ASCO 2017: Ipi 3 mg vs 10 mg in advanced melanoma and as adjuvant

Ipilimumab (Yervoy - anti-CLTA4) a type of immunotherapy, was FDA approved for Stage IV melanoma in 2011 and as an adjuvant treatment for Stage III patients in 2015.  Despite its significant side effect profile, the limitations of its 15% response rate, time has proven the durability of many of those responses.  In whatever light you see it now...it was an unbelievable boon to those of us with melanoma in the years before 2011 when our choices were limited to conventional chemo (known to be dismally ineffective against melanoma), IL-2 or interferon.

As such, with the advent of the anti-PD-1 products Nivolumab/Opdivo and Pembrolizumab/Keytruda with their response rates of 40% and decreased incidence of adverse effects the the role of ipi is....undefined, shall we say...except by the FDA, who in their wisdom have ordained the following:
1.  Stage IV melanoma patients may be given the ipi/nivo combo (also FDA approved in 2015)...in which ipi is dosed at 3mg/kg...for a response rate of 50+%.
2.  Stage IV patients shall be given ipi, if they desire or if they have failed other things...alone at a dose of 3mg/kg.
3.  Stage III patients may use ipi (but not the anti-PD-1 products nor the ipi/nivo combo) at a dose of 10mg/kg.

So...here's the question(s)...  Why give ipi at a greater dosage for Stage III folks than for Stage IV folks?  Why can Stage III folks not have access to the other options?  Which dose of ipi is better?

To the first two pregunta's....the answer is simply:  that is how the trials with the meds in question were set up when they were submitted for FDA approval.  Can the FDA not extrapolate between various studies? No!  Can the FDA use common sense?  No.  I could go on....but...  As to the last question...which dose is better???  Most experts and studies have indicated that despite the sad fact that folks who have already taken ipi respond less well to anti-PD-1 later should they need it [ Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????  ] the 3 mg/kg dose provides almost the same responses as the 10 mg/kg dose with a much lower side effect profile...though Weber has admitted that should you be able to tolerate the 10 mg/kg dose the response ARE actually, a little better.

However, I was a little concerned when I read and posted this study:  Ipi - 3mg vs 10mg/kg - Increased OS with increased SE on 10!

Now, there is this from ASCO comparing ipi at 3mg/kg to 10mg/kg in advanced melanoma...
(Oh, and of course, if Kirkwood has his name on it...interferon will be involved...even if it does nothing more than torture innocent ratties...even if it has nothing whatsoever reportable to offer...it is a horse he is going to ride until he drops.  Please dear God, never, ever, ever, ever let us be THAT person.  The person who is unwilling to admit error.  Unwilling to move on with the times.  Unwilling to stop the suffering of others when all he would have to say is...I was wrong.)

A randomized phase II study of ipilimumab at 3 (ipi3) or 10 mg/kg (ipi10) alone or in combination with high dose interferon-alfa (HDI) in advanced melanoma (E3611).

ASCO 2017. J Clin Onco 35, 2017. Tarhini, Len, Rao....Kirkwood.

Background: Interferon-α (IFN) favors a Th1 shift in immunity. Combining CTLA4 blockade with IFN may downregulate CTLA4 suppressive elements. Prior data from a phase II of tremelimumab and HDI showed promising efficacy supporting the current study. Methods: E3611 had a 2x2 factorial design (A: ipi10 + HDI; B: ipi10; C: ipi3 + HDI; D: ipi3) to evaluate (i) no HDI vs. HDI (across ipi doses) and (ii) ipi3 vs. ipi10 (across HDI status). We hypothesized that median progression free survival (PFS) would improve from 3 to 6 months (mos) with HDI vs. no HDI and with ipi10 vs. ipi3. Based on the log-rank test for 80 patients (pts) these comparisons would have 82% power at 2-sided type I error of 0.10. Results: Median follow up 26.4 mos. PFS and overall survival (OS) (eligible and treated pts; N = 80: 18 III/M1a, 24 M1b, 38 M1c) are shown in Table 1. There were no significant differences in PFS or OS when evaluating HDI vs. no HDI or ipi10 vs. ipi3 (Table 1). Response (RECIST) among response evaluable pts (and 4 pts with early death) (N = 76) is shown in Table 1. Stable disease (SD) in 7 (A), 6 (B), 8 (C) and 6 (D). Adverse events (AEs) were consistent with the toxicity profiles of ipi and HDI and included 3 grade 5 AEs considered at least possibly related: 1 in A (suicide), 1 in B (lung infection and hemorrhage) and 1 in C (adult respiratory distress syndrome). One patient in B died of gastrointestinal bleed and cardiac arrest while on corticosteroids to treat temporal arteritis and vision loss. Conclusions: Within the limitations of the sample size, there were no significant differences in PFS with HDI vs. no HDI or ipi10 vs. ipi3. Response and PFS with ipi10 were superior to historical controls and similar to the combination. Correlative studies are ongoing. 

