For Melanoma: Ipi and Nivolumab (the BMS anti-PD1 drug)....better together!!!! Safe too!!!

Safety and clinical activity of nivolumab (anti-PD1, BMS-936558) in combination with ipilimumab in patients with advanced melanoma.
Authors:  Wolchok, Sznol, et al.  From:  Memorial Sloan-Kettering, Yale School of Medicine, Bristol-Meyers Squibb, NJ and CA.
J Clin Oncol, 31, 2013 (abstr 9012) for ASCO Meeting

CTLA-4 and PD-1 are critical immune checkpoint receptors. In melanoma patients, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (ant-PD1) produced an objective response rate of 31% in a phase I trial.  PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced anti-tumor activity in [mouse] models.  Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy.

Method:  Melanoma patients with greater or equal to 3 prior therapies received IV nivolumab and ipi concurrently, every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for four more doses.  At week 24, combined treatment was continued every 12 weeks for 8 cycles in patients with disease control and no dose limiting toxicities.  In 2 sequenced-regimen cohorts, patients with prior standard ipi therapy were treated with nivolumab every 2 weeks for 48 cycles.

Results:  Per Dec. 6, 2012:  69 patients were treated.  Data on 37 patients with concurrent therapy in completed cohorts 1-3:  Overall objective response rate (ORR) = 38%.  In cohort 1:  ORR = 21%.  In cohort 2: ORR = 47%, and 41% of patients had greater or equal to 80% tumor reduction at 12 week mark, with some patients showing rapid responses, prompt symptom resolution, and durable complete responses. Related adverse events for concurrent therapy were similar in nature with some higher frequency than those seen typically for monotherapies and were generally manageable using immunosuppressants.  Cohort 3:  ORR = 50%, BUT exceeded the maximum tolerated dose (MTD) [which happened to be ipi at 3mg/kg and nivolumab at 3mg/kg]. [NOTE:  Cohort 1 was treated with ipi at 3mg/kg and nivolumab at 0.3mg/kg.  Cohort 2 = ipi at 3mg/kg and nivolumab =1mg/kg]  At the MTD, grade 3/4 adverse events occurred in 59% of patients and included  uveitis/choroiditis, colitis, and reversible lab abnormalities.

Conclusion:  The combined therapy had a manageable safety profile.  Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (80% tumor reduction at 12 wk) in 30% (11/37) of patients.  A phase III trial is planned to compare concurrent combination dosing with each monotherapy.

Table of data:

Cohort          Ipi (mg/kg) plus        N       Complete         Partial             Overall         >/= 80% tumor  

                    antiPDI (mg/kg)                  Response         Response        Response      reduction at 12 wk
      1                3 + 0.3                     14            1                      2                    21%                  4/14 (29%)
      2                3 + 1                        17             3                      5                    47%                  7/17 (41%)
      3                3 + 3                        6              0                      3                    50%                   0/6   (0%)
      2a              1 + 3                        12            ongoing
      6                Prior + 1                  14            ongoing
      7                Prior + 3                  6              ongoing


ASCO 2013:  Phase I Trial Suggests Ipilimumab and PD1 Drug Nivolumab May Be Better Together than Alone for Advanced Melanoma
By:  The ASCO Post
Posted: 5/17/2013

Key Points:

• In a phase I trial, patients with inoperable stage III or IV melanoma who had undergone up to three prior therapies received combination therapy with ipi and nivolumab.
• In the three completed treatment arms, tumor shrinkage rates were 21%, 53%, and 50% with the highest rates seen in patients treated with the highest dose of both drugs.
• While the data are still preliminary, it appears that even patients who initially had little benefit from ipi, had significant tumor shrinkage after subsequent treatment with nivolumab.

Results from a phase I study with combined ipi (yervoy) and investigational drug nivolumab (BMS anti-PD1) led to lasting tumor shrinkage in approximately half of patients with aggressive, advanced melanoma.

"The complete and near-complete response rates we're seeing are unprecedented for an immunotherapy in melanoma, " said Jedd Wolchok, MD, PhD, a medical oncologist at Memorial Sloan Kettering.

Phase I trial:  In this trial, patients with inoperable stage III and stage IV (metastatic) melanoma who had undergone up to 3 prior therapies were assigned to 6 different treatment arms. The current results are based on 52 patients in 3 completed arms, in which patients received concurrent treatment with the two drugs.

In those three arms, tumor shrinkage rates were 21%, 53%, and 50%, with the highest rates seen in patients treated with the highest dose of both drugs.  The responses to therapy were rapid for an immunotherapy.  Three out of 4 patients who responded to the concurrent treatment experienced tumor reduction within the first 3 months, which is faster than with single-agent ipi. Thirty-one percent of patients (16 out of 52) experienced significant tumor shrinkage of more than 80%.

Two of the remaining three arms enrolled patients who had undergone prior ipi treatment. Those patients received only nivolumab on this study.  While the data are still preliminary, it appears that even patients who initially had little benefit from ipi had significant tumor shrinkage after subsequent treatment with nivolumab. 

Side effects have been manageable in the trial and did not impact the positive therapeutic activity for the majority of the patients in this analysis.  A randomized phase III trial of the nivolumab/ipi combination as first-line therapy for patients with advanced melanoma scheduled to begin in June 2013.

MY THOUGHTS and QUESTIONS: 

• All of the commentary, report, and table above are direct quotes from the two articles.
• Were patients with brain mets admitted?
• What time frame are we using for "durable"?
• While this is good news and I do believe that concurrent or sequential therapies will offer improved outcomes for many melanoma patients....I find it very strange and even suspect that headlines report the "big" numbers of "SUCCESS" on very SMALL numbers of patients and in the fine print admit that...Yes, the best results came from the group with the highest doses of meds, but we can't actually use that dose, because there were way too many side effects...but we're still going to use those numbers to sing our praises although we can't really give that to anybody!!!!  Look carefully at the table.  Especially at cohort number 3.  There were only 6 patients.  NONE of them had a complete response and only 3 had a partial response. NONE had the "80% tumor reduction at 12 weeks".  Yet, they are touting a 50% overall response.  Yes...that is the math.  But, I'm not sure it has real meaning with real patients and they state that that cohort had "dose limiting toxicities".  So....we'll see.
• The OVERALL objective response rate...so far...is 38%. We'll see what the final report at ASCO has to say.
• FYI:  I am being treated with this same anti-PD1 drug at 1mg/kg.
• Thanks to every rattie who went there for the rest of us.  Bless you every one. - c