We’ve finally gotten around to publishing Melanoma Thought Leader Panel #31 2012-07. As always, if you’re a patient, email me (firstname.lastname@example.org) and we’ll figure out which sections will be helpful for me to give you, Pro Bono. I’ll get to the pharma sales pitch later. But first…
I’ve gotten a couple of questions from patients since ASCO asking about getting on trials. Most have been asking about the PD-1 inhibitor, BMS-936558. This weekend I asked Toni Ribas what trials are actively looking for patients, and his response is as follows:
Jeff, I would encourage these patients to look for clinical trials with any of the anti-PD-1/PD-L1 inhibitors currently on study besides the Curetech/Teva one. The only one we have open right now at UCLA is the Merck MK3475 trial, but it is currently not enrolling. In two months we should have new slots. After that it would go to a randomized trial in patients previously treated with ipi that should be open in many sites across the world. We are also working with BMS to open their similar randomized trial, but we have not yet received the protocol from either site.
If you come across patients with BRAF mutant metastatic melanoma who have not yet started on a BRAF inhibitor, we have slots in the ipilimumab+vemurafenib phase 1 trial (one available immediately), and also in vemurafenib+MEK inhibitor trial. I would regard these two options as better than single agent Zelboraf. Being phase 1 trials there are several visits at UCLA to be done, but these are mostly during the first one to two months, and then it becomes manageable to do from a distance. You are welcome to give out my email if any of the patients you are in contact want to consider either study.
Toni’s email is: “Ribas, Antoni” <ARibas@mednet.ucla.edu> If you are using BOLT’s blog as a reference, please let me know that you reached out to him.
Okay, so this has been an amazing two years for the advancement of melanoma therapies. ASCO 2012 served as the coming out party for PD-1 and PD-L1 checkpoint inhibitors, for BRAF/MEK combination therapy (dabrafenib / trametinib), and for a host of new MOAs and combinations of immunotherapy + targeted therapy. Our report captures all of the discussions and debates on these and other issues. In this blog, I want to share a little bit of the commentary that we heard from our Thought Leaders on how they are thinking about combining I + T therapy in the era BEFORE some of the clinical trials can shed more definitive light on the matter:
- BRIM-2 showed that vemurafenib can stabilize metastatic BRAF mutant melanoma patients generally in the range of 6-16 months. These patients derive significant symptomatic benefit. So, while BRAF inhibition is obviously an important improvement for these patients, it is not going to cure them. For the most part, they will relapse. Thus, there is an ongoing debate on how to best sequence Yervoy and future immunotherapies, e.g. anti-PD1 therapy, with targeted therapy. There are a variety of ongoing trials designed to answer this question. At this time, the Panel can only give their “gut feelings”, and we try to capture those in this section. But the first trials to delineate the optimal sequencing for approved therapies vemurafenib and ipilimumab are underway. Vemurafenib crossed over to ipilimumab and vice versa is ongoing at ECOG and SWOG (E1612). The point of crossover is chosen by the physician, not predetermined by a set time period or by progression. Also, concurrent vemurafenib + IPI therapy is also being explored (NCT0140051).
“You are raising a more general question for all the targeted therapies which are available for melanoma and maybe for other cancers as well, about the durability and how many of these patients will need another subsequent salvage therapy. In my opinion, I believe that not the majority of patients will have an immediate relapse once they responded to the BRAF inhibitors. The longest patient under treatment now without a relapse. So you might have stable situation after a while where you know the PR is let’s say 80 percent reduction of tumor sites and it doesn’t go down further, but it is still stable. So we have the data from second line treatment, the BRIM-2 trial, which was 16 months median survival time. So once you have a progression-free survival of six months the patients live in median at least 10 months, which is not so bad. It speaks against the hypothesis that each and every one will have a progressive disease. But I agree, it is not time to talk about cure of metastatic melanoma now. Therefore, my hope is to combine either CTLA4 antibodies like it is done in phase I right now with BRAF inhibitors or you go ahead with a very effective…I would say that the effectiveness of combining a drug which works more than immediately after one to two weeks and destroying tumor cells and releasing tumor antigens and combining with CTLA4 antibody or PD1 antibody is superficially very attractive, but also if you go into the depth if there are no toxicity issues, and I don’t know at the moment if there will be toxicity issues, but if there are no toxicity issues this is the most attractive combination I am seeing at the moment”.
