Ipi, BRAF/MEK, Anti-PD1 [and NO MORE DACARBAZIN???!] - per chat with Antoni Ribas

A conversation in the wake of data presented at the European Cancer Congress 2013....

Ipilimumab Goes the Distance in Melanoma
Antoni Ribas, MD and Caroline Robert MD.  Medscape.com.  October 8, 2013 [excerpts]

Ribas (David Geffen School of Medicine at the University of California Los Angeles):  We have BRAF inhibitors, the BRAF plus MEK combinations, ipilimumab, PD1, and PD-L1 antibodies. We have heard important updates... Let's start with the long-term updates on ipilimumab (ipi).

Robert (Dpt of Dermatology at the Institut Gustave Roussy in France):  We are happy to see that plateau with...ipi.  We would like to have more patients responding, but we are happy to see that when patients survive at 3 years, the odds are that they are still going to survive at 5 years.

Ribas:  [We] have talked many times about this hallmark of immunotherapy - that when you have a good immune response to the cancer, that can be extremely durable.....we are seeing that play out with ipi, which is great information.

How is [the combination] of BRAF and MEK inhibitors improving on what we have with BRAF inhibitors alone?

Robert:  It is the ideal combination...together, [these 2] drugs, have better efficacy with a longer duration of response, and you have fewer adverse events.

Ribas:  ...the data from dabrafenib and trametinib (BRAF and MEK inhibitors) published in the New England Journal of  Medicine, suggesting a higher response rate, a more durable response with fewer skin side effects from blocking a paradoxical MAPK pathway activation.  [In another study], a dose escalating phase 1 trial using vemurafenib, a BRAF inhibitor, with cobimetinib, ..another MEK inhibitor.  By putting them together...the response rate was extremely high.  They reported a 95% objective response rate.  It is close to a near guarantee of having a response at these levels, and we haven't reached the median progression-free survival, telling us that the curve is staying up quite a bit.

As we get more responses, are they lasting longer?  The BRAF-plus-MEK combination is telling us this.

Robert:  Unfortunately, what we hear is that when patients have failed a BRAF inhibitor previously, then not a lot of them respond.  Only about 15% of patients responded.

Ribas:  This study is telling us something...biologically important....we can get a secondary response by adding a MEK inhibitor to patients who are progressing on a BRAF inhibitor.  Whenever there are mechanisms that are dominant in activating MEK...all of theses patients respond.  The problem is that it is not a durable response.  And when we add the MEK inhibitor, we find another mechanism of resistance. So, melanoma is still trying to fool us, but we are also making progress on other fronts, by taking away another checkpoint:  PD-1 and PD-L1.

Robert:  We are amazed at the results that we see with PD-1 blockade....a lot of patients responding: 30-40%. And though we have less follow-up than we have with the drugs that are on the market, we have the feeling that we are seeing long-term responses, and the side effects are not bad.  Now we think that it can be combined with an anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4)  {like ipi} agent for an even higher level of response.

Ribas:  ...follow-up data on the combination of ipi (an anti-CTLA-4 blocking antibody) and Nivolumab (a PD-1 antibody)...[shows] a very high rate of objective responses, more than 50% in the dosing regimen that is taken forward, with most responses continuing on.

Robert:  This is also why we might now have to change our endpoint....when we know that we have drugs that are so effective, to wait until overall survival is confirmed at the end of a phase 3 study.  What do you think about using progression-free survival as an endpoint for our patients?

Ribas:  Flaherty (from Mass General) presented... a study in which they looked at...data from patients who were in randomized trials that had dacarbazine as the control arm.  We are not even using this word anymore in conversations about melanoma because so many agents have improved overall survival....and taking all the studies...comparing ipi and dacarbazine vs dacarbazine, ...vemurafenib vs dacarbazine, dabrafenib vs dacarbazine, and trametinib vs dacarbazine - all of these studies have shown that another treatment was better than our old standard.  For you and me it is difficult to sit in front of a patient and talk about the control group to which (for the purpose of the phase 3 study) we cannot give a highly active agent that is already out there.  Knowing that progression-free survival may be a hard endpoint that correlates with overall survival would be a great thing.

Amen!  Stop using crap as a control arm.  Patients deserve better.  As a last ditch effort, when all else has been tried....sure....if the patient wants to throw some dacarbazine at melanoma...by all means.  But, stop wasting rattie time, energy, dollars and lives in testing new and better drugs against old meds we know they beat already.  To continue to do so does not produce effective trials....only pseudo science.  And benefits whom?  Drug companies?  It certainly doesn't help anyone else!

Hang in there ratties!!! - c