Outcomes of acral, mucosal, and uveal melanoma with treatment from checkpoint inhibitors - spoiler alert - get the immunotherapy combo!!!!

As I've said many times, Melanoma sucks great big hairy green stinky wizard balls.  Sadly, ocular, mucosal, and acral (think -fingers, palms, soles, nail beds) sucks even more.  Here are some prior reports:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=mucosal+melanoma

Now, there's this ~

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma.  Klemen, Wang, Rubinstein...Sznol.  J Immunother Cancer. 2020 Mar 8.

Checkpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.

We reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.

We treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral, 18 months for mucosal, and 12 months for uveal. For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 and 20 months after combination therapy. There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI.

Long survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%-32% of these patients.

In this report 90 patients with "sun shielded melanoma" (either acral, mucosal, or uveal) first treated with anti-PD-1 or anti-PD-L1 had median survival of 9 months vs OS of 18 months with anti-CTLA-4 vs 20 months OS with combination therapy.  21 of these 90 patients achieved 3 year survival, with 20 of those getting both anti-CTLA-4 and anti-PD-1 either sequentially or together.  80% of the 3-year survivors were also treated with local therapy after immunotherapy.

My take - if you have this sort of melanoma.  Get the combo - from the start!!!

For what it's worth.  Take care.  - c

Late addition:  

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.  Najjar, Navrazhina, Ding, et al.  J Immunother Cancer.  June 2020.

Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.

Methods: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.

Results: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).

Conclusions: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

For what it's worth - c

CheckMate 172 - nivo used after progression on ipi - report on those with acral,ocular and mucosal melanoma

As difficult as it is to treat cutaneous melanoma, folks with mucosal melanoma and other subtypes face even greater challenges.  Here are some previous reports:  Mucosal Melanoma 
Now, there's this:

Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172).  Nathan, Ascierto, Haanen, et al. Eur J Cancer. 2019 Aug 21.

Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab.

CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade greater than/= to 3, treatment-related select adverse events (AEs).

Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade greater than/= to 3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively.

The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival.

Not the numbers we wish for...but it is something!  Let's make them better for everyone SOON!!! - c

ASCO 2016 - Anti-PD1 for acral and mucosal melanoma

Acral and mucosal melanoma often fail to play by even the random rules that other melanoma tumors share and as such make treatment of them even more difficult.  But...there is this:

Clinical activity of anti-programmed death-1 (PD-1) agents in acral and mucosal melanoma.  ASCO 2016. #9516.  J Clin Oncol 2016.  Munhoz, Shoushtari, Kuk, et al.

Background: Antibodies against PD-1 resulted in a paradigm shift in the management of melanoma. Nevertheless, melanoma is a heterogeneous disease: compared to cutaneous melanoma, mucosal melanoma (MM) and acral melanoma (AM) have distinct genetic and clinical characteristics, lower somatic mutational burden, and poorer prognosis. We sought to investigate the efficacy of PD-1 blockade in patients (pts) with advanced mm and AM. Methods: We conducted a multicenter retrospective study of pts with advanced mm or AM treated with nivolumab or pembrolizumab. Clinical, pathologic, and treatment data were retrieved from electronic medical records. Response rates were assessed by RECIST v1.1 and survival intervals were calculated using the Kaplan-Meier method. Variables associated with response and survival were investigated. Results: Sixty pts were identified; 35 (58%) with mm and 25 (42%) with AM. Fifty-one (85%) pts had received prior therapy, including 77% with prior ipilimumab. Forty pts (67%) received pembrolizumab at 2mg/kg or 10mg/kg and 20 (33%) received nivolumab at 1mg/kg or 3mg/kg every 2-3 weeks. Objective response rate (ORR)  was 23% (10-40%) in mm and 32% (15-54%) in AM. ORR did not vary by age, primary site, or prior therapy outcomes. With a median follow-up of 10.6 months (mo) for mm and 20 mo for AM, the median progression-free survival was 3.9 mo and 4.1 mo, respectively. Median overall survival for the entire cohort was 16.8 mo; in mm it was 12.4 mo, and in AM 31.7 mo. Only two pts (3%) discontinued treatment due to toxicity. Conclusions: PD-1 blockade resulted in clinically meaningful activity in pts with mm and AM. Response rates and safety profile were comparable to published clinical trials which largely consisted of cutaneous melanoma and support the use of PD-1 blockade for mm and AM as well. The role of specific driver mutations, immunologic infiltrates and potential biomarkers of response and resistance in these melanoma subtypes needs further investigation.

Here, the roughly 40% response rates with anti-PD1 for treatment naive cutaneous melanoma patients were not achieved.  But, 85% of these patients had been previously treated....something many studies shows diminishes response rate and then there is the fact we are dealing with mucosal and acral melanoma.  Response rates of 23 and 32% are certainly something and definitely worth pursuing!!!  Interestingly, mucosal melanoma can often be NRAS positive.  Earlier I posted this: Good news for NRAS positive folks re: Anti-PD1 In that report, where NRAS positive patients were evaluated for response to IL2, ipi, vs anti-PD1 they found:  

"Within specific immune therapy types, patients with NRAS-mutant melanoma experienced the greatest benefit in CR/PR compared to patients with WT melanoma when treated with anti-PD1/PD-L1 agents (70% vs 20%)."   
 
Which got me thinking:  "A ray of light for folks with NRAS mutation. And maybe one more reason not to make them go through ipi before they get to take anti-PD1???!!!!!"  
Not all mucosal or acral melanoma are NRAS positive...but that info would probably be a good thing to find out!  Hang in there, dear ones!  Hang in there.   - c

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

Strategies for treating melanoma subtypes - Acral, Mucosal, Uveal, Nodular, Lentigo

 

While melanoma, despite the huge improvements made when targeted and immunotherapies gained FDA approved in 2011 remains a very difficult cancer to treat and survive, the subtypes noted in the title make cutaneous melanoma look like a walk in the park.  This LINK takes you to reports on those subtypes that I have previously posted.  The link below takes you to a pretty thorough report addressing these particular forms of melanoma as well as a good history regarding BRAF status.  I have included much of the report below.  Words are from the authors - not me.  However, checking out the link is valuable, as it includes tables and references not reported here.

Emerging strategies to treat rare and intractable subtypes of melanoma. Gretchen and Vito. Pigment Cell Melanoma Res. Jan 2021.

Melanoma is the deadliest form of skin cancer, possessing a diverse landscape of subtypes with distinct molecular signatures and levels of aggressiveness. Although immense progress has been achieved therapeutically for patients with the most common forms of this disease, little is known of how to effectively treat patients with rarer subtypes of melanoma. These subtypes include acral lentiginous (the rarest form of cutaneous melanoma; AL), uveal, and mucosal melanomas, which display variations in distribution across (a) the world, (b) patient age-groups, and (c) anatomic sites. Unfortunately, patients with these relatively rare subtypes of melanoma typically respond worse to therapies approved for the more common, non-AL cutaneous melanoma and do not have effective alternatives, and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in these high-risk melanoma subtypes represents one of the greatest challenges of the field. This review aims to collate and highlight effective preclinical and/or clinical strategies against these rare forms of melanoma.