And here - ipi 3mg/kg vs 10mg/kg as adjuvant... (the same caveats noted above apply!)

A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms.

2017 ASCO. J Clin Oncol 35, 2017. Tarhini, Lee, Hodi, …Hamid, ….Sosman, ...Sondak, ...Flarherty...Kirkwood.

Background: In the U.S., 3 regimens have regulatory approval as adjuvant therapy for high-risk melanoma, including high-dose interferon-alfa (HDI) and ipilimumab 10 mg/kg (ipi10). Ipilimumab 3 mg/kg (ipi3) has regulatory approval for metastatic inoperable melanoma. The toxicity of ipi is dose- dependent, and following the recent approval of adjuvant ipi10, it has become urgent to evaluate the relative safety and efficacy of adjuvant ipi at the 2 dose levels that have been tested in E1609. Methods: E1609 randomized patients (pts) with resected high-risk melanoma (stratified by stages IIIB, IIIC, M1a, M1b) to ipi10 or ipi3 versus HDI. Co-primary endpoints were RFS and OS. The current analysis investigates the relative safety and preliminary, non-comparative RFS of the ipi arms as of 3/2/17. Results: E1609 was activated on 5/25/11 and completed adult pt accrual on 8/15/14. Accrual to ipi10 was suspended due to toxicity between 9/23-11/16/2013. Final adult pt accrual was 1670 including 511 ipi10, 636 HDI and 523 ipi3 pts. Treatment related adverse events (AEs) were reported among 503 ipi10 and 516 ipi3 pts. Worst degree (Gr 3+) AEs were experienced by 57% ipi10 and 36.4% ipi3 pts and were mostly immune related (Table 1). AEs led to discontinuation of treatment in 271 (53.8 %) of 503 ipi10 and in 180 (35.2 %) of 512 ipi3 pts during the initial 4 dose induction phase. Gr5 AEs considered at least possibly related were 8 with ipi10 and 2 with ipi3. At a median follow-up of 3.1 years, an unplanned RFS analysis of ipi3 and ipi10 on concurrently randomized pts showed no difference between the 2 arms. Three-year RFS rate was 54% (95% CI: 49, 60) with ipi10 and 56% (50, 61) with ipi3. Conclusions: Adjuvant therapy of pts with high-risk melanoma is associated with significantly more toxicity at ipi10 compared to ipi3. An unplanned RFS analysis of concurrently randomized pts on the 2 ipi arms showed no difference in RFS. 

Grade 3+ ae's	ipi 10 (%)	ipi 3 (%)
colitis	19.5	13
endocrine	10.7	5.4
liver	8.2	3.5
skin	8.8	5.8
pancreas	5	3.7
neuro	1.8	1.2

So....in both studies above....progression free survival and relapse free survival was no different in either the advanced melanoma patients nor the Stage III melanoma patients no matter the dose of ipi they were given.  As expected, however, side effects were much greater at the 10 mg/kg dosage.  Also as expected:  interferon didn't do a damn thing!!  As ever.  Can you and your compatriots possibly be done Mr. Kirkwood???  We deserve better.  WE KNOW better.  When will YOU get a clue?????

Sorry.  Interferon rant over...for now....  Ipi 3 vs 10 - equal success.  More side effects with 10. FDA....are you listening?????? - c

PS:  The Edster shared this link where Dr. Weber addresses his Top 5 important picks from ASCO, including this one. See his review here:  http://www.medscape.com/viewarticle/880602