“I think the understanding of resistance is increasing. None of that to date has meaningfully allowed us to reverse the resistance. I think it will be a bit of the issue that you already highlighted of figuring out how long you can get away with doing one thing that is more dramatically able to remit disease up front and follow that at a fixed timing with one of the immunotherapies. So the other big question that was discussed at a couple of junctures doesn’t really yet have any solid data to buttress it is the whole issue of as to whether if you have the opportunity with BRAF mutated to do a molecular therapy like vemurafenib. But you also have the opportunity to do an immunotherapy, say ipilimumab. The question of whether doing one is going to be preferable to doing the other first. A suspicion that has been voiced by a number of members of the community even fairly sage and longstanding members of the community is that after you give a BRAF inhibitor you rarely get to immunotherapy because when they finally flunked that kind of therapy they are never able to partake of any of the immunotherapies with their longer window to having antitumor effect. So I guess a proper trial has now been proposed and mentioned a couple of times at ASCO, the trial 16112 of ECOG but also joined now by the Southwest group will test that. Take BRAF mutant patients and randomly assign half get vemurafenib and the other half you get ipilimumab and see what two longer terms of these controls from the second modality may be. I think that is going to be an interesting and extremely important question. So those patients will all crossover when they advance on their first line? You hit upon the really central question how to arrange for the crossover. We talked about six times crossovers and then we said should we just have everybody take the therapy until there is some progression and then crossover. Ultimately it was the latter decision of the physician to make the choices because physicians can kind of answer this for and not just schedule an arbitrary three or four or five or six month crossover, but that would be another way to do the study”.
- Generally, if a patient is responding to targeted therapy, most people would not consider taking them off the targeted therapy and switching them to an immunotherapy. Rather there will have to be some overlap, so by definition there will be a period when patients are receiving (and experiencing toxicities from) both therapies. As long as the patient is responding to the e.g. BRAF inhibitor, it makes no sense to discontinue that and switch them to e.g. ipilimumab; which may produce durable cures in only 20% of patients. Some patients continue response on BRAF inhibition past 3 years, and while this is a small minority, Panelists don’t view that number to be significantly lower than the long term response rate to ipilimumab. So the procedure that is actually being used by Thought Leaders (and being supported by Roche/vemurafenib and BMS/ipilimumab in the setting of a clinical trial; CA184-161) is 3-4 weeks of vemurafenib or dabrafenib, then 4 doses of ipilimumab followed by reintroduction of the BRAF inhibitor.
“How do you think about the logistics of combining the targeted therapy plus immunotherapy? So let’s just do two products that are currently on the market so you can write the prescriptions for them. So let’s say you are considering a patient on vemurafenib and ipilimumab. If you were to do so from time zero what dose schedules would you see yourself using? In other words, are you ever going to have those patients receiving the same drug within the same week or are you going to sequence them somewhere? Excellent question. I would love to do a randomized phase II trial in addressing this question. And my idea would be at least theoretically I would believe that combining them immediately is the best choice. The protocol right now is using vemurafenib given first and then after four weeks you are stepping in with ipilimumab. Whereas my idea would be to give the CTLA4 antibody concurrently immediately, because we know that it needs 12, 14, 16 weeks to work. Therefore, it is at least superficially more attractive for me to use them simultaneously. The other issue is if this is a randomized phase II trial I would use the arm with concurrent treatment. The other one which steps in after four weeks, and the other one which could also be very attractive, is to use ipilimumab first. And then after four to eight weeks you step in with the BRAF inhibitor simply because we know, and this has been presented by Mike Adkins group at ASCO, that even if the patient with a progressing disease under the CTLA4 antibody the response rate is exactly the same as in the first line situation. This speaks for the third hypothesis, using ipilimumab first and then after four or eight weeks you step in with a BRAF inhibitor”.
“This entire discussion is driven by the concept that you are not getting long-term survival in the patients who are treated with BRAF inhibitors. Do you challenge this? Yeah, I am not so convinced about that at the moment. There is also a small subset of patients getting BRAF inhibitors who are on treatment now for more than two or three years. We also have patients who are now almost close to three years. It is a small subset but three years survival rate for ipilimumab is also only 12 percent. I think that is very difficult in my view, but still I think it is attractive to combine different agents which have shown some clinical efficacy and I think that is true for ipilimumab and that might also be true for the PD-1 antibodies in the future. But on the other hand we have to keep in mind that we have no clear data on the real and the best sequence. So what we should do should we start with a BRAF in inhibitor or the combination MEK/BRAF and then add at what time point which immunomodulating antibody? What does your gut tell you about that at this point? I think that is quite difficult to make the point. I think the current idea is to start with a BRAF inhibitor first (and then because you anyway need some time with ipilimumab to expand the T-cell repertoire) and then follow with ipilimumab. But possibly you could do it parallel, I don’t know. I think that needs to be tested and from what I have seen there are trial proposals already put forward trying to address this. Do the vemurafenib first and then follow with ipilimumab, and others start with ipilimumab and follow with vemurafenib. I think there are several translational studies needed in order to solve this question. I think it is extremely early to talk about that. And in addition, what you have to keep in mind maybe not so much with the BRAF inhibitor which are quite specific, but for the MEK inhibition, one has to keep in mind that the MEK inhibitors are much more broadly active in terms of possible also having effect on the T-cell function. We have absolutely no idea how, for example, MEK inhibitors and T-cell function and modulation by ipilimumab or PD1 antibodies is having an additive effect, a synergistic effect. Or, are we eliminating part of the effects by ipilimumab in certain cells or amplifying some effect of ipilimumab by using MEK inhibitors. That is a completely unexplored area which is not studied at all from what I know”.