INTRO - 

The melanoma field represents a paradigm for preclinical and clinical advancements in targeted and immune therapy modalities, with 13 new FDA-approved therapies since 2011. The catalyst for the development of targeted therapy modalities was the identification of activating NRAS mutations and BRAF mutations in 1984 and 2002... which paved the way for molecular stratification of the melanoma patient population. Approximately 45%–50% of non-acral lentiginous (AL) cutaneous melanoma patients have tumors that harbor activating BRAF mutations, with a single amino acid substitution of valine for glutamic acid at codon 600 (V600E) occurring in 90% of cases. Activating NRAS mutations at codon 12, 13, or 61 are detectable in 15%–20% of non-AL cutaneous melanoma patients and serve as an independent predictor of worse patient overall survival. Mutations of BRAF and NRAS are considered mutually exclusive; however, there are rare reports where both mutations exist in different regions of the same tumor or at different metastatic sites of the same patient. To date, it remains unclear whether the same melanoma cell can harbor both a BRAF and an NRAS mutation, or at the single-cell level, these mutations are indeed mutually exclusive.

With discoveries revealing that ~70% of non-AL cutaneous melanomas contain mutations constitutively activating the mitogen-activated protein kinase (MAPK) pathway came intense development of inhibitors capable of targeting various nodes of the mitogen-activated protein kinase (MAPK) pathway (i.e., BRAF, MEK, and ERK inhibitors) that continues to date. The first targeted therapy approved for the treatment of patients with BRAFV600E/K mutant melanoma was the small molecule inhibitor vemurafenib, an agent designed to have high specificity against the mutant V600E, V600K, V600D, and V600R forms of BRAF. Vemurafenib had response rates of ~48% in phase II and III clinical trials leading to the 2011 Food Drug and Agriculture (FDA) approval. A few years later, the combination of a BRAF inhibitor and a MEK inhibitor was observed to further increase the response rate to ~76% leading to the 2014 FDA approval of dabrafenib and trametinib. There are now three BRAF inhibitor plus MEK inhibitor combinations FDA approved for melanoma patients with BRAFV600E/K mutations (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib.

For patients with wild-type BRAF, treatment with BRAF inhibitors that specifically target V600E/K mutant BRAF may increase melanoma aggressiveness due to the paradoxical activation of wild-type BRAF and downstream MAPK pathway signaling. Preclinically, targeting downstream of BRAF with MEK inhibitors in BRAF-wild-type melanoma cells demonstrates the importance of the MAPK pathway for their survival, with significant anticancer activity. However, clinical trials testing multiple MEK inhibitors (i.e., binimetinib, trametinib) have concluded that although encouraging response rates and small increases in progression-free survival could be achieved in certain trials relative to dacarbazine, no significant increase in overall survival of patients with BRAF-wild-type melanoma was achieved with MEK inhibition. In an effort to increase MEK inhibitor efficacy, combination strategies with other agents (i.e., PI3K inhibitors, CDK4/6 inhibitors) are being clinically tested in the BRAF-wild-type (i.e., patients with or without NRAS-MT melanoma) setting after failure of immunotherapy. ERK inhibitors are also being clinically investigated to see if durable efficacy can be achieved in patients with wild-type BRAF, with reports showing the first-in-class ERK1/2 inhibitor ulixertinib has an acceptable safety profile and early evidence of clinical activity. Preclinical evidence suggests that concurrent inhibition of multiple nodes of the MAPK pathway in NRAS-mutant melanoma (i.e., MEK and ERK) may have synergistic activity on par with the BRAF inhibitor and MEK inhibitor combination in BRAF-mutant melanomas, and further studies evaluating this strategy are under way.

In parallel, large strides have been made in the development of immune checkpoint blockade strategies with the FDA approval of antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA4, ipilimumab) in 2011 and programmed cell death 1 (PD1, pembrolizumab, nivolumab) in 2014  and the combination of ipilimumab and nivolumab in 2015. Immune checkpoint blockade describes the use of therapeutic antibodies that overcome immunosuppressive checkpoints with the goal of unchaining antitumor immune responses. CTLA4 and PD-1 are both receptors that suppress effector T-cell activity. These immunotherapy-based strategies elicit long-lasting responses in a subset of patients and represent a therapeutic strategy suitable for all genotypes of non-AL cutaneous melanoma. However, the majority of patients treated with immunotherapy progress within 5 years due to poorly understood primary resistance mechanisms, and clinicians still cannot reliably discriminate which patients will respond or not respond. Both tumor intrinsic (i.e., insufficient tumor antigenicity, tumor interferon-γ signaling, tumor stemness) and extrinsic (i.e., regulatory T cells, myeloid-derived suppressor cells) resistance mechanisms have been reported, and there are intense efforts focused on overcoming these therapeutic hurdles to further increase the efficacy of immune checkpoint blockade strategies.

The promising efficacy of these new therapeutic strategies has been demonstrated largely in non-AL cutaneous melanoma patients with either superficial spreading melanoma (SSM), nodular melanoma (NM), or lentigo maligna melanoma (LMM). SSM, NM, and LMM represent the most common forms of melanoma in Caucasians (>85% of cases). It is important to appreciate that most of the recent pivotal discoveries in melanoma were performed on SSM cell lines, short-term cultures, animal models, and tumor biopsies taken from patients with SSM largely due to their greater availability. AL melanoma represents the fourth and rarest subtype of cutaneous melanoma. In addition, mucosal melanoma and uveal melanoma are other rare subtypes of melanoma that are non-cutaneous in origin. The efficacy of immune checkpoint blockade is lower in rarer subtypes of melanoma relative to patients with non-AL cutaneous melanoma, which will be discussed later. There is also little information regarding the efficacy of combination BRAF inhibitor and MEK inhibitor therapy in these subtypes. 

Acral - 

Acral lentiginous melanoma is an uncommon yet relatively aggressive subtype of CMM that accounts for 2%–3% of all melanoma cases. AL melanoma arises on sun-protected, glabrous skin of the soles, palms, and nail beds. AL melanoma has been historically associated with worse 10-year survival rates relative to other forms of CMM (67.5% vs. 87.5%). Further, 10-year AL melanoma survival rates are highest in non-Hispanic Whites (69.4%), intermediate in Blacks (71.5%), and lowest in Hispanic Whites (57.3%) and Asian/Pacific Islanders (54.1%), as found by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute evaluating data from 17 population-based cancer registries from 1986 to 2005. Another analysis of AL melanoma prognostic features in a cohort of German, Swiss, and Austrian patients suggests no significant difference exist relative to other subtypes of cutaneous melanoma; however, this conclusion may stem due to differential ethnicity landscapes between this patient cohort and that in the SEER study. There does not appear to be a gender bias, with a similar frequency between men and women and a comparable median age of diagnosis of 63.1 years for men and 62.2 years for women. The incidence of AL melanoma increases with age, and for reasons poorly understood, men are twice as likely to develop AL melanoma relative to women after the age of 80.

The distribution of AL melanoma varies geographically among populations throughout the world. While AL melanoma represents only ~2%–3% of all melanoma cases in Caucasian populations, AL melanoma makes up 50%–80% of all cases in non-Caucasian individuals in the United States (i.e., those of African, Latin American, and Asian descent). Furthermore, the incidence in Hispanic Whites doubles compared to non-Hispanic Whites after the aged of 70. A 2009 SEER study found the overall incidence rates of AL melanoma were similar between non-Hispanic Whites and Blacks; however, Hispanic Whites have statistically higher incidence rates relative to non-Hispanic Whites . Updated epidemiological studies should be performed to continue understanding the differential incidence trends that may exist across different ethnicities. Of note, the incidence of other subtypes of cutaneous melanoma (i.e., NM, SSM) is much lower in non-Caucasians relative to Caucasians. As this subtype of melanoma is not related to ultraviolet radiation (UV), there are different theories of the cause of AL melanoma. Some reports state that trauma and pressure in the foot (a predilected area of AL) is causal. However, the hand is also exposed to trauma but its location is less favorable. The main sites of AL melanoma metastases are the lungs, distant lymph nodes, scalp, contralateral limb, and liver.

