Tuesday, September 12, 2017

Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!!


For those of you who don't know...back in 2010 I joined 33 other ratties with resected Stage IV melanoma in a trial of nivo (with peptide vaccines that did NOT help).  I had had 2 cutaneous lesions, a positive node, went on to have a resected lung met, SRS to a brain met, and surgery for a tonsilar met, but was NED at entry to my trial.  There were 30 ratties in an advanced melanoma arm as well. Eventually that trial morphed into many, many different arms to include:  folks with prior use of ipi, to stop requiring the vaccines and HLA positive typing, the ipi/nivo combo and all sorts of things.
However, here are the results of my NED 33:  C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!

With my thoughts:  My Nivo (Opdivo) trial - first dose - 4 years ago 12/29/2010 - thoughts...
FYI:  I was treated with only 1mg/kg of nivo, every 2 weeks for 6 months, then every 3 months for 2 more years.

Now there is this:

Adjuvant Nivolumab vs Ipilimumab in Resected Stage III or IV Melanoma. Weber, Mandala, Del Vecchio, et al. NEJM. September 10, 2017.

Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma.

In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population.

At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% in the nivolumab group and 60.8% in the ipilimumab group. Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.

Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab

Here is a link to the full article:  Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. Weber, et al. NEJM

So here's the deal:

Stage IIIB, C, or Stage IV melanoma patients were allowed...even those with brain mets...as long as all were completely resected.

Patients joined from March 2015 to November 2015

There was a 5% cutoff for PD-L-1 staining (ie positive for PD-L-1 staining on tumors)

Nivo was given at 3mg/kg every 2 weeks or ipi was given at 10/mg/kg every 3 weeks for 4 doses then every 12 weeks.  Either drug was given for one year.

Patients were assessed via CT's of body and MRI of the brain every 12 weeks for 2 years, then every 6 months until year 5.

905 patients were studied, none of whom were still getting the drug by the final report.
Only 397 of these patients completed the full year of drug treatment.
Of the 452 in the nivo arm, 275 completed the year.  Of the 453 in the ipi arm, 122 completed.

Nivo outcomes were better than ipi no matter the patient's age, sex, disease stage, or BRAF status.  Nivo had fewer side effects.

In prior studies, ipi has demonstrated a pretty consistent 60% recurrence free survival in Stage III NED patients when used as adjuvant.  That number held in this study even when Stage IV patients were included.

Recurrence free survival at 12 months:
70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:
66.4% for nivo                    52.7% for ipi

Median distant metastasis free survival was not reached in either group.  However, it was longer in the nivo group with mets developing in 93 of the 369 peeps in the nivo group and in 115 of the 366 ipi group.

OVERALL recurrence free survival was 70.5% for the nivo group (vs 60.8% for ipi) at 1 year...but...when you pull out the Stage IV folks the number was 63% for nivo vs only 57% for ipi.

Back to me and my ratties, as of September 2015...of the 33 Stage IV ratties enrolled, only 10 of us had relapsed.  That is a recurrence free survival percentage of 69%....but with longer time out from treatment.  Interestingly, in my study....only 2 of the 10 brain met patients had relapsed.  

And finally, I am asked at least weekly by someone via email, MPIP, or my blog...
"So, when will I be safe?  If I make it out 1 year (2, 3, etc) I'll be free of melanoma, right????"

That is the zillion dollar question if you are lucky enough to have made it this far, isn't it?  Sadly, it is one that we do not yet have an answer to....though we ratties are doing our best to give you some great numbers with the treatments at hand.  

Here is one such discussion with references to other arms developed in my study:  9 months after Nivolumab trial...stats, f/u, what we learned....  

I have listened to B and Weber discuss Kaplan Meier curves until I thought my brain would develop ANOTHER tumor!!!  B arguing for 2 years being the point they flatten out....Weber hedging his bets and noting 3 years as that magical point.  Bottom line:  Every day out is one day better.  Researchers agree now, pretty much across the board, that one year out with no disease is great, 2 years out is amazing and 3 years out there is a plateau which may mean....a CURE!!!!    We shall see.  Melanoma is a sneaky bitch.  However, every day forward is another day.  Another day to live and enjoy. Another day down the road to a cure....whether via current treatments already attained...or even better ones that may save even more dear ones.

Here's to the ratties!!! - les

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