ASCO 2017: Hope for NRAS melanoma

Melanoma is a complicated disease entity to say the least.  Tumors, that are now all lumped together as 'melanoma' demonstrate many different mutations and develop via a variety of pathways.  About half of us are BRAF positive.  Aboust 20% of us have the NRAS mutation.  Then there's all sorts of other delineations!  This post:  What tangled paths we weave...
Which contains this diagram:

Probably makes the pathway as clear as anything else!!

Thus far, targeted therapy (using a combination of a BRAF inhibitor with a MEK inhibitor) has been found to be most effective for only those with a V600 BRAF mutated melanoma.  However, this post in 2016 addresses how nelfinavir (also called Viracept, an HIV protease ihibitor) can be used to decrease resistance to those meds in both BRAF and NRAS mutant melaonma:  Stopping resistance to targeted therapy- nelfinavir- for BRAF and NRAS mutant melanoma

Here an older cardiac drug was paired with a MEK inhibitor: Digoxin and trametinib for BRAF wild type melanoma

Recently I posted this study in which binimetinib (a MEK inhibitor) was paired with encorafenib (a BRAF inhibitor):   Encorafenib/binimetinib, a BRAF/MEK combo = 14.9 month PFS
Within it was noted that, "In March, Array withdrew its FDA new drug application for single-agent binimetinib as a treatment for patients with NRAS-mutant advanced melanoma, based on feedback from the FDA during a preplanned review meeting."

However, from ASCO  2017...this study pairs binimetinib with ribociclib (also named Kisquali [What the f@%K?????] a  CDK 4/6 inhibitor, approved this year for use in HR+/HER 2 breast cancer):  

Phase 1b/2 trial of ribociclib+binimetinib in metastatic NRAS-mutant melanoma: Safety, efficacy, and recommended phase 2 dose (RP2D).

2017 ASCO. J Clin Oncol 35, 2017. Schuler, Ascierto....Postow....Sosman....Daud...et al.

Background: Simultaneous inhibition of MEK and CDK4/6 may suppress MAPK pathway activation and cell-cycle checkpoint dysregulation in NRAS-mutant melanoma, resulting in enhanced antitumor activity. Phase 1b data are reported. Methods: The phase 1b primary objective was to determine maximum tolerated dose (MTD)/RP2D. A 28-d cycle of oral ribociclib (RIBO) once daily (QD) for 21 d + oral binimetinib (BINI) twice daily (BID) for 28 d, and a 21-d cycle of RIBO QD + BINI BID, both for 14 d per cycle, were evaluated. Secondary objectives were to evaluate efficacy, safety and pharmacodynamics. Results: Based on dose escalation, MTD was 600mg RIBO/45mg BINI for the 21-d and 200/45 for the 28-d regimens. Due to promising activity, the 28-d cycle was selected as RP2D (unconfirmed partial response [PR] with limited follow-up occurred in 35% of pts).  As of Jan 2017, the RP2D was received by 16 pts in phase 1b (ECOG PS 0/1/2, 63%/31%/6%; elevated lactate dehydrogenase, 44%; stage IVM1c disease, 50%; prior ipilimumab [ipi], 44%; prior anti–programmed death [PD]-1/PD-L1, 31%). Median (range) exposure was 4 (0–13) mo. Common adverse events (AEs) were increased blood creatine phosphokinase, elevated AST, peripheral edema, acneiform dermatitis, diarrhea and fatigue. Common grade 3/4 AEs were elevated AST and ALT (19%/6%), nausea (19%/0%), rash (19%/0%), vomiting (6%/6%) and neutropenia (12%/0%). Confirmed PR (cPR) occurred in 4 pts (25%; time to response, 48–168 d), stable disease in 7 pts (44%), disease progression in 3 pts (19%); 2 pts (12%) were not evaluable. Among cPR pts, 3 had prior ipi and/or anti–PD-1/PD-L1. Median progression-free survival (mPFS) was 6.7 mo. Sequence analysis of synchronous non-RAS genetic alterations will be presented. Conclusions: Combined RIBO/BINI at the selected RP2D had a manageable safety profile and favorable efficacy (based on mPFS) for NRAS-mutant melanoma in phase 1b. Based on these promising data, the phase 2 expansion is underway to assess antitumor activity at the RP2D. Clinical trial information: NCT01781572

So both are oral meds...given in a 28-day cycle as noted above, to 16 patients - 44% of whom had increased LDH, 44% had been previously given ipi, 31% had been previously treated with anti-PD-1 or anti-PD-L1.  Meds were given for an average of 4 months.  There was a confirmed partial response in 4 patients, stable disease in 7, disease progression in 3 and 2 were not evaluated.  For what it's worth...