Acral lentiginous melanomas possess a significantly lower mutational burden relative to the more common cutaneous melanoma subtypes, likely due to the sun-protected locations they arise from. BRAF mutations in are found in 1 in every 5 Al melanoma patients, leaving ~80% ineligible to receive BRAF inhibitor and combination BRAF/MEK inhibitor strategies . Therefore, new targets specific for AL melanoma are needed. 80% of AL melanomas display genetic aberrations of cyclin-dependent kinase 4/6 (CDK4/6) pathway-related genes (i.e., amplification of CDK4 and CCND1, and/or loss of CDK2NA), representing the most frequent copy number alteration detected . Additionally, activating KIT mutations are present in ~6% of cases. AL melanoma displays similar incidence of NRAS mutations as non-AL cutaneous melanoma, detectable in 15%–28% of AL melanoma patients, and NRAS mutations are an independent prognostic factor of worse overall survival.

Considerable barriers exist to treat patients with AL melanoma: (a) a contrasting genomic and genetic landscape relative to non-AL cutaneous melanomas, (b) unclear targetable drivers, and (3) sparse experimental models available for preclinical drug development. Unfortunately, FDA-approved targeted therapy strategies for melanoma are not available for the majority of AL melanoma patients (i.e., BRAF inhibitors since AL melanoma has a low frequency of BRAF mutations), and the efficacy of immune checkpoint blockade strategies is not well known in AL melanoma, with differing overall response rates (ORR) differing by country. For example, the ORR of anti-PD-1 in AL melanoma patients was found to be similar to that in non-AL cutaneous melanoma patients within the United States. In contrast, the ORR was 66.7% for SSM patients and 28.6% of AL melanoma patients in a recent Japanese study, suggesting the efficacy of immune checkpoint blockade may vary with ethnicity. The lower mutational burden observed in AL melanoma cases is thought to drive the reduced efficacy of immune checkpoint inhibitor strategies (e.g., PD-1 blockade) in patients. Although AL melanoma patients with Kit mutations can be treated with a KIT inhibitor per National Comprehensive Cancer Network (NCCN) guidelines, resistance mechanisms that reactivate downstream MAPK and PI3K pathway signaling have been suggested to blunt long-term durability. Due to the high percentage of AL melanoma tumors with CDK4/6-pathway aberrations, CDK4/6 inhibition represents one of the most promising targeted therapy strategies for AL melanomas clinically. However, durable responses are not observed in all patients due to resistance and CDK4/6 inhibitor-based combinations will likely be needed to improve the curative rate for patients with AL melanoma. Preclinical investigation to optimize targeted therapy strategies has not been extensively performed in AL melanoma models, but the rich body of literature that exists from studies in non-AL cutaneous melanoma models strongly suggests that single-agent approaches will not be durable due to the nearly universal onset of resistance. In SSM models, treatment with a MAPK pathway inhibitor plus a CDK4/6 inhibitor has shown synergistic activity in BRAF-MT and BRAF-wild-type settings; however, residual disease persists. Resistance mechanisms to CDK4/6 inhibitors and/or MEK inhibitors must be delineated to develop combination strategies that produce durable responses in AL melanoma patients.

Mucosal Melanoma - 

Mucosal melanoma (MM) is one of the rarest types of melanoma, accounting for only 1% of all cases, and has a significantly worse prognosis relative to the other subtypes. Distinct from cutaneous melanoma, MM arises from melanocytes located in mucosal membranes inside the body (i.e., genitourinary, anorectal, nasopharyngeal). The head and neck (55), vulva (18), and anus (24) are the most common observed sites; however, MM can also occur in the gut, lungs, and urinary track. It is rarely diagnosed at early stages due to difficult visual detection, which is much more tractable for cutaneous subtypes of melanoma. The overall median age of diagnosis is 70 years, with the exception of MMs arising in the mouth that manifest more frequently in younger patients. The incidence of MM has been stable for the last few years with the exception of MM in the genital tract, which is higher in females relative to males for reasons not clearly understood.

Approximately 3%–15% of MMs harbor an activating mutation in BRAF, with ~63% located on the V600 codon and 37% located on a non-V600 codon. This is in contrast to non-AL cutaneous melanomas where <10% of BRAF mutations are outside of the V600 codon, and more closely resembles the high prevalence of non-V600 mutations found in 48% of lung adenocarcinomas. A closer analysis of the most common non-V600 mutations reveals (a) a difference between the frequency of mutations on D594, G469, and K601 between non-AL cutaneous melanomas and MMs, and (b) convergence in the non-V600 mutational landscape between MM and lung cancers where mutations are often associated with genotoxic agents.

In regard to NRAS mutations, approximately 12% of MMs harbor activating mutations, which is lower relative to cutaneous melanomas where NRAS mutations occur in 15%–20% of cases. There is also a divergence in the location of NRAS mutations between MM and cutaneous melanoma, with 54% located on codon 61 in MM versus 88% in cutaneous melanoma, and 46% located on codons 12 and 13 in MM versus 12% for cutaneous melanomas. Approximately 7%–22% of MMs have v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) somatic mutations or amplifications. MMs located in the genital area appear to be driven by mutations in SF3B1 which encodes the subunit 1 of splicing factor 3b, a component of the spliceosome that processes pre-mRNA into mature transcripts. A recent study analyzing the mutational landscape of MM identified IGF2R mutations in 31.7% of MM samples relative to 6.3% of SSM cases. Interestingly, a lower frequency of UV-induced DNA damage, a lower number of mutations and a link to high tobacco exposure have also been identified in MM.

Unfortunately, MM is typically detected at relatively more advanced states due to difficulty in early detection. The main treatment for MM differs slightly on where the tumor is located; however, like any other subtype of melanoma, patients are initially treated with surgical excision. MMs arising in the head and neck are treated with complete surgical excision of the tumor when the patient is in stages III and IVA. However, this is associated with a high rate of recurrence. MMs that have arisen in the vulvovaginal or anorectal area also receive radiation in addition to surgical tumor excision. Therapeutic efficacy may be improved in select patients when treatment is personalized by tumor mutational status. Clinical trials targeting KIT with imatinib show no clear effect in unselected metastatic melanoma patient populations, but encouraging clinical benefit has been observed with KIT inhibition specifically in patients with melanomas harboring KIT mutations (not in patients whose melanoma harbor KIT amplification only). Nonetheless, disease progression ultimately occurs in the majority of cases. These data support the practice of determining KIT mutational status for MM patients to have a higher chance of receiving additional clinical benefi. Subsequent phase II clinical trials now require a KIT alteration for enrollment. For the relatively small number of MM patients whose tumors harbor BRAF mutations (relative to the ~50% in non-AL cutaneous melanoma patients), treatment with combination BRAF inhibitor and MEK inhibitor therapy is available. However, the efficacy of targeted therapy specifically in the MM patient population is not completely understood due to the low number available for analysis.

