Posted by Jeff Berk, BOLT International;
As I pen this blog, it is 85 degrees (Fahrenheit, for you poor 3rd-worlders condemned to the metric system) and dry as a bone in Scottsdale, AZ. As an aside, I once had a European client who insisted on sending payments to me in Azerbaijan. And don’t even get me started on those websites that have a drop down menu that lists about 200 countries before United States.
Where was I? Oh, yeah. Just so you know, and are jealous, I’m outside my casita, sitting pigeon toed and naked, pondering the universe… and having my heart tugged on by two groups of people.
Me, sitting pigeon toed and naked, and pondering the universe.
First, on my FB there was this message from a Blue State commuter, saying how she has developed a bad case of road rage associated with her horrible daily drive. While I can’t really do much to change her (fully clothed I assume) lot in life, I can scribble out a limerick in her honor:
Melanie’s red in the face.
Lost all her sweetness and grace.
Our shining light sage
Succumbed to road rage.
She’s trapped like the rat in the race.
So the other group of people I’m thinking about today are melanoma patients. My GF told me about a friend of her workout partner: 33 years old, melanoma diagnosis to death in 4 weeks. Now to be clear, I work with a lot of tumor types. Hundreds. And I grant that there have been some outstanding clinical advances over the past few years in melanoma therapy. But frankly, durability (except for the 20% of you ipilimumabbers) sucks. So there’s a long way to go.
So today I’m posting another melanoma blog.
First, here’s the crass commercial message:
BOLT just published Melanoma Thought Leader Panel #28
2011-11. If you’re a patient, we’ll be happy to share with you/your oncologist. Email me at email@example.com If you’re Pharma, go to the Buy Now link on BOLT’s main page www.boltinternational.com (on the top row), and buy the report. Trust me, this was a really strong Panel.
Here’s the blurb:
Hematology/Oncology Panel #28 summarizes the perspectives of six renowned US and European Thought Leaders who specialize in the treatment of melanoma. The Panel discusses the incidence and prevalence of melanoma, identifies demographic variations in mutations (BRAF, NRAS, cKIT, GNAQ, GNA11), and what is known about acquired resistance to BRAF mutations.
The panel then discusses competition between and possible synergy of BRAF inhibitors and CTLA inhibitors, BRAF + MEK, MEK + PI3K and other ways to put two hits on pathways that are driving melanoma.
Other mechanistic targets covered are c-KIT, other RAFs, MEK, PD-1, other immunotherapies, antibody-drug conjugates (e.g. a warhead to GPNMB MAb), PI3K pathway alternatives, interferon, IL2 and IL-15.
Companies/compounds discussed in this report:
Zelboraf / vemurafenib / RO5185426 / PLX-4032/RG-7204 (Plexxikon / Roche)
dabrafenib / GSK2118436 (GlaxoSmithKline)
PLX-4720 (Plexxikon / Roche)
XL-281 (Bristol-Myers Squibb; Exelixis)
Temodar (temozolomide; Bayer-Schering)
Abraxane NAB-paclitaxel (Celgene)
Yervoy (ipilimumab; Bristol-Myers Squibb)
gp100: 209–217(210M) peptide (NIH)
Proleukin (aldesleukin; IL-2; Prometheus)
GSK2132231A MAGE-A3 (GlaxoSmithKline)
MDX-1106 / ONO-4538 (anti-PD-1 antibody; Medarex / Bristol-Myers Squibb / Ono)
MK-3475/SCH 900475 (Merck)
AMP-224 (Amplimmune / GlaxoSmithKline)
Tasigna (nilotinib; Novartis)
Gleevec (imatinib; Novartis)
Sutent (sunitinib; Pfizer)
Sprycel (dasatinib; Bristol-Myers Squibb)
GDC-0973 (Genentech / Exelixis)
MSC1936369B (Merck Serono / Sanofi-Aventis)
AZD-6244 (a.k.a. ARRY-142886; AstraZeneca / Array)
MEK-162 / ARRY-162 (Novartis / Array)
BAY 86-9766 (Ardea / Bayer-Schering)
CDX-011 (CR011-vcMMAE; CuraGen)
mTOR / PI3K / AKT
SAR245409 (XL765) (Sanofi-Aventis / Exelixis)
Avastin (bevacizumab; Genentech)
Nexavar (sorafenib; Bayer-Schering / Onyx)
aflibercept (VEGF Trap; Sanofi-Aventis / Regeneron)
ARQ-197 (ArQule / Daiichi-Sankyo)
cabozantinib; XL-184 (Exelixis)
Xalkori; crizotinib (Pfizer)
Okay, so now, finally, I can get to the market uptake of ipilimumab – the subject of this blog:
- The uptake of ipilimumab in the US is far greater than in the EU. First, the situation in the US: Community oncologists are referring candidates for ipilimumab to tertiary centers because at a cost of $120,000 for 4 infusions (one course) they do not want to deal with buying and stocking the drug themselves. There is also a reluctance to administer the infusions due to acute toxic death. Even so, the drug is being considered in BRAF wt patients, and there are some Panelists who are considering using Yervoy ahead of a BRAF inhibitor in slow growing BRAF mutant melanomas. The rationale is that all patients will progress once on a BRAF inhibitor, but 10%-20% of patients on ipilimumab will have durable responses that last many years.