When looking at immunotherapy in NRAS patients, I posted this in 2015:  Good news for NRAS positive folks, especially in regard to anti-PD1!!!! Now there is this:

NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.

2017 ASCO. J Clin Oncol 35, 2017. Kirchberger, Ugurel, Mangana, et al.

Background: About 20% of metastatic melanomas harbor NRAS mutations which constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. The response of patients with NRAS-mutated melanoma to checkpoint inhibitor therapy is so far unknown. A previous study suggested a higher response rate of NRAS-mutated melanoma to anti-PD-1/anti-PD-L1 with an objective response in 7 out of 11 (64%) patients compared to 35% and 21% in BRAF wildtype or BRAF V600-mutated melanoma, respectively. Methods: In total, 224 patients with NRAS-mutated melanoma were analyzed. Of these, 180 patients received ipilimumab, 98 anti-PD1 monotherapy, and one patient combined ipilimumab and anti-PD1 therapy. We evaluated overall response rate (ORR), disease control rate, progression-free survival (PFS) and overall survival to checkpoint inhibitor therapy in these patients. Results: In this patient cohort with NRAS-mutated melanoma, 27% had brain metastases, 62% an elevated LDH and 22% an ECOG greater than/ = to 1. ORR was 15% for treatment with ipilimumab and 34% for anti-PD1 therapy. Disease control rates were 27% for ipilimumab and 52% for anti-PD1 therapy. PFS was 4.5 months for ipilimumab and 11.4 months for anti-PD1 therapy. Overall survival of all patients was 29 months. Conclusions: The efficacy data of ipilimumab or anti-PD1 therapy in NRAS-mutated melanoma patients were similar to the known response rates of NRAS wildtype melanoma patients.

In this study, 224 NRAS mutated melanoma patients were studied. 180 were treated with ipi, 98 with anti-PD-1 and 1 was given the ipi/nivo combo.  The overall response rate was 15% for those treated with ipi and 34% for those treated with anti-Pd-1....which is in keeping with response rates for those drugs generally.

Good to know. - c

Good news for NRAS positive folks, especially in regard to anti-PD1!!!!

Abstract presented at the American Association for Cancer Research, April 2014

NRAS mutation as a predictor of response to immune-based therapies in patients with metastatic melanoma.  Iams, Johnson, Flavin, Zhao, Sosman, et al.

"Immune based therapies are playing an expanding role in the treatment of advanced melanoma.  Reliable biomarkers to predict benefit from these agents have not yet been identified....  Approximately 15-20% of patients with melanoma harbor an NRAS mutation...  We assessed whether NRAS mutations impact the response to immune-based therapy..."

Examined 171 patients from 3 institutions with advanced melanoma and known tumor genotype.  All were treated with either IL-2, anti-CTLA-4 (ipi/yervoy), or anti-PD1lPD-L1 inhibitors.  "We compared the rates of clinical response between patients with NRAS mutant melanoma and those without NRAS or BRAF mutations (wild type)..." 

End points: CR = Complete Response, PR = partial response.  Secondary end points:  CB = clinical benefit (defined as CR/PR or stable disease for more than 24 weeks), PFS = progression free survival, and OS = overall survival.

59 patients (35%) had NRAS-mutant melanoma.  112 patients (65%) had WT (wild type)... There was a significantly higher rate of CR/PR and CB in patients with NRAS vs  patients with WT melanoma.  (32% vs 18% for CR/PR and 49% vs 29% for CB).  "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%)."  No statistically significant differences in median PFS or median OS were observed.

Conclusion:  Patients with NRAS mutation experience a higher rate of CR/PR and CB when treated with immune-based therapy vs patients with WT.  Data suggest that routine assessment for NRAS mutations in patients with melanoma is warranted.