The efficacy of immune checkpoint inhibitor therapy also remains unclear in MM patients, with conflicting evidence of whether MM patients respond as well as non-AL cutaneous melanoma patients. In one multi-institutional analysis of clinical trials focusing on all the subtypes of metastatic melanoma, patients with MM had similar responses compared with non-AL cutaneous melanoma patients when treated with anti-PD-1 single-agent therapy, with a progression-free survival of 3.9 months . In another pooled analysis, MM patients treated with nivolumab as monotherapy or nivolumab in combination with ipilimumab experienced reduced clinical benefit relative to non-AL cutaneous melanoma patients. MM patients experienced 50% shorter progression-free survival (3.0 months) relative to patients with non-AL cutaneous melanoma (6.2 months) for monotherapy (nivolumab) and for nivolumab plus ipilimumab (5.9 vs. 11.7 months. Another recent study combining axitinib (small molecule receptor tyrosine kinase inhibitor) with toripalimab (anti-PD-1) found a median progression-free survival of 7.5 months in among 29 patients with chemotherapy-naïve mucosal melanoma. Although these data suggest that MM patients may not achieve as much benefit with immune checkpoint inhibitor therapy as non-AL cutaneous melanoma patients, it should be considered that in each of the pooled analyses, the number of MM cases was only 10% of patients compared to 75% from cutaneous melanoma. Also notable, another prospective study where 44 patients with unresectable MM were treated with immune checkpoint inhibitors concluded that the site of origin for MM (i.e., vaginal, anal) may not have a significant impact on the objective response rate, which was 8.2% for ipilimumab and 35% for pembrolizumab. The lower mutational burden in MM relative to non-AL cutaneous melanoma may explain the decreased efficacy of immune checkpoint blockade in MM.

Uveal Melanoma -

Uveal melanoma (UM) is the most common form of ocular melanoma, as well as the most prevalent form of non-cutaneous melanoma, accounting for 5% of all melanomas . It most commonly arises in non-Hispanic Whites relative to other races (i.e., African and Asian Americans), with a slight predominance for men (52.3%) relative to women (47.7%). The incidence of UM has remained stable over the last few decades and is diagnosed in 4–5 per million individuals in the United States each year. The median age of diagnosis is 62, and the incidence of UM increases with age. Early detection of UM provides a favorable 85% survival rate; however, this survival rate significantly decreases to 15% once UM cells have disseminated. Approximately 50% of UM patients develop metastases, and among patients with metastatic disease, 90% have liver involvement and ~70% have liver-only disease. This is a distinct metastatic pattern relative to cutaneous melanoma or mucosal melanoma.

Unlike non-AL cutaneous melanomas, UMs have a much lower mutational burden due to the sun-protected site they arise from within the ocular cavity. Activating mutations in BRAF or NRAS are not detected (extremely rare) in tumor cells of UM patients. In contrast, the main drivers for UM are activating mutations of guanine nucleotide-binding protein G (GNAQ/11), splicing factor 3B subunit 1 (SF3B1), eukaryotic translation initiation factor (EIF1AX), and inactivating mutations of the tumor suppressor BRCA-associated protein-1 (BAP1). The GNAQ/11 genes encode specific GTP binding proteins that mediate signal transduction from the inner cell surface to the MAPK pathway through activation of the protein kinase C (PKC) enzyme. GNAQ and GNA11 mutations are mutually exclusive, and thus in total are detected in 85%–94% of UM across all stages of disease. Due to their detection in benign uveal nevi, GNAQ/11 mutations are thought to be early mutational events.

BAP1 (located on the short arm of chromosome 3) loss-of-function mutations are posited to serve as a predisposing factor for diverse hereditary cancers including mesothelioma, cutaneous melanoma, renal cell carcinoma, and UM. A recent comprehensive review identified that among 174 patients harboring germline BAP1 mutations, 130 developed tumors that were either UM (31% of cases), cutaneous melanoma (13% of cases), renal cell carcinoma (10% of cases), or MM (22% of cases). In UM, loss of BAP1 returns melanoma cells to a more stem cell-like state as BAP1 is involved in melanocyte differentiation. BAP1 is frequently mutated in metastasizing uveal melanomas, which supports the growing evidence that stem-like melanoma cell states drive elements of the metastatic cascade.

There has been a recent decline in UM patients treated solely with surgery due to micrometastases that develop years before primary tumor detection. The current approach for treatment of metastatic UM is radiation; however, the survival rate is not significantly improved relative to what is possible from surgery. There have been an array of clinical studies trying to identify efficacious therapeutic strategies for patients with metastatic UM. UM patients that possess GNAQ or GNA11 mutations can be treated in clinical trials with targeted therapy approaches specific for the MAPK pathway (i.e., MEK inhibitor, ERK inhibitor) as these tumors display elevated MAPK activity. Preclinical studies have shown that treatment of UM with a combination of a MAPK pathway inhibitor and a PKC inhibitor may provide synergistic efficacy relative to what is achievable by either agent alone. Clinical trials with selumetinib, a MEK inhibitor, reported a higher progression-free survival among UM patients (15.9 vs. 7 weeks); however, no clinically meaningful increase in overall survival was observed in comparison to the chemotherapeutic temozolomide in the metastatic setting (10.8 vs. 9.4 months). Additionally, preclinical studies identified that targeting the PI3K/AKT pathway (in GNAQ and GNA11 mutant xenograft models) in combination with a MEK inhibitor may be an effective treatment strategy for patients with GNAQ or GNA11 mutations; however, clinical trials using this combination have stopped due to low response rates and high toxicity. Inhibitors against bromodomain and extraterminal (BET) proteins have had encouraging activity preclinically in UM, which could be further increased by concurrent inhibition of escape mechanisms mediated by fibroblast growth factor receptors. Similarly, targeting microenvironment-derived factors including HGF can also increase MEK inhibitor efficacy against UM cells, preclinically. For UM with BAP1 mutations, it has been shown preclinically that treatment with a histone deacetylase (HDAC) inhibitor could be beneficial. Because BAP1 mutations are associated with loss of melanocytic differentiation, treatment with HDAC inhibitors (valproic acid) are postulated to inhibit the growth of uveal melanoma in vivo by inducing morphological differentiation.

While immune checkpoint inhibitors are the standard of care for cutaneous melanoma, UM has not yet had a phase III clinical trial for immune therapy. Small studies in UM patients (10 patients) treated with pembrolizumab (anti-PD-1) after treatment with ipilimumab reported a median progression-free survival of 18 weeks; ranging from 3.14 to 49.3 weeks. Of the eight evaluable patients, four rapidly progressed, one had stable disease, two had partial responses, and one had a complete response. Although this small study resulted in comparable results seen in patients with non-AL cutaneous melanoma, other studies suggest far lower response rates to single agent anti-PD-1 and combination anti-PD-1 plus anti-CTLA-4 in UM patients. An analysis of Danish UM patients observed partial responses in 7% of patients to anti-PD-1 and 21% to concurrent anti-PD-1 plus anti-CTLA-4. Metastatic UM patients treated with ipilimumab from two additional clinical studies had a median overall survival of 9 months (in contrast to 19.9 months in non-AL cutaneous melanoma). Despite the reduced efficacy of immune checkpoint blockade in UM patients, this option may represent the most effective strategy to date.

Nodular Melanoma -

Nodular melanoma represents the second most common subtype of melanoma, responsible for 10%–15% of total melanomas in Caucasians. NM is the melanoma subtype most associated with increased thickness at clinical presentation, which is attributed to the relatively poorer prognosis of patients with NM. The median age of diagnosis for NM is 53 years, with thicker tumors more common in older patients. NM is more common in women than men for reasons poorly understood and commonly presents de novo on the head, neck, or trunk of patients.