“In the real world I think there are financial and kind of logistical issues as well as issues with physician comfort with using ipilimumab. In all the large academic centers we are going to have access to ipilimumab and I think there are going to be people who know how to use it. If we think it is appropriate we are going to do it. But what I am finding in the community if someone is BRAF mutant they go straight to the pill regardless if ipilimumab potentially might be the better choice. And the reason is, one, it is a pill and it is easier to use. Two, there is a perception that the toxicities are less with a pill. And then three, the community doctors don’t get stuck with a $120,000 dollar pharmacy bill. They just write the script and then it is the patient’s problem. Exactly. So I talk to a lot of community doctors and just talk about recommendations and even if I think ipilimumab is a better choice they tend to start with Plexxikon unless they refer the patients over here”.
“Ideally I think what we would do is basically you get the BRAF status up front and you get NRAS and c-KIT and the whole thing. But if someone had a BRAF mutation where they are eligible for both therapies, what we have been doing here is that if patients have low volume relatively and relatively slow growing disease and have time to wait for the benefit from ipilimumab which can take three, four to five months to work, then we like to start with ipilimumab first. The reason for that is you do get the tail of the curve. You do get the improvement one, two, three-year survival where that is still not clear with the RAF inhibitor. And the time to recurrence with the RAF inhibitor is still six to eight months. So some of the responses with ipilimumab potentially can be more durable than the BRAF inhibitor responses”.
“If there is toxic deaths with ipilimumab in the adjuvant setting at 10 mg/kg that is being used in the current EORTC study then maybe the risk will outweigh the potential benefits”.
“The majority of BRAF mutant patients will be treated with a BRAF inhibitor either in an early access program or in a clinical trial. But I believe there is a niche in patients who have a slowly growing stage IV disease with low tumor load with a history of slowly growing disease. So there is a long time spent between primary tumor and the first metastasis, between first metastasis and subsequent metastases, and so on. These patients might also be good candidates for Yervoy in the first line setting”.
“We are seeing that patients come from community oncologists referred for infusions of ipilimumab because of their relative reluctance to purchase the agent and then infuse it when they are not used to it. But I think with time that is improving and more of the community oncologists ask us do you think this is a good idea that they go on and do it themselves. I am surprised to see that ipilimumab is being implemented quite well I think, more than what I would have expected”.
“One of the comments made to me by one of your colleagues was that even in patients who upon screening show BRAF V600E mutation if the oncologist imagines that this tumor has been quite slow growing they may start the patient on ipilimumab even before using a BRAF inhibitor.
“Yes. The rationale for that is that the majority of patients on a BRAF inhibitor will progress. Although we still don’t know if this statement holds true for a long time because we have patients from the phase I that are still responding, but the majority of patients will progress. With ipilimumab there are few patients that respond but those tend to be durable responses. So if a patient gets ipilimumab front line and responds there is no need for any other treatment in the majority of cases where there is a response; but that is only 10 percent of the cases”.
- In Europe, ipilimumab was only approved for 2nd and later line therapy. EMEA had the same 1st-line ipilimumab + DTIC data available to them as did FDA, but opted to give the more conservative approval. NICE, in the UK actually rejected reimbursement for ipilimumab, deciding that the proven survival advantage wasn’t worth the cost. Frankly, this “Death Panel” decision was reached for blatantly transparent reasons.
“In Europe only ipilimumab is approved so far and it is only approved for second and pretreated patients. Really? So that is certainly different than the States. Why is that? Because the European authorities decide…
Oops… The “FreeMeter” just expired. Buy the report.