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???!!!!!  Best - c

Another possible option for NRAS mutant melanoma patients

Sadly, today's post is in keeping with those of the past two days, in that this abstract doesn't give a great deal of definitive info.  By way of explanation, here is a link to prior posts (with links within) that address treatment for folks with:  NRAS-mutant melanoma

This ASCO 2017 report noted:  NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.

After which I wrote this:  In this study, 224 NRAS mutated melanoma patients were studied. 180 were treated with ipi, 98 with anti-PD-1 and 1 was given the ipi/nivo combo.  The overall response rate was 15% for those treated with ipi and 34% for those treated with anti-Pd-1....which is in keeping with response rates for those drugs generally.

Despite the fairly optimistic (For melanoma world, don't 'cha know???!!) report above, there are other studies (and more importantly ~ real live NRAS friends and peeps) who have struggled with attaining good responses on current therapies.  The mice and researchers now share this:

Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma. Echevarria-Vargas, Reyes-Uribe, Guterres, et al. EMBO Mol Med. 2018 Apr 12. 

Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.

Perhaps this will help send therapy for NRAS-mutant melanoma in a better direction.  Hang tough my dear NRAS ratties!!! - 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

COX-2 expression correlates with PD-L1 expression on melanoma cells - or....how NSAID's like aspirin and advil might help melanoma patients????

COX-2 expression in melanoma cells is what has given the hope (??? data) that the use of NSAID's (advil, aspirin, etc) might enhance the response from immunotherapy in melanoma patients as noted in this post (with links to others within):  Sooo....advil works for SOME melanoma patients?????

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. Botti, Fratangelo, Cerrone, et al. J Transl Med. 2017 Feb 23.

The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma.

Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro.

BRAF^V600E/V600K and NRAS^Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions. COX-2 expression significantly correlated with PD-L1 expression in both primary and not matched metastatic lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines.  

COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

Breaking it down:  This report supports the notion that there is a relationship between COX-2 and PD-L1 expression in melanoma. Therefore, if we could block COX-2 we would reduce PD-L1 expression in melanoma cells and make anti-PD-1 drugs more effective. That's the theory anyway!!   - c

ASCO 2017: ERK inhibitor - Ulixertinib (BVD-523) working in NRAS as well as BRAF V600 and non-V600 melanoma

Many "innovative" combinations that would make targeted therapy better have long been discussed, including: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors and then some.  Data is more readily available on some than others.  Keeping the diagram posted yesterday in mind...as well as this one:

 Here is a report on Ulixertinib, an ERK inhibitor:

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.

ASCO 2017. J Clin Oncol 35, 2017. Li, Janku, Patel, ...Flaherty, ...Sznol, Sosman..., Ribas, ….Infante.

Backkground: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head and neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head and neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429

Despite a lot of back and forth about cohorts and expansion cohorts....as best as I can tell, 108 patients with various sold tumors, took ulixertinib, 600 mg orally, twice daily.  Most common side effects were rash, diarrhea, fatigue and nausea...no drug related deaths, though 32% required a drug reduction.  Of 83 evaluable patients, 9 had a partial response.  Three of these were NRAS mutant melanoma and 4 had tumors that were BRAF V600E mutant, but only one of those had melanoma and they had been refractory to prior BRAFi/MEKi treatment.  

So...incredibly small numbers period...especially in regard to melanoma...but...you gotta start somewhere!!!  Hang in there ratties. - c

Straight Outta Boston!!! Latest melanoma research ~

From the recent Boston meeting of the Society for Melanoma Research:

 Preventing resistance by combining BRAF with hydroxychloroquine (HCQ). 

High response rates with combined BRAF and autophagy inhibition: results of 2 phase I trials  Gangadhar, et al.