Activating BRAF mutations are detected in patients with NM at a slightly lower frequency relative to SSM, with 43%–47% of patients possessing mutations mostly (88% of cases) in V600E. A recent study identified evidence that BRAFV600E expression may serve as a prognostic marker in primary NM associated with ulceration and reduced survival. Preclinically, it was reported that hyperactivation of the downstream MAPK effector ribosomal protein S6 kinase (RSK1) is detectable in metastatic tumor tissues derived from NM to a higher extent relative to SSM. Activating NRAS mutations are detected at a significantly elevated frequency in NM relative to SSM in 30%–33% vs. 19% of cases, respectively. Interestingly, BRAF and NRAS mutations may not be as mutually exclusive in NM relative to SSM, with the identification of both mutations in the same tumor specimens when assessed by laser capture dissection followed by direct sequencing analysis of exons 11 and 15 of the BRAF gene and exons 1 and 2 of the NRAS gene. Additional high-throughput sequencing of patient-derived samples of single nucleotide variations (SNVs) expected to impact protein coding reveals NOTCH4, RPSKA6, BCL2L12, TERT, ERBB3, ZNF560, SSPO, and SNX31 to be significantly under-mutated in NM relative to SSM.

An analysis of the most recent Surveillance, Epidemiology, and End Results (SEER) cohort and the New York University (NRU) cohort suggests that relative to patients with metastatic SSM treated with BRAF inhibitor (BRAFi) therapy, patients with metastatic NM may respond worse to BRAFi for reasons not completely understood, suggesting the potential existence of distinct clinical and biological properties between NM and SSM. The observation of activated RSK1 via constitutive phosphorylation at the Ser-380 residue may explain the poorer efficacy of BRAFi and/or BRAFi/MEKi in patients with this melanoma subtype. In contrast, no significant difference in response rates and survival was detected in NM versus SSM among a cohort of 154 patients treated with either anti-CTLA-4, anti-PD-1, or the combination of both immune checkpoint inhibitor approaches. Immune checkpoint blockade may serve an ideal first-line therapy for patients with this subtype.

Lentigo Maligna - 

Lentigo maligna (LM) is the third most common subtype of melanoma, comprising roughly 4%–15% of all melanoma cases and its incidence has dramatically increased over the past few decades across the United States, and other regions of the world. LM melanoma typically presents on chronically sun-damaged (CSD) skin of the head and neck, appearing as an irregular brown macule commonly on the head and neck in the elderly. In contrast to the mean age of diagnosis of SSM between 40 and 60 years, the mean age of diagnosis for LM melanoma is 66–72 years. Credit is given to Sir John Hutchinson for the earliest description of LM melanoma in 1890. LM melanoma was initially referred to as “Hutchinson’s melanocytic freckle” due to the prevailing thought that it was benign, non-infectious lesion owing to its slow growing nature. Critical work by Ackerman and Silvers in the late 1970s–1980s finally led to wide acceptance of LM melanoma as a malignant disease worthy of clinical attention and intervention. Chronic ultraviolet radiation is the major risk factor for the development of LM melanoma, which differs from NM and SSM that are associated with intense intermittent ultraviolet radiation exposure. LM melanomas arise most frequently on the face and other sites of chronic sun damage which also differs from NM and SSM that arise most commonly on the trunk in men and legs in women. LM melanoma is thought to occur in older patients due to the increased lifetime sun and ultraviolet radiation exposure.

Lentigo maligna melanomas have a relatively high mutational burden compared to other melanoma subtypes due to chronic ultraviolet exposure. The frequency of activating BRAF mutations in LM is unclear, with reports finding 16.7%–53.4% of LM patients harboring BRAF mutations. The large variation may, in part, be attributed to the regional differences among tested patient tissue cohorts. In a Greek cohort, 16.7% of LM melanoma cases expressed BRAF mutations and 50% of LM cases in a Japanese cohort expressed BRAF mutations. When BRAF mutations are present, the V600K substitution is frequently observed (~77%) relative to the V600E (~23%) as observed in SSM, in this small set of 13 LM patient tumor samples. This finding is consistent with V600K mutations arising on chronically sun-damaged skin. Activating NRAS mutations have been reported to occur in ~8.1%–16% of LM cases .

The treatment of choice for patients with localized LM melanoma consists of surgical excision as first line of therapy, followed by radiation therapy with fractionated superficial radiotherapy, or topical imiquimod cream as an alternative to surgery. Once LM melanoma metastasizes to visceral organs, the five-year survival is similar to SSM. Interestingly, the efficacy of immune checkpoint blockade may be significantly higher in patients with LM melanoma relative to the other subtypes discussed. A study investigating the overall response rate (ORR) of anti-PD-1/PD-L1 in different subtypes of melanoma found patients with melanoma on CSD skin (including LM melanoma, desmoplastic melanoma, and subtype not-specified cases) exhibited an overall response rate of 70%, which fits the theory that cancer cells with high mutational burdens may be more sensitive to immune checkpoint blockade due to the increased presence of immune-stimulatory neoepitopes. Additional investigations on the efficacy of targeted and immune-based therapy are needed specifically for patients with LM melanoma to ensure the optimal treatment(s) is identified for this cohort and further improved through preclinical experimentation and clinical trials.

To date, this is the most comprehensive review of the data and treatments best suited for these melanoma subtypes that I have found.  So hoping that understanding and effective treatment options increase for these patients very soon.  -  c

Evaluation of response to nivo or ipi/nivo in Cutaneous and Mucosal Melanoma

As noted in these two prior posts (additional link within) 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!)

Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. D'Angelo, Larkin, Sosman, Lebbe, …., Hodi...Sznol, Weber, ...Wolchok. J Clin Oncol. 2017 Jan 10.

Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months and 6.2 months for mucosal and cutaneous melanoma, with objective response rates of 23.3% and 40.9%, respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months and 11.7 months for mucosal and cutaneous melanoma, with objective response rates of 37.1% and 60.4%, respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.

Hang in there dear peeps!!! - c

Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Combining immunotherapy and targeted drugs for melanoma: Weber and Agarwala
(Late note:  since publication of this post, the link above has been taken down.  However, the points below are my transcription of their commentary. - c, 2018)

The link above connects to a video discussion and slides by Dr. Jeffrey Weber and Dr. Sanjiv Agarwala regarding combination therapies and other treatment information as it relates to melanoma.  Much like the prior link I discussed, material is presented in an understandable manner in the form of a continuing education program for general oncologists and others in the field...from the horse's mouth.

Points I noted:

• BRAF is the only predictive marker for the use of BRAF inhibitors.
• 40-50% of melanoma is BRAF positive.
• The RAS-RAF-MEK-ERK MAP kinase pathway is a critical signaling path in melanoma.
• MELANOMA SUB-TYPES via landscape as origin:  
• Skin with sun damage = 50% BRAF, 20% NRAS, 0 KIT
• Skin without chronic sundamage = 22% BRAF, 0 NRAS, 19% KIT
• Mucosal = 9% BRAF, 12% NRAS, 25% KIT
• Acral = 22% BRAF, 16% NRAS, 24% KIT
• BRAF resistance develops due to reactivation of the MEK pathway.  This is why the addition of MEKi to BRAFi prevents that resistance, thereby increasing effectiveness and decreasing side effects.
•  The COMBI-d trial (dabrafenib plus trametinib vs dabrafenib alone), the Combi-V trial (dabrafenib and trametinib vs vemurafenib alone) and the CoBRIM trial (vemurafenib with cobimetinib vs vemurafenib and placebo) all demonstrate the effectiveness of combination therapy when compared to one targeted therapy alone.

