Yervoy (ipilimumab; CTLA4 inhibitor) is in Bloom

Posted by Jeff Berk, BOLT International; We survived our raindrops.  But golly, how do the rest of you cope with the clouds and mud and stuff?  On the bright side, we did get our first flowers of the spring to bloom (picture below).  But you really want to hear about melanoma, right?…





We’ve been telling our clients for a few months that BOLT’s MELANOMA THOUGHT LEADER panel, interviewed in December 2010 predicted that BMS’ Study 024, the 1st line combination of Yervoy (ipilimumab; CTLA4 inhibitor) plus DTIC vs DTIC monotherapy, would show an overall survival benefit.  Bristol-Myers Squibb announced yesterday that this was, in fact, the case.  First, our panel was amazing in predicting the outcome of this trial; and we’re very grateful to them.  Later in this blog, if you haven’t been a subscriber to our Hem/Onc panels, you can read some of their comments which we published in that report.  But more relevant to a lot of our pharma buddies is the question of how ipilimumab will get sequenced relative to a BRAF inhibitor.  We include in this blog some of that discussion as well.


Ø  As an expensive monoclonal, payers are unlikely to reimburse for off-line use of Yervoy in the 1st-line setting.  They will force physicians to first give DTIC.  This should change in March 2011, when the 1st-line data on ipilimumab vs. DTIC is presented.  We predict this study to be “spectacularly positive” for ipilimumab.  The basis for this is that it is an event driven trial, with 50% of patients on DTIC and 50% on ipilimumab.  The trial has been ongoing for more than 2 1/2 years and still has not reached enough deaths to stop it.  The survival on DTIC is known, and by all expectations, all DTIC patients should be dead by now.  Thus, it appears that the mortality rate in the ipilimumab group is much lower than expected.  The take-home is that ipilimumab is going to be approved for 1st-line use in all metastatic melanoma patients; regardless of BRAF status.  In practice, the only patients who are going to get a BRAF inhibitor upfront will be those with very aggressive disease and confirmed BRAF mutations.  Otherwise, regardless of their what their BRAF or their HLA A2.1 status is, expect ipilimumab to be widely accepted as the standard of care for metastatic melanoma.


“I agree with you, I think that anything with durable impact trumps a magnitude of benefit even as great as 60% to 70% in objective remission or disease for patients who are considering the survival outcome”.


“I don’t think insurance companies will be able to force us to give first DTIC and then give PLX afterwards.  I think they could do it for ipilimumab because ipilimumab is a monoclonal and it is going to be priced much more expensively”.


“So it is different for ipilimumab because ipilimumab is a non-targeted therapy which has an interesting mode of action.  But we don’t have a clear target.  So in principle every patient is first or second line, for me it doesn’t matter, so every patient can be treated with this drug”.


“To be honest, not everyone is so optimistic with the ipilimumab first line trial as the person who presented that data.  The trial is delayed by no more than 1.5 years and the release of the trial of ipilimumab in first line.  But the design is completely different.  It is 10 mg/kg in contrast to 3 mg/kg for second line, DTIC plus/minus ipilimumab.  So it is a complete different story.  And if you ask me I would say yes if the first line trial is positive and it shows a median overall survival improvement of three months as expected it will not change the situation.  It can only change the situation if the first line trial shows overwhelming overall survival improvement of, whatever, nine months survival improvement.  Then the question might come up if you give ipilimumab first and after progressive disease in BRAF positive patients the BRAF inhibitor as a second line treatment.  That is the only scenario which I assume which can bring ipilimumab to the true first line treatment in BRAF positive patients”.




