Merck EAP PD1 or MedImmune PD1 - question?

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4/28/2014 8:52pm
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Any thoughts whether I should do Merck or MedImmune PD1 or something else?

Just found out today I failed the taf/mek combo. So I'm trying to figure out the next treatment. At least I have choices. I'm thinking either merck or medimmune PD1 but my gut tells me there is something better I just haven't found it but I do feel it is something with PD1.

Merck EAP PD1 will be the 3mg/kg which they only reported results for all doses not this low dose. Otherwise seems to be no washout period or anything else bad about it that I could find. I can get this at Mayo where I'm already in their system. If I do this it disqualifies me for MedImmune PD1. NCT02083484

MedImmune PD1 would probably be the 10mg/kg. Has a 28 day washout period. Is phase 1 so is fairly unknown. I can get this at Sarah Cannon where I'm already in their system. Can do this and still qualify for Merck PD1. NCT02013804

NCT01753089 wdvax shows up as PD1 on search which looks interesting but is phase 1.

NCT01621490 BMS PD1 the folks at MD Anderson were not too eager for me to be in this when I asked them. Not sure why since it does allow ipi failures.

Not really seeing any other PD1 out there that I qualify for that has started.

The failing of the taf/mek combo was fairly minor according to the doctor's PA. One tumor grew about 50%. 2 new supraclavicular lymph nodes demonstrating increased FDG uptake. Everything else either stayed the same size or shrank by a tiny amount.

 

 

 

Artie, I can't tell you how impressed I am with how much you have learned and matured since you first started posting here. You are handling the emotional ups and downs of this disease with strength and grace and constantly trying to research the best treatment options available for melanoma. Considering how much work and frustration is involved in planning any treatments, especially clinical trials, and considering that you probably don't feel all that well or energetic most of the time, I think you're doing great. 

I'm sorry that the BRAF/MEK was not 100% successful for you, but it's good that you had at least a partial response and your tumors are stable for now. BRAF/MEK is not usually a permanent cure, anyway. As you hoped, the extra time you gained from the BRAF/MEK allowed you to have at least 2 new treatment options-- Mercks' EAP or the Medimmune anti-PD1-- plus a couple of new clinical trials.  

You seem to have a very good handle on your treatment options and some very excellent melanoma specialists advising you so there is nothing much I can add. The only thing you might want to think about is that the 2014 ASCO meetings will be held in Chicago starting May 30th. There might be some exciting new developments and helpful new data from melanoma clinical trials presented at the meetings. So if you are comfortable with a one-month "washout period" you might choose to wait a month to see what comes out at ASCO before making your final treatment decision.

In the meanwhile, has your tumor been tested for expression of the PD-1 ligand? I've heard that for people who are PDL-1 positive, the anti-PDL1 antibody works even better than does the anti-PD1 antibody. Just one other option for you to consider.

Anonymous - (4/29/2014 - 9:19am)

Pfizer may be trying to accelerate talks in part because the British drugmaker is scheduled to present promising data at the annual meeting of the American Society of Clinical Oncology, which begins May 30 in Chicago, according to one person familiar with the situation who asked not be named.

A deal would help Pfizer add early stage drugs in a field of cancer treatments that use the body's immune cells to recognize and attack tumors. In January, AstraZeneca announced an agreement with Immunocore Ltd. to develop new treatments that use immune cells, and it also has several of its own immune-based drugs being tested in multiple cancers.

 

 

 

Pfizer is back in the megamerger game.

The U.S. drugmaker has proposed buying AstraZeneca for $98.7 billion, in what would rank as the industry's biggest takeover, surpassing Pfizer's $64 billion purchase of Wyeth in 2009. AstraZeneca spurned the offer as too low, and Pfizer said it's considering its options.

If AstraZeneca agrees to a deal, it would create a company incorporated in Britain for tax purposes and run from the U.S.

The renewed approach comes amid a wave of mergers and acquisitions in the sector, pushing the value of deals to $153 billion this year, as the industry restructures amid health care spending cuts and competition from cheap generics.

"Society wants products faster, they want more products and they want value," Pfizer Chief Executive Ian Read said Monday. "Industry is responding to society's request for increased efficiencies and productivity."

AstraZeneca's stock climbed Monday above the offer price, gaining the most in more than two decades. It closed up 12 percent, at $77.01.

Pfizer, known for its Viagra drug, is headquartered in New York City.

