Weber presentation on ipi combo's and combo's coming soon!

Here is a link to Weber's presentation in Paris July 2014:
Combination therapy presentation by Weber

My synopsis:

Nivolumab (anti-PD1) and ipilmumab (anti-CTLA-4) given concurrently-
Nivo at 1mg/kg and ipi at 3mg/kg for 4 doses then followed by nivo alone for 96 weeks.
Best results so far, but with significant toxicities.
Trial requires that when dose limiting toxicity develops, patient must stop trial.
Weber feels you can treat the patient with steroids and then safely resume with nivo alone.
Positive or negative BRAF status did NOT matter in regard to response.
PDL1 tends to "fall out" as a factor...folks positive or negative for it could still respond to concurrent therapy.
In concurrent cohorts = 43% overall response, 17% complete response, 79% 2 year survival
Though that still leaves 50% of patients who did not respond.

Nivo and ipi given sequentially-
Group with nivo first, followed by ipi - another with ipi first, followed by nivo
He is working on the study currently with Hodi.
The hope is that a higher dose of ipi can be administered in this manner without invoking dose limiting toxicity and yet increase response rates.

Ipi and Tvec-
The idea here is that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic ipi.
Overall response rate of 56%, with 6 of 18 patients acquiring complete responses.
Weber likes the idea of priming tumors locally and following with systemic therapy, either ipi or anti-PD1.

Ipi and INCBO24360 (an IDO inhibitor)-
The problem with immunotherapy is that there are suppressive influences in the immune system - the absence of effector cells, the presence of t-reg suppressor cells (activated by LAG-3), myeloid suppressor cells, IDO (which is generated by antigen presenting cells as well as T-cells)....all working to prevent an immune response against melanoma! In this study, an IDO inhibitor was given (at either 25 or 50mg) orally, twice daily, everyday.  Ipi was given at 3mg/kg every 3 weeks.
Was well tolerated.  33% response rate.
Immunotherapy naive patients did better.
This study speaks to the ability to overcome micro-environmental immune suppression as well as increase the influx of effector cells by decreasing IDO.

Nivo and peptide vaccine-
Idea was that if you gave multi-peptide vaccine you could amplify the immune response against the peptide, and get a better response from nivo.  No evidence that this worked at all, though nivo itself did well.
100 patients, initial ones got peptide vaccines with escalating nivo dose, depending on cohort, every 2 weeks for 6 months, then nivo alone every 3 months for 2 years.
Cohort was added (later) that allowed patients who had dose limiting effects on ipi-
20 evaluable patients as one dropped out.
Got nivo alone (no vaccine).
8 confirmed partial responses and 3 stable patients at 24 weeks.  All patients who responded still remain in remission, with one being out 1 1/2 years.
Only 2 patients had dose limiting toxicity on nivo...rash and pneumonitis.
However, these were not the same DLT that they had experienced on ipi.
40% response rate.
Most anti-PD1 trials haven't allowed patients with prior bad responses to ipi.  Weber feels as these patients go to doctors seeking anti-PD1 as it comes on the market, they should be treated with it!
Back to general results-
The presence of peptides or not, ipi refractory or naive - made no difference in results.
26% response rate in these very ill patients, s/p multiple treatments.
NOTE by Weber:  The pembro studies demonstrate a significant difference in response rate between ipi naive and ipi refractory patients [with refractory doing less well].  "It makes you wonder- Are these drugs really the same?"
Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.
There was worse overall survival in female patients.
Given responses in this group with 2 1/2 year end-point of anti-PD1 infusion...Weber questions whether patients really need to continue anti-PD1 infusions until progression as the Pembro trials/indications have been written.

Ipi and Peg interferon-
Ipi at 3mg/kg every week for four doses with 3mg/kg peg interferon sub-q weekly for up to 3 years.
30 patients. 1 compete response. 13 partial responses. 3 with stable disease.  46% response rate.

Planned combo's-
Pembro and T-vec
Pembro and IDO inhibitor
Pembro plus BRAF plus MEK
MEDI 4736 and anti-PDL1
Nivo and anti CD137 (to start in the next month or so!!!)
Nivo and anti-LAG-3
Adjuvant ipi and Nivo (now being expanded with 1,500 patients!!!!)
     So far, in patients in the first cohort - there has been a 45% response rate, with only 20 patients and only at 8 month f/u...no relapses, and includes patients with Stage IV/IIIC melanoma.

So there you have it folks.  Hope this helps! - c