Autophagy is a resistance mechanism to BRAF inhibitors that can be targeted with hydroxychloroquine (HCQ). We launched a Phase I trial of vemurafenib and HCQ in BRAFV600 melanoma patients. 7 patients in the 1st dose level (vemurafenib 960 po bid + HCQ 400 po bid) had 2 dose limiting toxicities ...  preventing further dose escalation. 6/6 patients evaluable for response had PR or CR. Prolonged PFS was seen in 1 CR (30+ mo) and 1 PR (20 mo).  Combined BRAF/MEK inhibition was adopted widely so this trial was closed, and a multi-institution phase I/II trial of dabrafenib (D), trametinib (T) and HCQ was opened. Phase I was completed with no DLT (n=7). Recommended phase II dose was HCQ 600 bid with D+T. Phase II enrollment continues. D+T+HCQ was well tolerated, with no evidence of visually significant ocular toxicity. Striking responses were observed: 6/7 patients responded and 5/6 patients had a CR. The only non-responder was found to have BRAFV600E amplification, and had pyrexia that required frequent dose interruptions. Only 1 of 6 responders has progressed (PFS for responders 7-19 months, ongoing, censored as of July 2016), with brain metastases harboring a BRAFV600E and PIK3CA mutation after 15 mo. A cell line created from this resected metastases showed continued sensitivity to D+T+HCQ in vitro. The patient developed progressive CNS disease despite brain radiation and restarted D+T+HCQ, benefiting from second response that continues to date. Patient derived xenografts were created from 4/4 pretreatment tumor biopsies from the 7 patients. A randomized PDX trial with all combinations of treatments is underway with PDX from responding and resistant patients to determine if the addition of HCQ to D+T is significantly contributing to the activity of this regimen. 

Stage IIIB/C treated with adjuvant BRAFi = 100% 6 month survival vs 28.6% with standard care!!!

Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma.  Amaria, et al.

The treatment of stage IV melanoma has been revolutionized by targeted therapy and immune checkpoint blockade, and there is a strong rationale to evaluate these agents in earlier stages of disease. The current SOC in patients (pts) with high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery +/- adjuvant therapy, but relapse rates are high. We hypothesized that treatment with neoadjuvant + adjuvant D+T in this population would result in lower relapse rates compared to SOC. Methods: We conducted a prospective randomized clinical trial (NCT02231775) in pts with resectable Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Pts were randomized in a 1:2 fashion to SOC (Arm A) or neo + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). Planned enrollment was 84 pts. Primary endpoint was RFS. Results: Randomization was halted after 21 pts were enrolled (arm A=7, arm B=14). Arms were well matched for gender and stage of disease, though pts in arm A were younger. Perioperative complication rates were similar and toxicity in arm B was manageable. At week 8 the RECIST response rate with D+T was 77% and the pathologic complete response (pCR) rate was 58%. Early analysis revealed a significantly higher RFS in the D+T arm over SOC, with 6-month survival estimated at 100% in Arm B and 28.6% in Arm A, leading to trial closure. Conclusions: Treatment with neoadjuvant + adjuvant D+T is well tolerated, results in high clinical response and pCR rates, and markedly improves RFS in pts with high-risk resectable metastatic melanoma. Correlative analyses are underway to characterize mechanisms of response and resistance to neo + adjuvant D+T.   

T-VEC plus ipi = OOR of 50% vs 27.5% for ipi alone.

Interim analysis of a randomized, open-label phase 2 study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected, stage IIIB-IV melanoma.  Chesney, et al.  

T is a herpes simplex virus 1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses. I (anti-CTLA-4 Ab) blocks inhibition of antitumor T-cells. Both T and I monotherapy are approved in the US and EU for the treatment of advanced melanoma. The primary endpoint for the phase 2 part was ORR by immune-related response criteria. Key secondary endpoints are safety, progression-free survival, time to response, duration of response, and survival. Key entry criteria are unresectable stage IIIB-IV melanoma, with 2 or fewer prior tx, measurable/injectable tumor(s), and no symptomatic autoimmunity or clinically significant immunosuppression. T was given on d1 w1; w4, then q2w in arm 1 until no injectable tumors, disease progression, or intolerance. I started with the 3rd dose of T in arm 1 or alone in arm 2 at 3 mg/kg IV q3w x 4. An interim analysis (IA) for efficacy was performed when 82 patients (pts) had ≥48 w of follow up. 173 pts were randomized: 88 T+I; 85 I. Characteristics for all pts were similar: 54% stage IIIB-IVM1a, 45% IVM1b/c. Median follow up time for 82 pts in the efficacy set was 61.2 w. Confirmed ORR was 35.7% (T+I) and 17.5% (I); unconfirmed ORR was 50% (T+I) and 27.5% (I). Of 165 pts in the safety set (85 T+I, 80 I), most common adverse events (AEs) for T+I, I (%) were fatigue (52, 39), chills (51, 3), diarrhea (39, 34), pyrexia (39, 8), rash (39, 31) and pruritus (38, 35). 20% T+I and 18% I pts had grade 3/4 tx-related AE. A grade 5 autoimmune hepatitis occurred in the T+I arm (investigator attributed to I). ORR was higher for T+I vs I alone at this IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T+I arm. 

