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November 18, 2014 at 10:48 pm #22249
I hope that I can ask a question without the complete background for different reasons.
The general situation is a person with melanoma stage M1a with regional metastases in skin and lymph nodes of one leg. Previous local/regional therapies have failed. General condition is good although the melanoma is constantly spreading in the skin.
Now there might possibly be a chance to get Pembrolizumab as first therapy in a clinical trial without any previous Ipi or BRAF inhibitor. The patient has asked his oncologist about the clinical trial but the oncologist does not support this and says (in translation):
“These drugs are being used for patients where the doctors have given up the thought (hope) of getting rid of all tumors permanently but are aiming to give relief and a prolonged life.”
Relief is my translation, could also be palliation. I find this extremely strange but I am not 100% sure how the melanoma experts actually view the new immunotherapies.
My spontaneous reaction is that if PD-1 increases the chances of survival, it really does not matter if it get rids of the tumors permanently or not. The important thing is the chance to survive. Also, I wonder what measures the oncologist suggests to get rid of the tumors permanently in this case.
I can see two possible explanations for the oncologist’s attitude: 1. concern about possible side effects from Pembrolizumab relative to the benefits for the patient 2. the wish to get other patients with worse condition on the study (which of course has a limited number of participants)
I can understand and from a general perspective respect number 2, but is number 1 reasonable? If the melanoma spreads to other organs in the body, the next proposed step would be Ipi where the side effects are even worse. Also, from my understanding it is quite possible that the melanoma could spread to the brain if/when it will be found and that would decrease the chances of survival even with immunotherapy and might even disqualify the patient from certain clinical trials.
I would appreciate any comments on this.November 18, 2014 at 10:55 pm #65859
Pembro (aka Keytruda) should be a first line therapy. If you can get it, go for it. It has one of the highest and most durable response rates we have seen in therapies for melanoma so far, with the exception of a small study that showed combining the other PD1 (opdivo) with IPI was higher. This is a not a palliative therapy at all but one of the first long lasting therapies we have had in 40 years. So I’m uncertain of your doctor’s knowledge but it doesn’t jive with current research.November 18, 2014 at 11:09 pm #65860 Thanks Catherine, to the point as usual.
I realized however that I was unclear. I think that if the clinical trial with Pembrolizumab would still be available, that would be the first choice if/when the melanoma spreads further. However, the number of participants is limited so I suspect that the trial would be full and then Ipi would be the only possibility for first therapy. Unless of course the melanoma behaves and no metastases occur in other parts of the body until PD-1 is approved as first line therapy or another “golden egg” clinical study starts.
How bad are actually the side effects from Pembro? I have read somewhere that it is considered to be a very benign therapy.November 19, 2014 at 12:22 pm #65861
You are correct, the side effects tend to be minimal with the PD1. Some patients have had some issues, and pneumonitis is the side effect most worrisome. It is less toxic than most other therapies including IPI.November 20, 2014 at 6:15 pm #65862 Thank you again Catherine!
I have another question about the recommendations from this oncologist.
As I wrote, the patient has stage M1a and skin metastases and metastases in one lymph node, but no other metastasis sites and the general condition is very good in all other respects.
Is there any reason that such a patient should receive BRAF inhibitor therapy instead of immunotherapy? That is what this oncologist recommends.
According to the official recommendation from health care authorities here, Ipi should be first line therapy because of the possibility to have a long term response, independent of BRAF status. BRAF inhibitors are second line therapy (in case of BRAF mutation). The recommendations mention BRAF inhibitors as possible first line therapy for patients with extended disease, big tumor burden, worse clinical condition, short expected survival and/or brain metastases.
These recommendations make sense to me, but the recommendations from the oncologist do not. Is there any possible explanation (except that the doctor’s knowledge is outdated)?November 20, 2014 at 7:06 pm #65863
I can also add that another clinical trials starts in January where Nivo can be given after progression on Ipi, but prior BRAF inhibitor is not a criterion. So Ipi would either do the job or the patient could get probably get Nivo. That one is a big study with more places.November 21, 2014 at 4:48 pm #65864 This is the message from the oncologist (my translation again):
“Yes, anti PD-1 could maybe be something for you but we are still trying to remove as much as possible with surgery with the hope that you won’t need any systemic therapy at all. So I do know about these drugs but since you have a BRAF mutation in your tumor, maybe you should rather have a BRAF inhibitor in first hand if we will do anything else than surgery/ECT.”
The patient has stage M1a, what are the chances to remove all metastases with surgery and not have a relapse?
Would it make sense in any way to get a BRAF inhibitor rather than immunotherapy in this situation?
I have already told him that I don’t trust the recommendations. Should I simply tell him to get out of there and find another doctor?
I am very upset and I don’t know what to do. I have asked Bettina for advice and she will have time after the weekend. Her quick reply about the first answer from the oncologist was that the oncologist should loose her license.November 21, 2014 at 5:24 pm #65865
Well surgical removal can be curative “if’ it is a clean surgery and all is removed. However, the chance is always there for recurrence and that is where the adjuvant therapy needs to come into play. Braf therapies can lower the tumor burden and the taf/mek is a good one for longer term response than zelboraf alone. If there is true first line access to PD1, I would give it a try. I hope this helps..November 21, 2014 at 6:25 pm #65866JonathanParticipant Sorry if this confuses things, but I’m an M1b patient on Pembro, so I have rather strong opinions on this issue. In general, I can support what Catherine has said, but I want to reinforce some points she’s made, and a couple she didn’t.
