will most certainly teach us a great deal.  However, the results of my NED arm from the nivo trial I have participated in can give some idea about how the Nivo/Opdivo arm in this trial might go for prospective patients.  Remember we were testing results of Nivolumab in NED vs NON-resected melanoma as well as doses that ranged from 1-3-10mg/kg and for some of us, combined with peptide vaccines as well.  (The vaccines provided no benefits, so no worries about missing out on that!!!) That report and review are here:

Results from 33 ratties in my Nivo/Opdivo trial - published!

Thoughts on my nivo/opdivo trial results, 4 years later

With this sum up from the published results:
"Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up."  AND:  "Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable."  Dosage (1, 3, 0r 10mg/kg) did not seem to have significant effect on relapse rate or adverse events.  AND:  "Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant."  BUT, lower MDSC levels at the start did demonstrate a positive effect:  "There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients."

But, what about the folks who are in the adjuvant ipi arm?  Here is an article reporting on a study that examined just that.

Adjuvant ipilimumab vs placebo after complete resection of high-risk stage III melanoma:  a randomized, double-blind, phase 3 trial.  Eggermont, Chiarion-Sileni, Grob, Drummer, Wolchok, Schmidt, Hamid, Robert, Lebbe, Weber, et al.  Lancet Oncol. 2015 March 31. [epub ahead of print]

"We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.  We did a double blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis greater or equal to 1mm or intransit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not had previous systemic therapy for melanoma from 91 hospitals located in 19 countries.  Patients were randomly assigned (1:1) receive IV 10mg/kg ipi or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years. ...Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints."

Between July 10, 2008 and Aug 1, 2011 951 patients were enrolled.  475 = ipi.  476 = placebo.  At a median f/u of 2.74 years there were 528 recurrence-free survival events: 234 = ipi vs 294 = placebo.  Median recurrence-free survival was 26.1 months for ipi vs 17.1 months for placebo.  3 year recurrence-free survival was 46.5% for ipi vs 34.8% for placebo.  

Most common grade 3-4 immune related adverse events in the ipi group:  GI (75 vs 4 in placebo), hepatic (50 vs 1), endocrine (40 vs none).  Adverse events led to treatment discontinuation in 245 patients in ipi group and 182 of these were in the initial treatment period of 4 doses.  5 patients died due to drug related adverse effects in the ipi group.  3 due to colitis (2 of which had GI perforation), 1 with myocarditis, and 1 with multi-system failure with Guillain-Barre syndrome.

"Adjuvant ipi significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma.  The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences...for endocrinopathies.  The risk-benefit ratio of adjuvant ipi at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value."

My thoughts: 
1.  Folks in my trial were much higher risk generally as we were all Stage IV patients (status post brain and lung mets, etc.) at the start, though Stage III peeps were added later.  
2.  I don't know the drug dosages to be used in the coming trial for either ipi nor nivo.  Nivo doses haven't seemed to have that much effect on adverse events, but ipi has proven that the higher the dose the more frequent those events. 
3.  The numbers of patients in the NED arm of my study were obviously very small.  The greater numbers expected for the coming study will certainly provide a great deal more information.
4.  Unlike many phase 3 trials (the ipi one noted above for example), both arms of the currently enrolling trial are likely to derive some benefit!!
I wish you all my best!   - c

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