Mo' Money....Mo' Bettah....Melanoma's Therapies (B-RAF, MEK, ipi, anti-PD1) and Their Cost and Availability

 Melanoma:  From Impossible to Treat to Poster Child for Targeted Therapies

AJMC.com  Published online:  October 23, 2013. Produced by Nicole Beagin.  In September, Mark Fendrick, MD, co-editor-in-chief of The American Journal Of Managed Care, led a discussion of experts about advances in the treatment of metastatic melanoma, which examined both the promise offered by new therapies and the issues surrounding cost, payment, and delivery.

Jeffrey Weber, MD, PhD, Moffitt Cancer Center, Tampa, Florida
Antonio Ribas, MD, PhD, Johnson Comprehensive Cancer Center, Los Angeles, CA
Jennifer Malin, MD, PhD, Manager and medical director of Oncology, Well-Point


(Quoted, but edited, by me!)

Weber:  Melanoma has gone from being regarded by many oncologists as an impossible to treat and hopeless malignancy to a disease...that is the poster child for new targeted and immunologic therapies...  That being said, there are major unmet needs in our field because...we still have a pretty narrow repertoire of drugs...[with] pretty serious toxicities, and we are a long way from curing a significant proportion of our patients.

Ribas:  Having seen this remarkable change in a short period of time...is a remarkable benefit to patients...but we are still faced...with many patients who are either not responding, responding for a short time and progressing, or having side effects.

Patients who were treated 2-5 years ago [with immunotherapies]...continue to respond and patients with T24 blocking antibodies, the longest...for 12 years...but we need to make it more efficient for everyone... The B-RAF inhibitors, vemurafenib...then the B-RAF that is called dabrafenib, which is a very recent approval. ....when we select patients with the B-RAF mutation, which is around 50% of melanomas, we are close to guaranteed to have some...patient benefit.

Over 80% of patients have some shrinkage of disease....but the majority - not all of them, but the majority - will progress...and the median duration of response is around 6-7 months, although there are some patients from the Phase 1 trial of vemurafenib who are now going beyond 4 years and are continuing to respond, but that is the minority.

These are targeted therapies that block the driver oncogene which leads to cell cycle arrest and response in the majority of patients... Around two-thirds of the progression mechanisms go through reactivation of the same pathway and a signal through an immediate downstream, a factor which is called MEK, which is a kinase under B-RAF... Then we have the MEK inhibitor trametinib that has been approved to use as a single agent in B-RAF mutant melanoma. But that is not where we are going to be using it because by itself, trametinib is less effective...and more toxic, so it is probably one of the only approvals by the FDA that we know from the start that we are not going to be using in the way the current label is written.  You can use it in combination with the B-RAF inhibitor and you can use it in patients who progress on the B-RAF inhibitor because there is actually no activity there. But there is a lot of activity when you put it together, ...it is one of the examples that I...know in medicine where you have 2 effective drugs, that you put them together and they are not only more effective but they are less toxic...which should impact on the cost-benefit ratio because even though...2 drugs are more expensive than 1, the side effects are decreased and the benefits of the drugs is markedly improved...  I think most of us would agree that this will be a drug that is cost-effective.

Weber:  I think everyone agrees...the expectation certainly is that the Phase II study results...with those 2 drugs are going to show serious benefit and major prolongation of survival, but again we don't have the data and they won't be out probably for another year...

Dabrafenib, trametinib, vemurafenib, and a lot of these drugs are...oral, you take them once or twice a day.  Whereas, virtually all of the immunologic agents that are in development are given intravenously.  Ipilimumab, for example is given every 3 weeks and to be honest, ...we haven't settled on the optimal dose.  There is a big trial of the standard approved dose of the 3mg/kg vs 10. Ten may be better...what implications [might this have] for the cost, because it is not a cheap drug?  If it turns out that the FDA will now approve 10 instead of 3 are they going to triple the price? 

I should add...that the excitement at ASCO...was because there was a combination trial of one of the PD-1 drugs, nivolumab, with the CTLA-4 blocking drug, ipilimumab...where you see in a graph the bars up or down indicating shrinkage or growth, it looked like it was a targeted drug, it was so good.  Toxicity, on the other hand, was not so trivial...Now, not only are we thinking about how do you combine the targeted drug, now you think about how to combine the immunologic drugs, so that is 5 more years of work at least, to work that out, and that will be impressive.

...The key question....is, what is the best sequence of a targeted drug and an immunologic drug?...and it is not just a (single) drug.  It is what combination of targeted drugs and what combination of immunologic drugs, what should be the proper sequence? ...  That is a major unanswered question...

Fendrick:  What can you say about a standard of care, or a lack thereof, in metastatic melanoma...?

Weber:  ...There are the NCCN guidelines...

Malin:  ...before this call, I checked how...NCCN was recommending use of the 2 new B-RAF inhibitors...FDA approved in May, and NCCN hasn't updated its guideline...there is a little bit of lag...

Weber:  I think practices will vastly vary at an academic center like mine where you have 25 melanoma trials.  At UCLA I'm sure it's the same. It is going to be a little different than if you are in Albuquerque, New Mexico, at a good private practice with 5 other oncologists.  It is going to be very, very different as to what you can offer the patient.

Malin:  This brings up the issue of access.  These therapies are very exciting and the benefits that some patients have are really tremendous.  It is exciting to see someone go into a complete remission following 4 treatments with ipilimumab and stay in remission...for a year...  But, the wholesale cost of just the drug...is $120,000... Most small, independent practices (are) concerned about...taking on the financial risk of a drug that is that expensive without knowing whether the patient's insurance is going to cover it, whether the patient can afford whatever their copay might be.  If they have a 10% copay, that is $12,000 right there, so the cost of these drugs, at least in combining them, is going to bring new questions regarding access for people...

