More info on some treatments out there...

I know folks have some questions on the terms I was throwing out like BRAF and Ipi.  Here is an article interviewing Dr. Chapman at Sloan (he's not my oncologist, but they all discuss the cases they see there).  To save folks from having to register on another site I copied the info below. 


Dr. Paul Chapman: Exciting Times Ahead—Things Are Changing Very Quickly in Melanoma Research
OncologySTAT Editorial Team. 2011 Feb 7, Interview by L Scott Zoeller
Paul B. Chapman, MD, is Head of the Melanoma Section Clinical Immunology Service Department of Medicine, Memorial Sloan-Kettering Cancer Center.
OncologySTAT: Dr. Chapman, you have been involved in groundbreaking research in the field of metastatic melanoma. Would you discuss the underlying mechanisms of advanced disease, the results of your research on BRAF inhibition, and the potential for development of novel targeted therapy?
Dr. Chapman: What we have learned in the last 8 years is that about half of melanomas have an activating mutation in the BRAF gene, which is a member of the MAP kinase pathway. It appears that these tumor cells are addicted to mutations in BRAF and that inhibition of BRAF is enough to stop their growth.
We have learned a lot about why this is the case. It’s a little complicated, and there is some controversy in the field; but, simply put, it seems that if there is a BRAF mutation, the cell signals through mutated BRAF monomers and are inhibitable by these drugs. In cells without a BRAF mutation, the BRAF (and other RAFs) are dimers. In this case, the drug appears to activate the pathway a bit. So, an inhibitor of BRAF has different effects in a mutated cell than in a wild-type cell.
We have been conducting a clinical trial with a BRAF inhibitor called PLX4032.1 It is also called RG7204. This has been a collaborative effort, initially, with Keith Flaherty at the University of Pennsylvania, who has subsequently gone to Massachusetts General Hospital. Then, after that, quickly, several other centers came together to complete these trials. We studied the pharmacokinetics of the drug, identified many of the toxicities, and identified the maximum tolerated dose. More surprisingly, we saw shrinkage in almost every tumor that had a BRAF mutation.
It appears that a little more than half of the patients achieved a formal RECIST response. Some of those were complete responses, but most of them were partial responses. Some of these responses were quite dramatic and quick, and occurred in metastases at all sites, although, patients with brain metastases were excluded. We saw responses not only in lung and soft tissue, but also in bone, liver, and small bowel. So, it was quite impressive.
We just completed a randomized phase III trial with 675 melanoma patients who had BRAF mutations and were randomized to receive either standard chemotherapy with dacarbazine or RG7204. At the interim analysis, which occurred just a few weeks ago, the independent data safety monitoring board (DSMB) determined that there were sufficient data that showed that patients who received RG7204 had improved overall and progression-free survival, and, so, recommended that the patients receiving dacarbazine be switched to the RG7204 arm, which is what we are doing now. This indicates that RG7204 is associated with improvement in overall survival. I personally have not yet seen the data; I have only the DSMB announcement, but we are all very excited about it!
OncologySTAT: Would you talk about the use of immunotherapy in patients with melanoma and also recent developments concerning the use of monoclonal antibody therapy in concert with vaccines?
Dr. Chapman: I think a lot of people know the long history of melanoma and immunotherapy. One such agent, which is FDA approved, for patients with metastatic melanoma is high-dose interleukin-2 (IL-2). This is a very toxic treatment which can only be given at select centers. It requires a physician who has had training, as well as an inpatient setting with an appropriate infrastructure, including nursing and other support.
The overall response rate with high-dose IL-2 is less than 20%. There is a 4% to 5% long-term complete response rate. So, there are some patients who do achieve a benefit from this treatment, but they are a small minority.
Recently, a big step forward was made using the monoclonal antibody against CTLA-4, which is called ipilimumab. Ipilimumab works by blocking CTLA-4 on T cells, which activates them. So, the T cells that are seeing antigen, but are normally not active, are now being activated. In trials done around the world, it has been clear that there are a substantial proportion of patients who achieve partial and complete responses and that there is also a group of patients who achieve long-term stable disease—1 or 2 years, sometimes longer.
We think that about 20-30% of patients will gain some benefit from ipilimumab therapy. As a result of this, two randomized trials have been conducted. In one, patients received either ipilimumab, or a peptide vaccine, or both.2 In this case, the peptide vaccine was, realistically, thought very unlikely to provide much benefit to patients. The results, published last year, showed that the patients who received ipilimumab enjoyed an improvement in overall survival. The 2-year survival rate improved from 14% in patients who received the vaccine to 24% in those who received ipilimumab. That is a small, but substantial, improvement in long-term survival.
So, ipilimumab is the first treatment for melanoma to demonstrate an overall survival benefit, and RG7204 appears to be the second. Neither drug is FDA approved at this time, but we all anticipate that ipilimumab will be approved by March. So, there has been a lot of excitement on the immunotherapy front as well.
In terms of vaccines, research has been actively pursued in this area since the 1970s and, in a desultory fashion, since the turn of the century. I think that it is fair to say that, to date, there has not been a lot of traction in terms of positive results for vaccines. People are still working on this, and we continue to learn more and more about how vaccines might be modified to become more active. But, to date, I think it is fair to say that vaccines are still quite investigative.
OncologySTAT: Where does chemotherapy fit into the treatment paradigm, and are there certain types of patients who respond better than others?