“People ask me that question in the community. Like they have people on Zelboraf and they are asking well should we just add ipi, like right now when they are responding or at the first sign of a little bit of progression. The problem is we don’t have the safety data out yet. The study is being done by Roche and BMS in centers which don’t include our center. It is like Toni Ribas and the Memorial people and others and they have not reported anything. So I don’t know if it is safety to combine. And if it I safe actually my preference would be to bring it on earlier. Give them like a running of BRAF, release some antigens and then bring on ipi and then continue BRAF basically. That is what I would do if I knew it was safe. Actually what I did in one patient, and I will see how that goes – I had him on dabrafenib and he started progressing so I took him off and then I put him on ipi standard of care. And of course he is progressing because he has aggressive cancer so ipilimumab takes forever to take. So as soon as I finished four doses of ipi, which actually as somebody mentioned there is like doing a concurrent because ipi hangs around for a long time, I put him actually on Zelboraf last Friday. Just switch him back to a different RAF inhibitor? Yeah, because I couldn’t put him back on dabrafenib because he progressed and it was a study. So I put him on Zelboraf and we will see what happens. There is actually data for reintroduction of Zelboraf. People reported case reports where you do Zelboraf, you stop for whatever reason and then you reintroduce it and they respond again, which is not surprising, people do that with renal cancer and targeted agents. In selected patients continuation of vemurafenib or with radiation or local therapy is actually possible. I have no doubt about that. But you still kind of hit the wall at some point no matter what you do”.
“One of my colleagues said to me and he is treating melanoma patients in the community so he doesn’t only do melanoma. He said his takeaway from all of that data was that all of those small molecules, either RAF or MEK inhibitors, he should be thinking of as a bridge until his immunotherapy kicks in. I thought that was an interesting comment. Yeah, and that is a very common thought. So that would only be if you start with one of these small molecule inhibitors. You stop the growth of the tumor, it regresses and then you give an immunotherapy that maintains that response. But why would you wait? Why not just bring them on? I would do it up front. I was going to go to, let’s say with vemurafenib, and I heard that somebody was doing this, that they say oh we will start the patients on Zelboraf and three months later we will stop Zelboraf and give Yervoy. I think that is a terrible idea. So you have a patient responding to Zelboraf, you stop the pill, you give Yervoy that has a 10 percent response rate and then 90 percent of the patients will progress. Right. That doesn’t make sense. It makes no sense to me. Let’s say it is great and 20 percent of the patients respond well, 80 percent of the patients will progress. So it doesn’t make sense to me”.
So, the soft-sell sales pitch…
Companies/compounds discussed in this report:
Yervoy (ipilimumab; Bristol-Myers Squibb)
gp100: 209–217(210M) peptide (NIH)
Proleukin (aldesleukin; IL-2; Prometheus)
GSK2132231A MAGE-A3 (GlaxoSmithKline)
BMS-936558/MDX-1106/ONO-4538 (anti-PD-1 antibody; Medarex / Bristol-Myers Squibb / Ono)
MK-3475/SCH 900475 (Merck)
AMP-224 (Amplimmune / GlaxoSmithKline)
MPDL3280A (Roche / Genentech)
TIM3 antibodies (Brigham & Women’s)
biochemotherapy (cisplatin, vinblastine, DTIC, IL-2, IFN)
Zelboraf / vemurafenib / RO5185426 / PLX-4032/RG-7204 (Plexxikon / Roche)
dabrafenib / GSK2118436 (GlaxoSmithKline)
BMS908662 / XL-281 (Bristol-Myers Squibb; Exelixis)
trametinib / GSK1120212 (GSK)
GDC-0973 (Genentech / Exelixis)
pimasertib MSC1936369B (Merck Serono / Sanofi-Aventis)
MEK-162 / ARRY-162 (Novartis / Array)
MSC1936369B (EMD Serono)
mTOR / PI3K / AKT
GSK2110183 (AKT GSK)
MK-2206 (AKT Merck)
GSK2126458 (PI3K GSK)
SAR245409 (XL765) (Sanofi-Aventis / Exelixis)
Avastin (bevacizumab; Genentech)
Nexavar (sorafenib; Bayer-Schering / Onyx)
Zaltrap (aflibercept; VEGF Trap; Sanofi-Aventis / Regeneron)
lenvatinib (E-7080; Eisai)
tivantinib / ARQ-197 (ArQule / Daiichi-Sankyo)
cabozantinib; XL-184 (Exelixis)
Temodar (temozolomide; Bayer-Schering)
Abraxane NAB-paclitaxel (Celgene)
Tasigna (nilotinib; Novartis)
Gleevec (imatinib; Novartis)
Sutent (sunitinib; Pfizer)