People can have long remissions...and some...benefit from retreatments...Does it mean someone is going to need to repeat treatment every couple of years?  ....When someone gets treated in the outpatient setting, usually the cost is double or triple, so just for ipilimumab, we are looking at a cost to the patient's payer....of $240,000 - $360,000...

Weber:  I think this is something that is at the top of everybody's consciousness...just about every professional group is going to emphasize the idea of trying to have biomarkers to select the right patients.  You can't just treat 100 patients and benefit  8 of them.  It is not going to happen in the future, the FDA has made it very clear how important they think biomarkers are.  ...  I predict that you are not going to get the (Oncologic Drugs Advisory Committee) and the FDA to approve drugs or push forward unless there is clear significant value; a 5 week prolongation of survival is not going to cut it in the next 10-20 years, not when the drug costs $120,000 for the wholesale price....

I suspect if you graph the price of current drugs over the last 20 years, you would see at least a linear increase with a doubling every 5 years and eventually what is it going to be, $300, $400, $500 or $600,000 to treat someone?  That is not practical....I'm not an economist, but I find it hard to believe that for [drug companies] to stay in business they need to charge $200,000 a year for dabrafenib and trametinib.

Ribas:  ...In places like the county hospital, it is hard to find any patient who has been on ipilimumab because it has not been approved for administration even though it is an FDA-approved drug and there are randomized trials that demonstrated approval and survival.  Those randomized trials showed improvement that is based on a small percentage of patients, around 10-15%...  We don't have a marker and possibly we will not have a marker, because it is an agent that is activating the immune system very far away from the tumor, so there are several thousand genes that are involved... It is unrealistic to think that there is going to be one biomarker that says this works or doesn't work in patients... We have dedicated over 5 years of research...and we are back to where we were...we give it to everyone because we don't want to miss those patients that can go on to have decades worth of life...free of metastatic melanoma. That is something I have trouble putting a price on, but the worst case is when we don't even have the chance to give it, and that is what is happening with the price of ipilimumab being so high....it is not only the wholesale price, it is the total bill that I see, and I am outraged every time a patient comes and says, this is what your clinic charged my insurance to give 4 doses of ipi.

Weber:  We have...the occasional referral...a charity patient who has either Medicaid from another part of the state, like someone from Miami, and the University of Miami will not treat them....and Moffitt will eat the cost of some percentage [for] those patients, or BMS will make the drug essentially free... A lot of companies have these programs where if you can't get anybody to pay for it, they will give you the drug for free...so eventually it happens, but it can be a huge hassle...

Ribas:  There are patients who don't get to our clinics.....when I talk to doctors [in county hospitals], they tell me that it is very seldom [they] are able to give ipi to a patient because of the cost.

Weber:  I can see that being an issue for the poorest patients....this was a huge topic...at [an] Advisory Board I recently attended at ASCO....the question was, what if the price were $300,000 or $400,000 to get treated with some regimen lasting a year, would that be realistic? 

Fendrick:  ...I want to ask one thing that comes up a lot...what [do you think] about the idea of a situation where patients would get better coverage...if they went to Centers of Excellence for specific types of cancers?  Do you think it would be a good idea or a bad idea for particularly rare cancers to follow a model that we've had in place for transplants for decades?

Weber:  ...I wouldn't have a problem with seeing more patients and bring more business to places that excel at what they do.  To be honest, if I had metastatic melanoma...I would probably go to the big center, no question...

Ribas:  I would agree.  Sometimes we see patients on a second opinion, coming from the community. The data the community doctor has are the same as we have, the drugs are the same, but the usage may be wrong because they are not thinking about melanoma every day.  My thinking is that regardless of the cost, if we treat, it is cheaper than if we don't treat.  I mean treat...a medical condition and the medical condition improves...

...With all of this discussion I wanted to bring up one thing...I know is going to change even further...the PD-1 and PDL-1 antibodies are going to change...the treatment of melanoma again within the next 2 years...   If we look at the data right now, [it] suggests that we will get a significant fraction of patients with metastatic melanoma to have durable responses with therapies that are basically non-toxic or [with] serious side effects that need [intervention] and will leave the patient in the hospital....There are 7 of those PD-1, PDL-1 antibodies in the clinic [under] development right now....  3 of them...positioned to have licensing potential in melanoma and maybe many other cancers.

Malin:  ...Clearly the cost of these new drugs is a challenge...in just a few years...the cost will be half of the median family income.  So, clearly, it is not conceivable that costs can continue to go up...  The good news is we think that 30% of what we spend on health care is waste, so if we can figure out how to stop doing the things that don't help people, we can insure that we can continue to make sure to make new therapies that are highly innovative available to people, but figuring out where that waste is, and getting people to stop doing things that don't provide value is challenging...

...You look at the fact that there are 3 aromatase inhibitors that have gone generic, in 2 of them the price dropped to $20 per month [yet] one of them is still $300 per month, but most oncologists don't even realize there is a difference in price, that either the patient...or the employer is paying...a difference in cost for a very active therapy that is equally effective...

Fendrick:  ...on the issue of clinical nuance, [it] is critically important to...identify...services that differ in the value that they create and the current benefit designs that patients see.  They pay the same out of pocket for lifesaving drugs as they do for drugs that I wouldn't give my dog... [We need to make] those services on which the evidence is strong accessible to patients and profitable to providers, and hopefully turn the corner and no longer make it profitable or easily accessible to patients,...services for which the evidence is weak, or in some cases, where there is true evidence of harm.

Audio link to discussion between Weber, Ribas, and Malin

Money, money, money!  My current working theme, huh?  Makes me tired.   - c