Ø  The ODAC for Yervoy (ipilimumab) in second-line metastatic melanoma was cancelled.  The PDUFA date is March 26, 2011.  The European MAA has been submitted and accepted by EMA for review.  We view the cancellation of the ODAC as indicative that there is little chance of FDA failing to approve Yervoy.  The drug will almost certainly be approved as 2nd-line therapy for BRAF mutant and BRAF wild type metastatic melanoma who are HLA 2+.   30%-40% of melanoma patients are BRAF wt, with no good treatment option on the horizon (besides ipilimumab).  Ipilimumab produces a lower response rate than PLX-4032, and it takes 3-4 months to see responses (much slower than RG-7204), but patients who do respond have dramatically long responses, and the drug has a proven survival advantage of 8%-10% in both BRAF wt and BRAF mutant melanoma.  Net, Yervoy should be approved April 2011, a couple of months before RG-7204.


“So if we assume that Yervoy (ipilimumab), which is going a month from tomorrow, I think tomorrow to ODAC, or I think December 2, so their indication would be in second line.  And PLX’s indication would be in second line but in the BRAF positive.  Since the first line drugs have not shown an impact in survival and the response rates are much lower – not an impact in survival that compares to ipilimumab – their response rate are dramatically much lower than PLX-4032 (RG-7204) then both drugs are likely to be used in first line.  Who will be giving DTIC in this day and age when you have a drug that can give a much higher response rate?  I agree with you that the indication will not be the use”.


You know the data from the second line ipilimumab trial and what does that show?  Well, at two years it shows 8% to 10% is the net benefit of ipilimumab after two years in the MDX010-20 trial”.


“We are talking about these patients and all the wild type patients are still in the same dilemma which is 30 to 40 percent of the patients where we don’t have really a good alternative at the moment”.


Ø  Ipilimumab is going to be used in a consolidation / maintenance role after tumor shrinkage by a BRAF inhibitor in BRAF mutant patients.  The strategy is going to be to give the BRAF inhibitor about 6-months to reduce tumor burden and then introduce ipilimumab.  One panelist conjectured that one of the reasons why ipilimumab will look so positive in the 1st line trial is because these patients start with a lower tumor burden than those typically enrolled in later-line trials.


“At the EORTC in Berlin just last week there was a thought leader who made some comment about expecting the first line trial to be very positive for survival for ipilimumab.  This person suggested that his expectation was that it was going to be positive in both BRAF mutant and BRAF wild type patients and that there was going to be a survival.  I completely agree with the guy, but I think we have completely different modes of action.  I think one has to keep that in mind having a patient sitting in front of an oncologist.  You have a drug like ipilimumab, whether it is given in first line or in second line that has shown some overall survival benefits.  However, the rate of patients who experience a real clinical response, so shrinkage of tumor, is only a minority.  So you have a certain discrepancy between prolongation of survival and no real tumor regression.  This is completely different with a BRAF inhibitor.  With a BRAF inhibitor, and possibly also the MEK inhibitors, you have a dramatic effect on the tumor in days or weeks.  So you have a drug which is reducing tumor in the majority of your patients.  I think the logical consequence of how these drugs will given is that the patient will be tested for BRAF/NRAS mutations or possibly ckit mutation.  Then these patients will get signal transduction blocker.  And then from the phase I and phase II data we know that the progression free survival time for these patients is between six to nine months.  So probably during that time or after six months you will have reduced the tumor by quite a bit, 50 to 60 percent on average.  Then I think it is an optimal point when you freeze the disease using ipilimumab.  I think there is no competition.  I think there is a perfect synergy between these drugs.  And possibly by doing so, by reducing the tumor mass at the beginning and then freezing the disease by ipilimumab we will even further increase survival benefit compared to patients treated with DTIC only.  This is just hand waving at this point.  But I think that is the concept which is ahead of most of the people right now and everybody is eager to start such a trial”.


Ø  The drug clearly prolongs survival in a small subset of patients, but there is no predictive marker that identifies which patients will benefit.   Ipilimumab and PLX-4032 may be useful in combination, as their mechanisms of action are unrelated.  There is some data suggesting that patients who will respond to CTLA4 have a similar cytokine signature as those who respond to IL-2.  Another marker may be ALC (absolute lymphocyte count); which if the level is over 1,000 by the second dose of ipilimumab, there is a >5% chance of response.