Dr. Chapman: I think that chemotherapy still definitely plays a role in the treatment paradigm. Dimethyl triazeno imidazole carboxamide (DTIC) is an FDA-approved treatment that is associated with a known response rate of 13%, which is on the order of magnitude of IL-2. There is a complete response rate—it is low, probably 1% to 2% —but the drug has the advantage of being very well tolerated. The oral form of DTIC, temozolomide, is also easy to tolerate and appears to have equivalent activity.
We use a lot of temozolomide or DTIC in patients who cannot tolerate other treatment or who are not eligible for clinical trials. Combinations of chemotherapy have been used, and they are associated, in general, with higher response rates, although it has been difficult to show that they have improved survival.
Truth be told, however, combination chemotherapy has really not been tested in a meaningful way in melanoma. There have been many randomized trials comparing combination regimens to DTIC, but, if you really look at these trials, very few of them are powered to detect any reasonable benefit. But, the few that have been done have not shown a benefit. So, people are a little hesitant about combination chemotherapy.
We use combination chemotherapy at our institution in selected patients. One point to make is that one of the new favorite chemotherapy regimens has been carboplatin plus paclitaxel. I should just point out that this is quite a toxic regimen and is not particularly effective either in patients who have received prior therapy or in those who have not. The objective response rates are approximately 15%, which are really no different from those achieved with dacarbazine alone. So, I would caution practitioners before they jump to such a toxic regimen.
OncologySTAT: Which agents or combination therapies currently being tested in clinical trials appear to be most promising?
Dr. Chapman: Well, I think, in terms of immunotherapy, ipilimumab clearly is very promising. Other trials are combining ipilimumab and another monoclonal antibody—anti-PD1—to activate T cells. There is great interest in developing a protocol of ipilimumab with RG7204, which has not happened yet, but we hope it will soon. In terms of the kinase inhibitors, RG7204 is the one I mentioned, but another BRAF inhibitor, GSK 436, also looks quite promising.
There are clinical trials currently ongoing here at Memorial Sloan-Kettering Cancer Center, and at other places around the country as well, using GSK 436 in a phase III trial, or using it in treatment of brain metastases. There are data showing that this drug can get into the brain and can cause responses there. So, we are quite excited about starting a phase II trial using GSK 436 in patients with brain metastases. There are many exciting things going on in the field over the last couple of years. One thing that would be important to understand if ipilimumab gets approved is that retraining will be required for community oncologists for a couple of reasons.
First of all, the types of toxicities encountered with ipilimumab are different from what they usually encounter. Patients have to be followed very closely because they can die from the colitis that can occur with this drug. Then, the kinetics of response to ipilimumab are very different from what we see with chemotherapy. With chemotherapy, we are used to giving one or two cycles of treatment, reevaluating tumor size, and, if the tumors have grown, we know that further therapy will not really help, and, so, we go onto something else. That is not true with ipilimumab.
With ipilimumab, it takes many weeks, sometimes months, before the immune system can actually shrink the tumor. So, it is a common scenario to get a week-12 CT scan and find that the tumor appears to be larger, but, then, at week 16, it is starting to shrink. So, treatment with ipilimumab is going to take a little more patience than we are used to with chemotherapy because if you abandon treatment too soon, you will cheat patients out of potential responses.
I think the standard regimen that the FDA is going to approve is going to be every 3 weeks times four. What we currently do is get a pretreatment scan, but we do not get another scan until we have completed therapy after 12 weeks. As I said, even at 12 weeks, we might not see an improvement, but if we continue to follow the patient with no further therapy, we do often see a response at 16 or at 20 weeks. So, it takes a lot more patience for physicians and for patients.
OncologySTAT: Are there trials in which you would recommend that community oncologists enroll their patients?
Dr. Chapman: There are studies of combinations of kinase inhibitors, which are just starting. There is a study of the BRAF inhibitor (GSK 436) plus a MEK inhibitor (GSK 212), which I think is very promising. It is, right now, just a phase I trial, but it will be a phase II trial later on in the year. You know, ipilimumab may become available this year.
There are many other trials open, or opening soon, but these change from month to month. I would recommend that practitioners contact the nearest melanoma research center to see what that center has open. Obviously, for patients in the New York City area, they can contact my office.
References
1. Flaherty KT, Puzanov I, Kim KB. Inhibition of Mutated, Activated BRAF in Metastatic Melanoma. N Engl J Med. August 26, 2010; 363:809-819.
2. Hodi, FS, O’Day SJ, McDermott DF. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. August 19, 2010; 363:711-723.
Related Link:

You Might Also Like

2 comments

  1. Great article! Thanks for sharing. I'm on GSK436 and have seen some amazing results. I know choosing a treatment is a tough decision. My advice is to get all the information you can regarding the treatments - which it looks like you are doing :), including doctor recommendations (multiple drs if possible) and then go with your gut. Hang in there! There have been some amazing advances in treatment and you will find the one for you.

    ReplyDelete
  2. Thanks Tina - I'm so happy to hear things are working so well for you! and yes you make a great point about recommendations - I've met with 3 medical oncologists :)

    I'm trying to get all the info I can. I should know in the next week or so if I'm BRAF + and we'll go from there!

    ReplyDelete