For now, Pfizer is trying to draw AstraZeneca into talks. "We tried to get a mutual announcement to say we were in preliminary discussions," Read said. "AstraZeneca rebuffed that, which is why we were forced to make the announcement."

If Pfizer consummates the deal, it would be one of the biggest U.S. companies to go abroad. Read said that although he hadn't discussed that with the U.S. government, he was confident that it could get done.

Pfizer's January proposal "very significantly undervalued" AstraZeneca, the British company said in a statement. AstraZeneca also was concerned that Pfizer wanted to pay 70 percent of the price in shares, AstraZeneca said. The company concluded that, absent a specific and attractive proposal, it was not appropriate to engage in discussions with Pfizer.

"They're sellers, we're buyers," Read said. "Of course they're going to say it's undervalued."

Another key component of the deal is moving Pfizer outside the U.S. for tax purposes. A deal would allow Pfizer to use about $70 billion of cash it has built up overseas that would be subject to taxes if brought back to the U.S. and, because the combined company would be incorporated in Britain, would lead to a lower tax rate.

"I don't see why there's any conflict in what we're doing with U.S. policy," Read said on a conference call Monday.

Under British rules, Pfizer has until May 26 to make an offer or say it won't bid.

Pfizer may be trying to accelerate talks in part because the British drugmaker is scheduled to present promising data at the annual meeting of the American Society of Clinical Oncology, which begins May 30 in Chicago, according to one person familiar with the situation who asked not be named.

A deal would help Pfizer add early stage drugs in a field of cancer treatments that use the body's immune cells to recognize and attack tumors. In January, AstraZeneca announced an agreement with Immunocore Ltd. to develop new treatments that use immune cells, and it also has several of its own immune-based drugs being tested in multiple cancers.

Many of the largest drugmakers face patent expirations that are cutting billions of dollars from their revenues, forcing them to look for new therapies. Pfizer has reorganized its business over the past three years, shuttering some research projects and emphasizing others.

"The size of the deal testifies to the depth of the crisis Pfizer's in," said Ori Hershkovitz, a managing partner at Sphera Funds Management, which owns Pfizer shares. "They are trying to buy what they think is feasible, not necessarily what is most strategic."

Thanks. Yes it is great to finally have a medicine that I responded to. Also the radiation was great for the t10 paralysis knocking at least 50% of that tumor out if I'm looking at the pet scan right. And that was the 2nd radiation to it which looking back the first one really didn't show much affect on the scan so I dunno what the difference was except the first they change to pallative radiation whereas this was stereostatic.

I think they had a similar conference in San Diago a couple weeks ago but I didn't hear super news.

I'm really concerned about this left shoulder blade tumor and its spread to lymph nodes. It has always been a very aggressive tumor growing much faster than anything except the t10. I see my radiologist Friday so I'm going to ask him about it. Once I hear from Mayo for the merck I'll ask him too. I would like to get some radiation in it since the t10 responded so well in my opinion and if it can be timed to maybe get that radiation/immunotherapy synergy then all the better. My only concern with merck is the low dosage. If it was the 10mg/kg I would be ecstatic with joy. The medimmune pd1 in nashville apparently was in the UK where they had some good results according to the nurse. I haven't found a report on it yet though I'll keep searching. She is checking on whether I can get into it but it has a lot more qualification criteria she said.

They haven't done hardly any testing on my tumor and supposedly there isn't any left from the original biopsy. They are also not wanting to do biopsies due to the risk of bones and possible infection and things. I would think they could though now that it is in the lymph nodes but they would only do that if it would change my treatment plan so I dunno. Maybe Mayo or Sarah Cannon will be better at such things than Siteman here in Saint Louis.

I asked my doctors   at MSKCC  whether their was a difference in the effectiveness of af the anti PD-1 drugs now being tested... I am currently using the BMS product (3mg) with positive results.... My query was part of the never ending fishing expedition for the next line of treatment if/when this gives out   The answer I got was that it will be some time before we can differentiate between these drugs.  ( it seems relatively easy to establish a chemical blockade of the same PD1 interaction  without a patent infringement-- and there appears to be a pile on in anti PD-1 marketplace --with the general assumption that a blockade is a blockade)  My guess is there will be differences that emerge, if not in effectiveness then in duration, speed of reaction and side effects.  For now, both appear to be good choices  -- I think the Merck product is further along in  the FDA testing process with unquestionably good results.... which may inspire confidence--I'm certainly impressed by the response rate.  Medimmune is further out, so the data  on effectiveness are probably scarce--- perhaps there are others on this site who can chime in with some study results.  It is fortunate that you have an anti/PD-1 option - Though I believe with regard to direct comparison  the jury not only out ---it has yet to hear the case.

