Adjuvant therapy for melanoma - a history, the latest from ASCO 2021 and a remembering...

 I have been screaming about the need for adjuvant care since I became Stage IV with a zapped brain met and surgically removed lung met in April 2010 and could not attain a position in ongoing ipi trials because I had "no measurable disease".  After yet another met (surgically removed) to a tonsil in October of that year, I did gain placement in the adjuvant arm of a nivo trial being run by Weber (then of Moffitt in Tampa) that December.  Here's the report on how I and my 30 fellow ratties did, published in 2014:  C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!  

Since then, both targeted and immunotherapy have been FDA approved as adjuvant treatments for Stage III and IV melanoma patients. Here is a post with a break down of the science and FDA approvals from 2020:  ADJUVANT therapy for melanoma!!!!!!!!!!!!!! State of the science....  Here are a zillion additional posts, filled with the science, data and rants: All things Adjuvant 

Now there are these reports from earlier this year:

Novel adjuvant options for cutaneous melanoma.  Dimitriou, Long, Menzies.  Ann Oncol.  March 2021.

Background: Patients with resected stage III and IV melanoma have a high risk of recurrence. As the outcomes for patients with metastatic disease have improved dramatically over the past decade due to systemic therapy, more recently so too have the outcomes of patients with resected stage III and IV melanoma with the introduction of checkpoint inhibitor immunotherapy and targeted therapy in the adjuvant setting.

Results: Anti-programmed cell death protein 1 monotherapy and BRAF/MEK inhibitors are currently deemed standard of care for resected stage III melanoma. For patients with stage IIIB melanoma, 2-year and 3-year recurrence-free survival is approximately 72% and 65% for nivolumab, 70% and 65.7% for pembrolizumab and 68% and 60% for dabrafenib/trametinib, respectively. For stage IIIC  melanoma, 2-year and 3-year recurrence-free survival is 60% and 53.5% for nivolumab, 60% and 54.3% for pembrolizumab and 59% and 47% for dabrafenib/trametinib, respectively. Adjuvant treatment is recommended for patients with stage IIIB-IIID melanoma, and may be considered for patients with stage IIIA melanoma. For resected stage IV, nivolumab is the only approved agent; however, recent results from a phase II clinical trial show promising efficacy for combined ipilimumab and nivolumab as well. Long-term data are required to determine which therapy has the greatest impact on overall survival. Schedules, delivery and toxicity are also important factors to consider when selecting adjuvant treatment.

Conclusions: Randomized studies of patients with resected high-risk melanoma have shown that immunotherapy or targeted therapy improve recurrence-free survival compared with placebo/ipilimumab. In order to optimize these treatments, prognostic and predictive biomarkers, as well as strategies to reduce treatment-related toxicities and overcome resistance, are required. 

Adjuvant Therapy of High-Risk (Stages IIC-IV) Malignant Melanoma in the Post Interferon-Alpha Era: A Systematic Review and Meta-Analysis.  Christofyllakis, Pföhler, Bewarder, et al. Front Oncol.  Feb 2021.

Introduction: Multiple agents are approved in the adjuvant setting of completely resected high-risk (stages IIC-IV) malignant melanoma. Subgroups may benefit differently depending on the agent used. We performed a systematic review and meta-analysis to evaluate the efficiency and tolerability of available options in the post interferon era across following subgroups: patient age, stage, ulceration status, lymph node involvement, BRAF status.

Methods: The PubMed and Cochrane Library databases were searched without restriction in year of publication in June and September 2020. Data were extracted according to the PRISMA Guidelines from two authors independently and were pooled according to the random-effects model. The predefined primary outcome was recurrence-free survival (RFS). Post-data extraction it was noted that one trial (BRIM8) reported disease-free survival which was defined in the exact same way as RFS.

Results: Five prospective randomized placebo-controlled trials were included in the meta-analysis. The drug regimens included ipilimumab, pembrolizumab, nivolumab, nivolumab/ipilimumab, vemurafenib, and dabrafenib/trametinib. Adjuvant treatment was associated with a higher RFS than placebo. Nivolumab/ipilimumab in stage IV malignant melanoma was associated with the highest RFS benefit, followed by dabrafenib/trametinib in stage III BRAF-mutant melanoma. The presence of a BRAF mutation was associated with higher RFS rates compared to the wildtype group. Patient age did not influence outcomes. Immune checkpoint inhibitor monotherapy was associated with lower RFS in non-ulcerated melanoma. Patients with stage IIIA benefited equally from adjuvant treatment as those with stage IIIB/C. Nivolumab/ipilimumab and ipilimumab monotherapy were associated with higher toxicity.