Intra tumoral HF10 plus ipi = good! 

A Phase 2 multicenter trial to evaluate efficacy and safety of HF10, oncolytic virus immunotherapy and ipilimumab in patients with unresectable or metastatic melanoma. Andtbacka, Ross, ...Agarwala,... Daud, et al. 

HF10 (intratumoral injection) shows activity in injected lesions and non-injected metastatic lesions presumably via an antitumor immune response elicited by viral destruction of injected lesions. An ongoing Phase 2 study of HF10 combined with ipilimumab (ipi) in melanoma pts is assessing whether the antitumor effect of HF10 is enhanced by concurrent ipi treatment. Efficacy and safety of HF10+ipi treatment are reported herein. An immunologic correlative data analysis is currently ongoing. Ipi naïve adults with stage IIIB, IIIC or IV unresectable melanoma with measurable non-visceral lesion(s) received HF10 injections into single or multiple tumors; 4 injections qwk; then up to 15 injections q3wk. Ipi (4X at 3 mg/kg, IV) was administered per SOC. Tumor responses were assessed at 12, 18, 24wks, and 36, 48wks for pts continuing HF10 monotherapy. Best Overall Response Rate (BORR) was determined at 24wks. Of 46 pts treated, 20% were stage IIIB, 43% stage IIIC, and 37% stage IV. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported; 3 G4 AEs reported, all not treatment related. 30.4% had G3 AEs. HF10-related G3 AEs (n=3) were left groin pain, thromboembolic event, lymphedema, hypoglycemia, and diarrhea. Of 43 efficacy evaluable pts, preliminary BORR at 24 wks per irRC was 41.8% (11.6% CR, 30.2% PR), disease stability rate 67.4% (25.6% SD). 8 responders (53%) were stage IV. Overall study BORR, including those after 24 weeks, by irRC was 48.8% (18.6% CR, 30.2% PR), disease stability was 67.4% (18.6% SD). In summary, HF10+ipi treatment does not appear to exacerbate ipi toxicity, is safe and well tolerated, has both local and systemic antitumor activity, with promising response rates when combined with ipi.

Ipi/Nivo for Stage 3 mel.

(Neo-)adjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage 3 melanoma – the OpACIN trial.  Blank, et al. 

 IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore depends on the amount of antigen present, arguing for that adjuvant immunotherapy willwork most efficiently, when initiated prior to surgery. Two-arm Phase 1b feasibility trial consisting of 20 high risk AJCC stage 3B/C melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split neo-adjuvant and adjuvant. To date, 17 patients are evaluable (9 neoadjuvant; updated data and first analyses of melanoma specific T cell responses will be presented.). Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 15/17 patients (88%) had to stop earlier due to grade 3/4 toxicities. ORR in the neo-adjuvant IPI+NIVO arm was 78% (3 pCR, 3 near pCRs [minimal remaining micrometastasis], 1 pPR [remaining metastasis of 0.5mm], 1 SD and 1 PD). So far, post-surgery, none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for 1 neoadjuvant SD patient and for 3 patients within the adjuvant arm. The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage 3 melanoma patients is feasible. However, severe grade 3/4 toxicity was more frequent than expected from stage 4 melanoma patient study data. In parallel, response rate and depth of response also may be higher than in stage 4 melanoma patients. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage 3 melanoma, which will be tested in adjusted schemes in the upcoming phase 2 OpACIN-neo trial, with the aim of preserving efficacy, but reducing toxicity. 