Here's a link addressing BRAFi info out this year as well as earlier articles about BRAFi combo's:   BRAFi : What predicts resistance.
Here's a link regarding an article this year that addressed CoBRIM as well as PDL1 in immunotherapy combinations (which the docs address later in the video as well.):  Combos looking good but if PDL1 positive - just do nivo!

 IMMUNOTHERAPY:

• CTLA4 and PD1 put brakes on the immune system (in 2 different areas, in different ways), but ultimately prevent T cells from eradicating melanoma and other cancers.  When you turn CTLA4 and PD1 "off" with ANTI-CTLA4 (ipilimumab) and ANTI-PD1 (Nivolumab/Opdivo or Pembrolizumab/Keytruda) you allow T cells to engage and do their job.
• Studies with ipi show a plateau in overall survival of 22% at 3 years.
• When ipi is combined with GM-CSF, 1 year OS is 68% vs 52% in ipi alone.
• When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone. NOTE: You can find more info on GM-CSF using the search bubble on my blog.  Here's a link to some of the latest on intralesional therapies out of ASCO 2015:  Intralesional therapy for melanoma: ASCO 2015
• Some questions remain with ipi: What is the optimal dose?  3mg/kg vs 10mg/kg? The 169 trial is a randomized Phase 3 trial, ongoing, looking at differences in dosage.  Trials are looking at whether ipi should be administered in the current 4 dose - then stop, protocol...or are maintenance doses helpful?  Weber feels 4 doses are sufficient, but trial results are still pending.
• Ipi as adjuvant?  The 1609 trial is looking at this question and the 10mg/kg dose is showing promise, results to be out in about a year or 2.
• Overall, ipi is showing a 10-15% response rate, BUT...there are significant numbers of those demonstrating 10 YEAR survival.
• Anti-PD1 (both products) give clearly greater responses than traditional chemo and better than ipi as well...with an overall response rate of about 40-45%.
• Folks with tumors that are positive for PD-L1 respond better to anti-PD1 products.   However, many problems remain with the clarity of the test, availability of the test, consistency of results, etc.  Therefore, it is a useful...though not a predictive...marker.
• Because CTLA4 and PD-1 work differently...combining the two antibodies....can provide even better responses.  Additionally, ipi failures can respond to anti-PD1 and anti-PD1 failures can respond to ipi.
• In an early combo study of nivo and ipi, patients experienced an ORR of 53% and 40% had significant tumor reduction.
• In another nivo/ipi combo study, there was a 61% response rate and 22% rate of complete response on the combo vs 11% and none with ipi alone.
• In PD-L1 positive patients: those in the combo had a 58% overall response vs 18% ORR to ipi alone.  PD-L1 negative patients: had an ORR of 55% to the combo vs 4% ORR to ipi alone.
• Responses were durable.  Almost all responders continued to maintain their response at a rate of 82%.  Even of patients who had to stop treatment due to side effects, 2/3 of them continued to respond.
• Grade 3/4 toxicities increase almost as much as the response in the combo with a rate of 55%, though almost all are reversible.
• In the CA209-067 study, the ipi/nivo combo was compared to ipi alone and nivo alone.  ORR were 57.6% for the combo, 19% for ipi alone and 43.7% for nivo alone.
• However, when looking at PD-L1 staining:  When positive, the difference between PFS with the ipi/nivo combo vs nivo alone is negligible. So the argument may be made to go with nivo alone...since the difference in response is minimal, but side effects are much less.  However, more definitive studies are needed.
• The ipi/nivo combo overall is providing increased response rates and increased progression free survival.  
• Survival may even be better with the combo than with sequential nivo or ipi.
• However, for PD-L1 positive patients (40% of the population) concurrent therapy may be no better than nivo alone, followed by ipi if there is progression.
• For PD-L1 negative patients, the majority of patients, the ipi/nivo combo is better than a single agent, though you have to keep in mind that fewer than 1/2 of responding patients are able to tolerate the combo longer than 24 weeks.
• A study is underway looking at planned sequential therapy giving patients ipi followed by nivo, OR nivo followed by ipi....with nivo maintenance....preliminary results to be out within a week at meeting in Vienna.
• HOW TO DECIDE, in the BRAF positive patient....between immunotherapy single vs combo vs BRAF inhibitors.  These docs report that they tend to treat indolent patients with anti-PD1 alone.  However, in patients with increased LDH and a heavy disease burden, they would lean toward using BRAFi or the ipi/nivo combo.  Or to put it another way:  BRAF positive and negative patients do equally well on anti-PD1, so BRAF positive patients with indolent disease and low tumor burden, would probably be wise to place on immunotherapy.  In fast growing disease, with a high disease burden...and BRAF positive...use a BRAF/MEK combo first.  If BRAF negative - use the ipi/nivo combo.
• Question with no current answer:  With a patient who initially responded to nivo, but then progresses...should you switch to ipi or ADD ipi?  Docs feel that a trial looking at survival with these two options should be done...though it is NOT underway currently.
• Final thought, ipi is no longer these doc's first line drug choice when used alone.  They feel that anti-PD1, even as a single agent, is going to prove to have durable responses. While ipi combo's are going to be very important.

Long, I know.  Hope it helps. - c

Vitamin D and melanoma - folks with higher levesl do better - again!!!

Vitamin D and vitamin D levels of melanoma patients have long been discussed.  Here is a link to a couple of prior posts:  Vitamin D - low levels associated with a worse prognosis in melanoma...again...

Now there's this:

High serum vitamin D level correlates with better prognostic indicators in primary melanoma: A pilot study. Lim, Shayan, and Varigos. Australas J Dermatol. 2017 Mar 23.

Sunlight is a major risk factor for cutaneous melanoma. However, its interaction with melanoma is complex. In particular, vitamin D is a UVB-derived hormone that has been shown to have anti-cancer effects. In this retrospective pilot study we sought to determine an association between the clinicopathological features of melanoma and the patients' corresponding serum vitamin D level.

In total, 109 primary melanomas diagnosed between 2001 and 2013 were retrospectively identified from our institutional database with a corresponding 25-hydroxyvitamin D3 level estimated within 6 months of diagnosis. Tumour, clinical (age, sex, tumour location) and pathological (thickness, mitosis, ulceration, Clark level, subtype, metastatic status) parameters were correlated with vitamin D. 

Vitamin D level was inversely associated with Breslow thickness as a dichotomous, categorical and continuous variable. The association remained significant when controlled for patient's age and sex. Vitamin D was higher in non-ulcerated tumours compared with ulcerated tumours and in tumours with mitotic rate less than 1/mm² compared with greater than/= to 1/mm². A significant association was found between vitamin D level and tumour histological subtype. On subgroup analysis, significant associations were found between superficial spreading melanoma (SSM) and nodular melanoma, and SSM and acral lentiginous melanoma.  

A high vitamin D status may benefit prognosis in patients diagnosed with primary melanoma. A prospective cohort analysis with a large sample and controlled for other vitamin D confounders would validate these findings.

And again....  Take that Vitamin D, folks!!! - c

With melanoma: You can never be too rich or too thin! But, you can be too young!!!

Definitions to keep in mind:
Thickness (Breslow) - actual thickest part of a slice of the tumor...remembering that the lesion can rise above the level of your skin.
Clark level - a description of how deeply the tumor penetrated the layers of your skin.

Thin melanoma and late recurrences:  it is never too thin and never too late.  Richetta, et al.  Med Oncol.  April 2014.