Thank you. I asked that same PD1 question to the doctor at Sarah Cannon in Nashville. He said last year he had 5 PD1s going at the same time and he could tell the effectivemess based on the manufacturer. I saw some details how they are made differently I think anyway here http://onlinelibrary.wiley.com/doi/10.1002/cam4.106/full. I dunno what fully humanized, fusion proteins or anything are but it certainly implies they tackle PD1 differently thus I would assume some are a more affective manufacturer process.

I never did make it to MSK in NY due to my back issue. I was supposed to see Dr Postow. Maybe now my back is better I can make that happen. Last time I talked to his nurse he had her say they had nothing for me so it wouldn't be worth the trip but that was several weeks ago so might be worth it now.

 

One thing I like about some of the smaller (or otherwise more accessible) cancer centers is being able to talk to clinical trial coordinators there on the phone and/or via email. MSK and MD Anderson won't do that in my experience.

One of the most useful things I've found about clinicaltrials.gov is the "contacat info" section of each trial listing -- phone#s and emails. The facility websites are also good if they have a "clinical trials" page/section. I was not willing to make a long trip to go in-person to MSK or MDA, in my case perhaps only to be told I didn't qualify for anything.

Artie, my quick 2 cents--there is a decent amount of data (trial results) behind Merck's product.  The dosage they are using is probably what they anticipate will be the FDA-approved dosage.  As far as I know (I may be wrong), MedImmune is just getting started with trials, i.e., little data.  If it were me, I'd only go with MedImmune if it were being combined with another agent in the trial, which doesn't appear to be the case.  As far as "something else", there was some talk on MIF within the past 2 weeks about the trial combining the BMS product (nivo) with anti-KIR (don't know much about it).  I also noticed that Moffitt will be combining the BMS product with TIL, but that trial does not appear to be recruiting at this point (per the NCI site).

Artie,

 

I am on Merck pd1 (10mg) , and NED. Data presented my Merck indicates that 10 mg showed a greater response than 6 or 3mg. I am sorry that I do not have a link to the data but you should be able to find it. I think the reporting was presented by D. Ribas at UCLa.

Something to think about if merck eap is ONLY giving 3 mg out.

Good Luck..and keep us posted.

 

Art,

I heard the same thing that killmel posted.  Some are speculating the only reason Merck went with the 3mg for the EAP is simply due to availability of the drug at this point.  Don't know if that's true or not.

You have a tough choice coming up but it's nice to at least have a choice.  If I were in your shoes the one thing that would worry me about the MedImmune PD1 is that it's unproven.  There was a PD1 trial done in the recent past (I can't remember which company it was) that had zero benefit.  Totally sucked for the patients in the trial because it eliminated them from entering the BMS or Merck PD1 trial.  You would think that the MedImmune would be as good or even better than BMS or Merck.  Wonder if there is anyone you could contact at MedImmune to see if they have any argument as to why they think their drug maybe better than BMS or Merck. 

Good luck,

Brian

Thanks all. Yes I did find some numbers showing the low dose Merck at 25% ORR where as the high dose every 2 weeks was 51% ORR. Seems like a huge difference to me. If they were offering the 10mg/kg I would be really happy but they aren't.

For the lirilumab(anti-kir) plus nivo NCT01714739 I was on the waiting list in Chicago a couple months ago and called other places. At the time NY said they were open and recruiting but when I started making the appointment the dr told his nurse to tell me it was not available which I thought was odd. I think this is the trial that my gut has been telling me I need to be in. I just called them and it is supposedly open so time to setup that appointment for NY so the Dr will have to look me in the face to say it is not available. Thanks.

Anonymous - (4/30/2014 - 12:15pm)

Hi-

Can you please share the link where you found the dosage comparisons for MK-3475?  I haven't been able to find any specifics.  Also, the dosage isn't listed in the NIH trial info.  How do you know its the lowest dose?

Thank you!

This site shows the ORR at 3 doses via irRC and RECIST standards. The data is from ASCO in 2013.

http://finance.yahoo.com/news/merck-announces-presentation-interim-data-...