Brain mets post SRS/crani: nivo vs pembro.

Control of brain metastases with anti-PD-1 therapy in patients with melanoma post-SRS/craniotomy.  Ozgun, et al. 

While anti-PD-1 antibodies have shown significant clinical benefit in patients (pts) with advanced melanoma, a majority of these pts develop brain metastases for which standard treatments remain radiation therapy and/or surgery. We examined outcomes in pts who were diagnosed with melanoma brain metastases (MBM) and received upfront locoregional therapy, to determine how well their subsequent anti-PD-1 therapy could control their MBM. We retrospectively reviewed 146 pts with advanced melanoma who were treated with anti-PD-1 therapy, to identify 23 pts who had received prior stereotactic radioasurgery (SRS) or craniotomy for MBM. There were 13 men and 10 women, with median age 56 (27-85). Most common site of metastases was in the frontal lobe (n=13, 57%). Primary treatment for the MBM was SRS in 17 (74%), and craniotomy in 6 (26%) pts. Median follow-up was 2 years post-locoregional therapy. Eleven pts subsequently received pembrolizumab and 12 pts received nivolumab; median duration of therapy was 5 months. Eight pts received these drugs as their first-line systemic therapy post-SRS/craniotomy, 13 as second line therapy, and 2 as third-line; other first-line therapies included ipilimumab, chemotherapy or BRAF-targeted therapies. While receiving their anti-PD-1 therapy, five (22%) pts had no recurrence of any brain metastases (n=2 with pembro, n=3 with nivo) and eight (35%) pts had stable MRI brain imaging with no new or growing lesions. However, ten pts (44%) had progession of their brain metastases while on anti-PD-1 therapy (n=3 with nivo, n=7 with pembro). Median overall survival from time of SRS or craniotomy was 24 months (5.6-32) for pts treated with pembro and 36 months (1.7-84) with nivo. While there may be a suggestion of improved outcome with nivolumab in MBM after locoregional therapy, larger analyses are needed for definitive conclusions.  

Aspirin helps NRAS affected mice!

Acetylsalicylic acid governs the effect of Sorafenib in mutant NRAS melanoma. Hammerlindl, et al. 

To date no therapies directly targeting mutant NRAS melanoma have been approved, leaving chemotherapy with very low response rates or immunotherapy for the treatment of mutant NRAS melanoma patients. Here we report a novel strategy to target mutant NRAS melanoma by combining the multi kinase inhibitor Sorafenib and the nonsteroidal anti-inflammatory drug acetylsalicylic acid (Aspirin), both of which are clinically tested and approved. The addition of Aspirin, but not isobutylphenylpropanoic acid (Ibruprofen) or Celecoxib significantly increased the invitro cytotoxicity of Sorafenib resulting in a fivefold reduced effective Sorafenib dose in WM1366, WM832, and WM1361 mutant NRAS melanoma cells. Mechanistically, combined exposure resulted in the simultaneous hyperactivation of AMPK and ERK pathways. Combining Sorafenib with other AMPK activators like Metformin or A769662 was not sufficient to induce cell death due to sole activation of the AMPK pathway. Accordingly, cytotoxicity of Sorafenib and Aspirin was blocked by concurrent inhibition of AMPK or ERK pathways using pharmacological inhibitors of RAF (LY3009120), MEK (Trametinib) and AMPK (Compound C) or shRNA targeting BRAF or AMPKα1/2. The combination was found to be specific for mutant NRAS and had no significant effect in wild type RAS keratinocytes or melanoma cells. In-vivo the treatment of SCID mouse xenografts with Sorafenib and Aspirin significantly reduced tumour volume compared to single treatment alone. Combined Sorafenib and Aspirin selectively target mutant NRAS melanoma cells by simultaneously affecting two independent pathways. The combination represents a novel treatment strategy for mutant NRAS melanoma by repurposing clinically approved drugs with the potential to reduce Sorafenib induced adverse effects while maintaining clinical efficiency. 