"In the absence of risk factors, thin melanomas [generally defined as 1mm or less] present a long-term survival; however recurrences may occur....Median disease free survival of the entire cohort [in this study] was 26 months and three patients developed late metastases. Nine patients developed extra-nodal metastases as first recurrence, while cases of positive sentinel lymph node biopsy were not found....No consensus exists as to which patients with thin melanomas are at risk for metastases or late recurrences."

Sentinel node biopsy improves prognostic stratification in patients with thin melanomas and an additional risk factor.  Mitteldorf, et al. Ann Surg Oncol.  March 2014.

"Sentinel lymph node biopsy for patients with thin melanomas is not generally recognized as a clinical standard...931 patients had sentinel lymph node biopsies.  210 had thin melanomas.  Of the 210...All..showed at least one of the following risk factors:  ulceration (4%), Clark level IV (44%), nodular growth pattern (11%), mitoses (59%), regression (38%) or age </= 40 years (27%)."

....observed surprisingly high SLN positivity rate of 18%.  [Most of the literature says that for thin, 1mm or less, melanoma lesions the rate of finding a positive node is less than or equal to 5%.  Now, while that may sound nice....that is one of twenty people!!!]  "There was a trend towards a higher SLN positivity rate in younger patients. Breslow, ulceration, mitoses, nodular growth pattern, and sex did not reach significance.  Regression was significantly more frequently found in very thin melanomas (</=0.75mm) and tended to be significant in this subgroup."

"SLNB improves prognostic stratification in patients with thin melanomas having an additional risk factor....Our data suggest that SLNB should be offered to patients with thin melanomas, if ulceration, nodular growth pattern, mitoses or regression are present, or if the patient is younger than 40 years of age."

Identifying high risk patients with thin (</=1mm) primary cutaneous melanomas.  Gimotty et al. ASCO 2013. 

"The prognostic factors used to identify patients with thin melanomas at high risk of regional nodal metastasis or melanoma specific death include:  thicker tumors (>/= 0.75mm), deeper levels of invasion (Clark level IV or V), ulceration and dermal mitosis....Study cohort = 42, 080 patients with only one primary and no clinical evidence of metastasis at the time of diagnosis....Five year melanoma specific death rates were not uniform in 100 tumor thickness groups, but were stable in each of the following ranges:  4.3% - 0.01-0.17mm, 1.3% for 0.18-0.66mm, 3.1% for 0.65-1.00mm.  Among all patients, ulceration and level were the strongest prognostic factors.  Thickness was a weaker prognostic factor.  Four risk groups for regional nodal metastasis risk were identified:  
1) level IV/V (11.8%), 
2) level II/III with nodular or acral lentiginous histologies (15.1%),
3) level III and 0.11-0.17mm and not nodular or lentiginous (9.3%),
4) level III and 0.01-0.02mm and not nodular or letiginous (6%).
...Stratification schemes comparable to this will inform decision making."

My story:  Well, you can never be too rich if you are sick, in need of care longer than 2 minutes, or have to travel for your care!!!  Clearly, being thin (as applied to melanoma lesions) is not terribly protective.  I try not to say too much on the forums as Janner attempts to lull people out of their terror after having been diagnosed with an "atypical lesion"....she's definitely correct there.  No great risk, people.  It is gone.  Watch your skin.  Move on.  But, with this "thin melanoma" business...things can get murky!  Trust me!!!  My initial stats:  2003.  On right upper back.  Breslow measurement = 0.6mm.  Clark level IV.  No ulceration.  1/mitosis/hpf(high power field).  Yet, I had one positive node with "micrometastasis, Starz classification 1" (per Dr. Starz of Germany himself).  Later, we had a report from Martin Mimh, MD of Harvard, who noted that, yes, my tumor was a Clark Level IV (there had been some confusion on the part of the local 2-wong-fu pathologist) and "as you would expect" in such a case, I had a "positive node".  Age at diagnosis - 39.

As the thickness of the lesion was less than that indicated for a SNB at the time, we pushed for it anyway.  I am certain I would not be here today had I not had it done.  Turns out now, I WAS in a high risk group, despite the thinness of the lesion.  I was less than 40 years of age with a Clark level IV lesion. 

I don't want to frighten folks with this information.  But, this is the data.  And I am LIVING proof.
Take care of yourself.  Discuss with your melanoma specialist!  Yours, c

Melanoma - All things adjuvant

I have kicked and screamed about the need for adjuvant treatment for so many years (especially the more effective anti-PD-1 products vs ipi) that it was almost unbelievable when they were finally FDA approved for adjuvant use in 2017 (Opdivo) and 2019 (Keytruda).  Sadly, recent trial results for the ipi/nivo combo as adjuvant did not prove more effective - providing instead only a greater side effect profile.  Here's a history of adjuvant care in melanoma - ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....   At this point, targeted therapy in the form of BRAF/MEKi combo's, for BRAF positive patients, and NEO-adjuvant treatments are also available for melanoma patients in need of such care.  Here are zillions of adjuvant related reports - Adjuvant care in melanoma

Now, there are these (my comments in red as ever):

Adjuvant Therapy is Effective for Melanoma Patients with a Positive Sentinel Lymph Node Biopsy Who Forego Completion Lymphadenectomy.  Farrow, Raman, Williams, et al.  Ann Surg Oncol, 2020 Dec 27.

Background: Multiple adjuvant therapies for melanoma have been approved since 2015 based on randomized trials demonstrating improvements in recurrence-free survival (RFS) with adjuvant therapy after surgical resection of high-risk disease. Inclusion criteria for these trials required performance of a completion lymph node dissection (CLND) for positive sentinel lymph node (pSLN) disease.

Objective: We aimed to describe current practice for adjuvant therapies in patients with pSLN without CLND (active surveillance [AS]), and to evaluate recurrence in these patients.

Methods: Melanoma patients with pSLN between 2016 and 2019 were identified at two institutions. Demographic information, disease and treatment characteristics, and recurrence details were reviewed retrospectively. Patients were stratified by recurrence and patient-, treatment- and tumor-related characteristics were compared using Fisher's exact test and t test for categorical and continuous variables, respectively.

Results: Overall, 245 SLN biopsies were performed, of which 36 (14.7%) were pSLN. Of 36 pSLN, 4 underwent CLND and 32 underwent AS, of whom 22 (68.8%) received adjuvant therapy with the anti-programmed death-1 (PD1) inhibitor nivolumab (16/22), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab (3/22), or BRAF/MEK inhibitors (3/22). At a median follow up of 13.3 months, 7/32 (21.9%) patients on AS recurred, including 4/22 (18.2%) who received adjuvant therapy and 3/10 (30.0%) who did not. Tumor ulceration was significantly associated with recurrence. While not significant, acral lentiginous subtype appeared more common among those with recurrence.

Conclusion: The majority (68.8%) of patients with pSLN managed without CLND were treated with adjuvant therapy. The 1-year RFS for patients managed with adjuvant therapy without CLND was 82%, which is similar to modern adjuvant therapy trials requiring CLND.

