lorvotuzumab mertansine; IMGN901 (ImmunoGen)

Posted by Jeff Berk, BOLT International;

 

I’m leaving for Paris in a couple of days, 13th International Myeloma Workshop.  And for that, I’m psyched.  I’m really looking forward to seeing a number of BOLT’s Myeloma Thought Leaders; some for the first time face-to-face, and others kind of a cozy see-again.  And if you’re going to be there, give me a shout by email.  So today’s blog, once we get the cactus flower (Stenocactus crispatus) and a certain rant-and-rave out of the way, is going to share a couple of my Panelists’ impression of ImmunoGen’s IMGN901, a.k.a. lorvotuzumab.  I like this drug.  I just like the concept of antibody drug conjugates.  A monoclonal missile delivering a diabolical payload right to the tumor…

 

Rant-and-rave time:  So here’s the deal-i-o.  I’m messaging with a colleague today and she points me in the direction of a “refuse to file” letter for Novartis’ panobinostat.  I was stunned.  I could NOT believe it.  And for the record, I own no stock in either Novartis or Seattle Genetics.  I think both have come up with pretty cool therapies for post transplant relapsing Hodgkin’s lymphoma.  Brentuximab (SGN-35) – a very sexy antibody drug conjugate.  Panobinostat?  Not so sexy, but still some response in this setting.  So what’s the problem?  ^%$*&#@ FDA.  That’s what.  Let me try to lay this out for you guys, using simple math.  Heck, REALLY simple math.  I’ll only make you count up to 2.  As in the number of years that post transplant relapsing Hodgkin’s patients usually live.  Currently there is nothing available for them.  Brentuximab will be there first.  That will buy these patients 1 year PFS.  Here’s the math part:  2 (years) -1 (year of PFS) = 0 (options once brentuximab fails).  Hey, FDA – we’re not talking about dyspepsia here (although you do give me a case).  Approve both, and let hematologists and their patients (and their payers) decide what’s best for them.

 

(Jeff takes a DEEP breath)… and on with the blog:

 

  • Lorvotuzumab is an anti-CD56 drug conjugate that delivers its chemotherapy by targeting CD56 on the cell surface.  A number of tumors, including MM, small-cell lung cancer, Merkel cell carcinoma, ovarian, carcinoid, and other neuroendocrine tumors express CD56.  Roughly 50% of MM tumors overexpress CD56.  In practice, an anti-CD56 may not be as effective as an anti-CD38 approach, but because CD56 is more limited to MM cells, this may have less off-target effects.

 

“I like more what Usher did with the lorvotuzumab when he used it as a monotherapy, the anti-CD56.  It is a drug conjugate.  That will give you an answer of yes or no.  We have activity, we can do something with this drug or it is a completely useless drug. Yeah, I really liked that. This drug, at least what I like, and I think Usher and other guys were doing the right thing, is let’s find first activity as a monotherapy or in parallel we can combine with others and see if we have any activity.  I think this is the right way to go”.

 

“CD56 we have looked at and we have been part of that study group and CD56 I still think we need to keep chasing because it is a marker of bad prognosis.  I would be very happy to see the landscape open up to allow a CD56 targeting antibody in the mix.  But I have to tell you that I am not sold that CD56 is going to be easier or better than CD38”.

 

“That one I think is of interest because of CD56 is a potential good target.  The problem with CD38 as a target is that there are a lot of other cells that express it.  So you can assume that the toxicity profile might be better for a CD56 targeted agent”.

 

“We have about some 50% of myelomas expressing CD56.  And CD56 expression is correlated with an adverse prognosis.  Some of our colleagues in our department of pathology here have done this work.  I think this really something where a patients could be benefited by such an approach since they have an adverse prognosis.  And it is a substantial number of patients who could get the beneficial effects.  50% is more if we get back to the FGFR3 story of 10%”.

 

 

 

  • Anti-CD56 causes immunosuppression.  In MM an active immune system is critical.  Impairing the immune system’s ability to deal with MM may be counter-productive.

 

“I think the one thing here and the caveat with all of these is that they target the immune system and NK immunity may be important in myeloma.  So tell me more about that because that brings up things like MAGE. I think none of the vaccines are yet ready for prime time.  Although, I think eventually we will have some degree of exploration of vaccine therapy for myeloma probably as an adjuvant to stuff that we do.  Now I think the same thing with the monoclonal antibody, most of us think that to be able to control the disease we are going to need to either reduce the tumor burden and stimulate the immune system whichever way we can come up with.  The problem with drugs at the same time eliminate or impair the immune system’s ability to deal with the disease may actually end up being counterproductive.  Give me an example of a drug. Like Campath, for example, not for CLL but Campath for ALL in the transplant setting.  Campath for myeloma in the transplant setting despite the fact that myeloma cells are actually CD22 positive some of them it didn’t work.  ATG has activity in vitro for myeloma.  ATG can kill myeloma cells.  But again, unfortunately it did not work.  This is just exploring the CD56 issue immediately.  So here I would say the problem with the CD56 story in myeloma is it may not work because of the fact that that you may be eliminating the immune system”.

Categories: CANCER, Hodgkin's lymphoma, Multiple Myeloma
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One Response to lorvotuzumab mertansine; IMGN901 (ImmunoGen)

  1. Schtuey says:

    Oh dear. Who rattled jb’s cage today? Agree with your overall sentiment regarding treatment of relapsing Hodgkin’s Lymphoma BUT a) patient access programmes can still allow access; b) everyone knows the FDA is getting tougher and the blame for that rests in part with Pharma itself; c) if companies better engaged the FDA through the development process then it wouldn’t be a surprise to hear that “FDA determined that a single arm trial did not provide sufficient evidence to support approval”

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