Ok.  I'm tired now.  But...some pretty interesting stuff. For what it's worth - c

New trials for NRAS and Mucosal Melanoma patients - ASCO 2021

Melanoma sucks great big green hairy stinky wizard balls for everyone!  Still, it remains even more challenging for NRAS positive and mucosal melanoma patients.  Here are prior posts on Mucosal Melanoma. Now, there's this neoadjuvant trial:

A phase 2 clinical trial of neoadjuvant anti-PD-1 ab (toripalimab) plus axitinib in resectable mucosal melanoma.  Cui, Wang, Lian, et al.  ASCO 2021.

Background:  The outcome of patients (pts) with resectable mucosal melanoma (MM) is still poor. Toripalimab combined with axitinib has shown impressive results in metastatic MM with an ORR of 48.3% and a median PFS of 7.5 months in a phase 1b trial. It was hypothesized that this combination therapy might cause pathologic response in neoadjuvant setting for resectable MM, so we conducted this single arm phase 2 trial.

Methods:  Eligible pts were adults (aged 18 to 75) with histologically confirmed resectable (localized or regional lymph node metastasis) MM disease. Exclusion criteria included ocular or unknown primary melanoma, distant metastatic disease or previous use of anti PD-1 ab. Pts received toripalimab 3 mg/kg Q2W plus axitinib 5 mg BID for 8 weeks as neoadjuvant therapy, then surgery and the adjuvant toripalimab 3 mg/kg Q2W starting 2±1week after surgery for totally 52 weeks. The primary end point is pathologic response rate according to the International Neoadjuvant Melanoma Consortium (pCR+pPR, pCR is defined as the complete absence of residual viable tumor and pPR less than/= to 50% of viable tumor cells). The secondary end point is RFS in the ITT population.

Results:  From Aug 2019 to Dec 2020, 21 pts have been eligible and enrolled. Basic characteristics: median age 62 years; M: F 28.6% : 71.4%; primary sites 8 female genital(1urethra, 7vagina), 5 esophagus, 4 ano-rectal, 4 head and neck(3 nasal,1 oral), in which 47.6% localized disease (T3/4 60%), 52.4% regional lymphatic disease; Gene mutation: 4 cKit (1 amplification), 2 Nras,1 Braf (N581), 1mTOR. This therapy was tolerable with grade 3-4 treatment related AEs of 23.8% (liver dysfunction 14.3%, hyperglycemia 9.5% and hypertension 4.8%). 13 pts had received surgeries (local excision 30.8%, wide excision ± CLND72.7%)and 5 pts still in neoadjuvant treatment. One patient was inoperable for bone metastasis, and 2 pts withdrew for covid 19 epidemic. At a median follow up time of 59 weeks, the pathologic response rate was 28.6% (4/14, 2 pCR, 2pPR). Of the post-surgical specimens, 61.5% (8/13) showed significant TIL infiltration, with 38.5% Brisk and 23.1% Nonbrisk according to the definition of AJCC 8th edition. Plenty of plasma cells, histiocyte and pigment with hyaline fibrosis were also found in responders. No recurrence or metastasis was observed in responders until now, with a RFS reaching more than 58weeks. 5 pts with pNR (greater than 50% viable tumor cells) got disease progression, with 1 local recurrence, 1 regional lymphatic metastasis, and 3 distant metastases. The median RFS has not been reached.

Conclusions:  Neoadjuvant toripalimab plus axitinib in resectable MM has shown promising pathologic responses with good tolerance, which supports further investigation of neoadjuvant therapies in MM. Survival is still in follow-up. Clinical trial information: NCT04180995.

And this report on patients with unresectable disease:

Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.  Si, Fang, Chen, et al.  ASCO 2021.

Background:  Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma.

Methods:  Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety.

Results:  By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (17.0%-59.3%). Median progression-free survival was 5.32 months (1.58-not reached), and the best confirmed DCR was 59.1% (36.4%-79.3%). The median confirmed DoR was not reached ( 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease.

Conclusions:  The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

The NRAS mutation has it's own challenges.  Here are prior NRAS Reports.  Now, there are these:

A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion. Shin, Lee, Kim, et al.  ASCO 2021.

Background:  Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts.

Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination.

Results:  A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date.

Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). Clinical trial information: NCT03284502.

Fingers crossed that there will soon be viable treatments for all melanoma ratties.  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