Tuesday, August 23, 2016

Anti PD-1 and Anti-PD-L1 treatments rarely confer durable remissions for metastatic uveal melanoma (and poor responses in acral and mucosal mel as well!)

As many of you know, I am frequently contacted by folks with melanoma (or those with peeps who are suffering) looking for answers, treatments, explanations.  I help as best I can.  In that capacity, I have discovered many who are facing more than just cutaneous melanoma and are gradually coming to realize that they or their loved one, is probably dealing with uveal, acral, or mucosal melanoma given the history, location, or results of testing.  Unfortunately, while we have made a great deal of progress since 2011 in the treatment of melanoma generally, these sub-types are notoriously unresponsive to the now conventional melanoma treatments.  For instance, this is a report out of ASCO this year: ASCO 2016: Anti-PD1 for acral and mucosal melanoma , where unfortunately it was demonstrated that rather than the more typical 40% response rate to anti-PD1 in treatment naive cutaneous melanoma, folks with acral melanoma had only a 32% ORR, while folks with mucosal attained only a 23% ORR....albeit these peeps were heavily pre-treated and perhaps that contributed to the lower response rates as well.
Additionally, these types of melanoma are less likely to be BRAF positive, removing yet another treatment option from their arsenal.  Here's data from a discussion between two melanoma specialists:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma
Here they note the following expected mutation rates -
Mucosal = 9% BRAF, 12% NRAS, 25% KIT
Acral = 22% BRAF, 16% NRAS, 24% KIT

The disconcerting aspect for me has been this response, "Oh, no.  We aren't [or - the doc isn't] calling it that! If that happened, she wouldn't be eligible for the trial!!"  I can hear the fear and desperation in their voice.  I really do understand!  I spent many years, even as a Stage IV patient, in melanoma land BEFORE the FDA approval of the BRAF inhibitors, anti-PD1, or ipi. I fully recognize the desperation and search for an effective treatment.   However, when you are allowed placement into a trial or treatment that we now KNOW provides little to no benefit for your particular mutation....what has been accomplished?  To my mind, time has been wasted, suffering continues, while other possibly more effective options go untapped.  Some Melanoma Big Dogs recently came together in this report regarding uveal melanoma response rates to anti-PD1 and anti-PDL1:

Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-1L antibodies.  Algazi, Tsai, Shoushtari, ... Daud, Sosman, Carvajal, Chmielowski, Postow, Weber, et al.  Cancer. 2016 Aug 17.

Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized.  Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined.  Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6%. Stable disease (greater or = to 6 months) was observed in 5 patients (9%). The median PFS was 2.6 months, and the median OS was 7.6 months. There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity.  PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population.

A sad acknowledgement to be sure.  These response and OS rates are really no different than those I was facing prior to the existence anti-PD1!  Frustrating and powerless do not begin to cover the feelings that this data engenders!!!  However, it is something I would want to know, if I were dealing with uveal melanoma.  For what it's worth.... - c

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