Thus the 52% at the highest dose of 10mg/kg every 2 weeks.

Surprisingly to me anyway only 27% at the highest dose of 10mg/kg every 3 weeks.

25% at the lowest dose of 2mg/kg every 3 weeks.

Thus the ORR at all doses is 38%.

 

As far as the EAP dosage I asked that question back in March on this site and MIF. Someone told me directly they believe it was going to be the 3mg/kg dosage. So whether that is true I do not know. That is one of my questions I intend to ask when I hear back from my doctor involved in this EAP. Also as you know clinincaltrials.gov shows it will be every 3 weeks but yes it does not list the dosage thus my question last month.

Based on those results I am quite stunned the trial treatment is every 3 weeks instead of every 2 weeks.

If true I am also stunned the dosage isn't the higher but it appears the lower and higher at 3 weeks are pretty much the same low results.

So I'm quite upset and angry that Merck who had an outstanding 52% in the one arm is probably going to proceed in the EAP and probably FDA the low performing 25% arm. It baffles me. As you said it is hard to find ORR by dosage and they seem to be hiding behind that 41% ORR of all dosages.

 

The full text of the 2013 ASCO report on Lambrolizumab (anti-PD1) can be found here: http://www.nejm.org/doi/full/10.1056/NEJMoa1305133#t=articleResults

A table that describes the details associated with Lambrolizuman can be found in the NEJM Supplement here: http://www.nejm.org/doi/suppl/10.1056/NEJMoa1305133/suppl_file/nejmoa1305133_appendix.pdf

It looks to me that, while the higher dose/frequency cohort had a higher response rate they also had more adverse events. The same thing happened with ipilumimab-- the 10 mg/kg dose worked better than the 3 mg/kg dose but with more side effects. Eventually, the FDA approved the 3 mg/kg dose.

While I understand the patients' frustration with the lower dose, from the company's point of view they are trying to accumulate data to support their FDA application and the FDA needs to see a good balance between efficacy with safety. 

Anonymous - (5/1/2014 - 4:00pm)

Thank you both for the links! 

Yeah my whole career of over 25 years I worked for 2 chemical companies so I can understand where they are coming from and in their position I would do exactly the same thing. But as a patient facing this nightmare it frustrates me. I would glady risk the affects in that report to more than double my chances as long as I have an experienced staff to take care of things like I did for ipi. But the taf/mek combo was only supposed to have a 19% chance of any reaction since I failed zelboraf and it held all except 1 tumor in check and shrank some a little for at least 7 weeks and maybe more since I'm still on it. So who knows maybe I'll be in the lucky 25% of merck's pd1 or whatever pd1 I get into.

Artie, the current dose expansion cohorts for the nivo/liri trial are split among 5 different cancer types (they just added liver cancer I believe), they have only 16 slots for melanoma in the recently opened dose expansion cohort. I imagine those probably filled up really quickly, although I don' know for sure.

Going in person for an appointment when I found a promising trial with the recruiting door *about* to open, seemed to help. For a phase I trial with limited slots, maybe when the door is actually open, it's almost too late? I went in to Portland to get into the MEDI4736 trial, which at the last minute delayed the cohort I was trying to get into, and I ended up getting into the Nivo/KIR trial there instead.

From talking to clinical trial coordinators around 2 months ago, some things I learned, at least at the time are:

* Nivo + anti-LAG-3 (NCT01968109) -- new cohorts weren't open yet 2 months ago when I was calling.

* Nivo biomarker study -- I didn't qualify I think (per trial coordinator in Boston).

* Medimmune MEDI4736 anti-PDL1 + (Dab or Trametinib) -- wasn't open yet 2 months ago (per trial coordinators at 2 sites).

* The Dana Farber NCT01753089 dendritic cell activating scaffold -- the trial coordinator said they want to see the trial participant in person "every day" for months in Boston (if I recall correctly)

Another thing I learned at Portland is that BMS tends to concentrate their phase I immunotherapy trials at 5 locations -- Dana Farber, MSK, U Chicago who you talked to, Portland Providence, and Sidney Kimmelman in Maryland.

Hope this information is in some way helpful. Something like the Merck EAP, being an almost wide open wiondow, may be the most doable to get into, especially when travel is a big issue.-

- Kyle 

Thank you Kyle.