Pembro should be a first line therapy for metastatic melanoma. It has a very high response rate, one report in the New England Journal of Medicine suggesting an overall survival rate over 2 years in the vicinity of 80-90%. The only better figures so far are for the combination of anti-PD1 (Nivo) with Ipi, but that’s for a very small sample and has comparatively severe side-effects. The side effects for Pembro are very slight in comparison to Ipi, for example. They are quite amazingly benign in most cases. The same is true for Nivo.I
Surgery before systemic treatment – this is a tricky question that depends on the patient’s particular condition. Anti-PD1 drugs do best on patients with lower tumor burdens, so taking out large tumors that are causing clinical problems is a good idea in concert with anti-PD1 therapy. I had major intestinal tumor blockages and also bleeding from the tumors (anemia) but began Pembro a month before I had major abdominal surgery to remove the major blockages. Since the surgery, the Pembro has reduced the remaining tumors substantially in my abdomen, as well as lungs. It is unlikely that I (or most Pembro patients) will get a Complete Response, but that does not mean I will be left with active tumors – those things will only become clear after a year or so, when further treatment may or may not be required.
BRAF treatment prior to anti-PD1 – while some trials have required BRAF treatment prior to admission to anti-PD1, this does not seem logical in the long run because in most cases BRAF alone does not provide long term relief. I do not understand the problem you’re having there. If anti-PD1 did fail for you, then BRAF in combo would be a good secondary option, I’d think
This is a conjecture, but perhaps your oncologist has not had a long familiarity with these immunotherapy drugs? Handling them is somewhat new and tricky, since, for example, patients can sometimes progress prior to tumor regression. And the side-effects are of a different character as well.
JonathanNovember 21, 2014 at 8:02 pm #65867
Catherine and Jonathan, thank you both so much!
I have understood that surgery is a good idea in any case so I’m not questioning that.
I just wanted to know if there could possibly be any reason to prefer BRAF inhibitor over PD-1 but I understand that both of you think that PD-1 should be first line therapy.
The patient saw this oncologist a couple of months ago and was told that “surgery is the only cure for melanoma, all drugs are just palliative”. I think it is completely logical to first try PD-1 and hope that it works. If not, the BRAF inhibitors would still be an option like Jonathan pointed out, but apparently this oncologist does not believe in immunotherapy.
Jonathan, I’m very happy to read that you are doing well on Pembro! Thank you for your encouraging input.November 29, 2014 at 3:52 pm #65868bettinParticipant
as I said before, one of the most sensible things to do is to change oncologist- to someone who has experience with and insight into the new therapies in Melanoma.
Targeted therapy- ideally, BRAF plus MEK combo- has the advantage of working very fast but in most cases, the response is short-lived. So it’s the ideal salvage therapy for BRAF positive patients. Having said that, the GSK combo study presented at ASCO this year showed that patients who had a complete response to the combo stayed on there forever and the survival was nearly as good as PD1 (for complete responders). It also appeared that the response to the combo was better, the smaller the tumor burden was- which makes sense if you think that with increasing tumor burden, tumor heterogeneity increases and with that the possibilities for the tumor to have a subclone to get away.
So the tricky thing is to decide which route to go- personally, I’d go for PD1 (great response rate, good tolerability), at the first sign that fails- Ipi (also because consecutive treatment seems to be as good as combination of the two, just with fewer side effects) and should that fail, BRAF plus MEK combo to reduce the tumor burden- and then argue for re-introduction with either PD1 or Ipi.
On treatment, I’d aggressively treat any lesion that can become problematic- like brain mets (there’s a great webinar on this website on that) or lesions in places that could become extremely painful/ dangerous if they grew there- like spine, genital area, trachea, close to nerval plexus.
Unfortunately, there is no such a thing as an established path through metastatic Melanoma, to which the only solution is to find a knowledgeable oncologist who does not unilaterally favour one therapy over the other, get several opinions and above all, to educate one-self- and then to make a decision.
What is ‘right’ will also depend on the person, not everyone might want to travel across the country in order to get on to a trial.
BettinaDecember 1, 2014 at 9:37 am #65869
Bettina, thank you so much!
If I would be the patient, I would definitely change oncologist.
Thank you for the information about the results from the BRAF/MEK combination. I did not know this. There has been no mentioning of BRAF/MEK or any clinical study (I think that it would only be available that way), so my impression was that the oncologist meant BRAF inhibitor only.
Your suggestion for a treatment plan sounds completely logical to me, at least if all drugs would be available any time.
Regarding location, if I would be in the same situation I would consider moving to somewhere close to a clinic specialized in melanoma, mostly because I would like to be in good hands in case of side effects. Not everyone has the possibility to do that and I won’t suggest it. It is up to him to decide if he wants to travel or make other arrangements in order to get the therapy.
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