Back in the day, including when I was first diagnosed in 2003 and when I recurred in 2007, patients were routinely treated with a complete lymphadenectomy (CLND) of the area around a positive lymph node.  I went through it twice, to both axilla.  Times have changed and the process of CLND is no longer recommended.  In fact, NEO -adjuvant treatment is being studied to see if starting treatment with the positive node in place provides better results and the data is looking positive.  In this report, researchers were looking for differences between melanoma peeps who had a complete lymphadenectomy and those who simply had the positive node removed and started adjuvant treatment.  Of 245 sentinel node biopsies they examined - 36 were positive.  Of those, 4 patients had CLND and 32 had only the positive node removed.  22 were given adjuvant treatment - 16 were treated with nivo, 3 with ipi, and 3 with BRAF/MEK.  At 13.3 months of follow-up - 7 of the 32 patients had recurred - 4 of whom had been treated with adjuvant therapy (abstract does not note which) and 3 had not.  Tumor ulceration was significantly associated with recurrence (which is not news).  Overall, the patients who had adjuvant treatment after a positive node, but NO CLND had a recurrence free survival rate of 82% which is similar to patients who were given a CLND and adjuvant therapy.  Again, this is no longer news, rather confirmation of what we have understood for some years now.

Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  2020 Nov.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up.

Patients and methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual, stage IIIA (at least one lymph node metastasis greater than 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors.

Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status.

Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups

At three years follow up, Stage III patients of all stripes did better after treatment with Pembro than those treated with placebo - demonstrating a recurrence free survival rate of 63.7% for those treated with pembro vs 44.1% for those given placebo.  YEP.

Adjuvant Therapy Failure Patterns in the Modern Era of Melanoma Management.  Rauwerdink, Molina, Tompers, et al.  Ann Surg Oncol.  2020 Dec.

Background: The management of patients with resected stage 3 melanoma has changed significantly due to adoption of the Multicenter Selective Lymphadenectomy Trial (MSLT)-2 guidelines and to the survival benefit of adjuvant anti-PD-1 immunotherapy and BRAF/MEK-inhibitor (BRAF/MEKi) therapy. Data are scarce regarding recurrence patterns, adjuvant therapy responses, and therapy-associated adverse events (AEs) in the modern era.

Methods: This single-institution, retrospective study analyzed surgically resected stage 3 and oligometastatic stage 4 patients who received anti-PD-1, BRAF/MEKi, or surgery with active surveillance only. The primary end point of the study was recurrence-free survival (RFS). The secondary end points were the location and clinical characteristics of recurrence and therapy-associated AEs.

Results: From a cohort of 137 patients, the study enrolled 102 patients treated with adjuvant anti-PD-1 (n = 46), adjuvant BRAF/MEKi (n = 3), or surgery alone (n = 26). During a mean follow-up period of 17 months, 20% of the ani-PD-1 patients, 13% of the BRAF/MEKi patients, and 42% of the surgery-only patients experienced recurrence. Log-rank testing showed a significantly longer RFS for the patients treated with anti-PD-1 [15.3 months; interquartile range (IQR), 8.2-23.2 months] or BRAF/MEKi (17.9 months; IQR, 12.5-23 months) than for those treated with surgery alone (11.9 months; IQR, 7.0-17.6 months). In the anti-PD-1 group, AEs occurred less frequently than in the BRAF/MEKi group (54% vs 80%).

Conclusions: Adjuvant anti-PD-1 and BRAF/MEKi were associated with significantly improved RFS for the patients with resected stage 3 or 4 melanoma. The BRAF/MEKi group had significantly more AEs than the anti-PD-1 group. This is the first study to characterize real-world recurrence in the modern era of adjuvant therapy for melanoma.

This study looked at 102 resected Stage III and Stage IV patients. (Stage III patients whose positive node was removed as well as Stage IV like me when I entered my Phase 1 Nivo trial in 2010, whose metastatic disease had been removed.)  46 were given adjuvant anti-PD-1.  3 were given BRAF/MEKi.  26 had surgery alone.  At 17 months 20% of those treated with anti-PD-1, 13% treated with targeted therapy, and 42% of the surgery-only patients had recurred.  Recurrence free survival lasted an average of15 months for anti-PD-1 patients, 18 months for the BRAF/Meki group, and only 12 months for those given surgery alone.   {While this type of data analysis of outcomes of adjuvant therapy is much needed - TAKE THESE NUMBERS WITH A HUGE GRAIN OF SALT!!!!!  THE 46 patients treated with anti-PD-1 and 26 given surgery only -is barely sufficient to make valid statistical analysis possible; the THREE treated with BRAF/MEKi does NOT!!!!!!!!!!!!!!!!!!!!}

The data presented in the reports included in this October 2020 post New follow-up data confirms effectiveness for targeted and immunotherapy as adjuvant in melanoma patients!!! is much better! To whit ~ 

From Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.  Drummer, Hauschild, Saninami, et al.  New England Journal of Medicine.  September 17, 2020.  

870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos.  At 5 years, the percentage of patients who were alive without relapse was 52% with dabrafenib plus trametinib and 36% with placebo.

From Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial.  Eggermont, Blank, Mandala, et al.  J Clin Oncol.  September 18, 2020.

1,019 patients with complete lymph node dissection ofcutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity.   3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively.

From Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.  Ascierto, Del Vecchio, Mandala, et al.  Lancet Oncol.  September 18, 2020.

906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months with nivolumab and 50·9 months with ipilimumab; 4-year recurrence-free survival was 51·7% in the nivolumab group and 41·2% in the ipilimumab group. With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths, 4-year overall survival was 77·9% with nivolumab and 76·6% with ipilimumab.

NOW - even with all this - it is hard to compare THESE numbers! (Though they are clearly more statistically valid than those noted in the article I started with and also demonstrate the falseness of the claim those authors purport in the last sentence of their abstract!!!!!)  To that end,  I noted when I published them - 

So, there you go.  ALL of these adjuvant therapies provided Stage III/IV melanoma patients whose obvious disease was removed via surgery or radiation better results - no matter if they were treated with ipi, nivo, pembro or the dabrafinib/trametinib combo - than when they were left untreated.  Per these reports, here's how things panned out ~

Dabrafinib/trametinib - at 5 years, stage III melanoma patients alive without relapse was 52% with treatment vs 36% with placebo.

Pembrolizumab (Keytruda) - at 3 years, Stage III melanoma patients with recurrence free survival was 63.7% when treated with pembro, vs 44.1% for placebo.

Ipilimumab (Yervoy) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 41.2%.  4 year overall survival was 76.6%.

Nivolumab (Opdivo) - at 4 years, in Stage III and Stage IV melanoma patients, 4 year recurrence free survival was 51.7%.  4 year overall survival was 77.9%.

My thoughts:

The fact that Stage IV patients were included in the study looking at adjuvant ipi and nivo (CheckMate 238 trial) is HUGE!!!!!!  It makes comparison to the studies using pembro and the dabrafinib/trametinib combo as adjuvant in Stage III peeps ONLY, difficult to say the least.   I would really like to see an adjuvant study in Stage III melanoma patients where Keytruda and Opdivo are compared head to head, using the exact same result parameters and time frames.  I doubt there would be any significant difference in results as that has already been found to be the case when those agents are used in treatment of Stage IV melanoma patients - but still.  And finally, while the numbers for adjuvant ipi weren't that bad, and certainly much better than placebo, the side effects were greater - so I don't find ipi as a single agent a good choice for adjuvant therapy given the other options.

FYI - Time frames of follow-up matter.  As time goes on, more peeps have a chance to progress.  So data at three years is often better than outcomes reported at five years.

For instance in this article:  2017 - Nivo better than ipi as adjuvant  The data (drawn from Stage III AND Stage IV melanoma patients who took the drugs as adjuvant) demonstrates this:

Recurrence free survival at 12 months:

70.5% for nivo                    60.8% for ipi

Recurrence free survival at 18 months:

66.4% for nivo                    52.7% for ipi

That is why it is important to compare apples to apples in all aspects.  c