“We are starting to be able to identify which patients are actually going to benefit.  How? Again, at ASCO there was some data about ALC.  There is a publication from our institution that will show that if your ALC is up over 1,000 by the second dose your chance of benefiting from ipilimumab is going to be 5 percent or greater.  So that is a simple marker.  And then there is microarray, trying to subtype tumors into those that are maybe immunologically responsive vs. not.  So there are going to be other more complex ways as well”.


Ø  Sequencing immunotherapy vs BRAF targeted therapy is not that straight forward.  Patients with V600E mutations are going to respond to BRAF inhibitors, and have PFS in the 6-8 month range.  But all melanoma patients with less aggressive disease, for example in-transit metastasis, regardless of BRAF mutational status, will be candidates for ipilimumab before they get PLX-4032 / RG-7204.  There are two reasons.  First, ipilimumab gives a shot at a homerun where you can treat melanoma and you get rid of it.  The same is not true for RG-7204.  Second, patients with BRAF mutations will respond to PLX-4032 after they’ve been treated with ipilimumab.  We don’t know if patients with BRAF mutant melanoma that has progressed after RG-7204 will respond to ipilimumab.



“Here will be a drug, ipilimumab, that has approval in first line whereas the others will not have it.  Does that change the practical use of the drugs in your mind and in Germany? That is a good question.  And you can assume that this question has already been discussed with those companies, BMS and with Roche.  So it is not a big surprise that the majority of key opinion leaders believe that patients with BRAF mutations will be treated with a BRAF inhibitor first simply because it is a rapidly acting drug which shrinks the tumors within some weeks.  Thereafter everyone would like to give ipilimumab as a sort of a consolidation treatment or maintenance treatment.  But there is no clinical trial available with sequencing the drug or even giving it simultaneously.  So we can only speculate”.


“It is just a question of the sequencing.  So let’s assume the following:  you have two patients, one is BRAF positive and the patient will certainly be treated with BRAF inhibitor first and then after progressive disease and most of the BRAF inhibitors are only causing partial responses; they are not complete responses.  Then the patient will receive ipilimumab.  In patients with negative BRAF status, these patients are very good candidates for ipilimumab in first line.  Subsequently they will not be treated with a BRAF inhibitor because they don’t have a BRAF mutation.  Therefore if you look at the market prospective I would say there is a better market for ipilimumab because it is a non-specific drug”.


“When is ipilimumab being offered to patients?  Right now we can only give it to them after they progress on the prior line of therapy.  So ideally our BRAF gene patients get some sort of BRAF targeted therapy and then at the time of progression they get ipilimumab on the compassionate use program.  And it is the same thing say with our kit mutant melanoma patients, they get imatinib, nilotinib or something and then at the time of progression can get ipilimumab.  Got it.  Okay. The question will be what happens when ipilimumab is approved.  That is where I am driving you towards.  How is that going to change? The approval will be in second line.  I mean if it is approved in December it will be in second line probably for HLA 2 positive patients only.  So we will probably stick by that initially.  As far as what the general community is going to do I am not sure.  I think there is going to be a steep learning curve for the general community once this drug is available in terms of both how the drug works, who the best patients are to use it and in managing the side effects.  I think because of the kinetics of the activity, this is not a drug you want to use in rapidly progressive widespread disease in the front line or second line or whatever.  So that is something that is going to have to be communicated to the community.  Although it does improve survival, it takes three or four months to see some sort of stability of response typically”.


“In patients who have BRAF mutation but the tumor presents as a slow growing tumor, for example, in-transit metastases or something that is not looking too aggressive I may use ipilimumab first.  Ipilimumab gives a shot at a homerun where you can treat melanoma and you get rid of it.  We don’t know if the same will hold in BRAF mutant melanoma that has progressed after PLX4032.  Maybe whatever secondary progression changes make those tumors resistant to ipilimumab.  Since it hasn’t been tested in patients and I suspect there is going to be time for one or two or three lines then I will probably use ipilimumab up front”.

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