Conclusion: Adjuvant therapy should not be withheld on account of advanced age or stage IIIA alone. The presence of a BRAF mutation is prognostically favorable in terms of RFS. BRAF/MEK inhibitors should be preferred in the adjuvant treatment of BRAF-mutant non-ulcerated melanoma.

Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis.  Bhave, Pallan, Long, et al.  Br J Cancer.  Feb 2021.

Background: Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods: Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results: Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy.

Conclusions: Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.

And these out of ASCO:

Management of resected stage III/IV melanoma with adjuvant immunotherapy.  Johnson, Atkinson, Bhave, et al.  ASCO 2021. 

Background:  Adjuvant anti-PD1 therapy reduces the risk of recurrence in resected stage III/IV melanoma and is now standard care. Limited data exist beyond registration trials. We sought to explore the use of adjuvant immunotherapy in routine clinical practice.

Methods:  Patients (pts) from 11 Australian centres who received adjuvant nivolumab (nivo) for resected stage III/IV melanoma were included in this study. Efficacy, toxicity, surveillance, recurrence characteristics, management and further treatment outcomes were examined.

Results: 471 pts received adjuvant nivo between 8/2018 to 3/2020. 318 (68%) were male, median age 64y (range 17-94), 28 (6%) were AJCC v8 IIIA, 194 (41%) IIIB, 175 (37%) IIIC, 11 (2%) IIID, and 63 (13%) IV. 65 (14%) pts had in-transit only disease, 152 (37%) pts were sentinel lymph node biopsy (SLNB+) and only 9 (6%) of these had CLND. 128 (27%) had BRAF mutant (BRAFmt) melanoma. Median time from resection to start of adjuvant nivo was 1.8 months (mo) (range 0.2-4.0). Median FU was 17.5 mo. 256 (54%) pts completed 12 months of nivo, 86 (18%) ceased early for toxicity, 76 (16%) for disease recurrence, 25 (5%) other reasons (COVID-19 8, co-morbidities 7, pt choice 10); 28 (6%) pts were still receiving nivo at data cut. Median duration of treatment was 10.4 mo (range 0-16.8). 117 (25%) pts recurred; 76 (65%) while ON nivo and 41 (35%) OFF nivo (greater than 1 month after last dose, including 20 pts who stopped early for toxicity). 24 mo RFS was 69%. Median time to recurrence was 6.0 mo. 56 (48%) had first recurrence with locoregional (LR) disease only and 61 (52%) had distant +/- LR recurrence. Of those who recurred with LR disease only, 46/56 (82%) underwent surgery, 15/46 (33%) then had adjuvant radiotherapy, and 15/46 (33%) had ‘second adjuvant’ therapy with BRAF/MEK inhibitors (15/21, 71% BRAFmt pts). 10/56 (37%) pts who recurred with LR disease subsequently recurred distantly. 58/80 (73%) pts received systemic therapy at either 1st or subsequent unresectable recurrence. For recurrences ON nivo, 18 pts received combination ipilimumab (ipi) and nivo (ORR 44%), 4 pts had ipi monotherapy (ORR 0%), 7 pts had anti-PD1 + investigational agent (ORR 57%), 11 pts had BRAF/MEK inhibitors (ORR 82%). 1 pt had PD with ongoing PD1 monotherapy. For recurrences OFF nivo, no patients responded to PD1 alone (n = 1) or with an investigational agent (n = 1), ipi+nivo (n = 3), ipi monotherapy (n = 4) or chemotherapy (n = 2); 6 pts received BRAF/MEK inhibitors (ORR 50%). 2-year OS was 92%.

Conclusions: Despite higher rates of discontinuation due to toxicity compared with clinical trial cohorts, the efficacy data appear similar. Most early recurrences are distant, and many with LR recurrence soon recur distantly thereafter. Second line adjuvant BRAF/MEK inhibitors are frequently used for resected LR recurrence. Both ipi+nivo and BRAF/MEK inhibitors appear to have activity after distant recurrence.

Final analysis of overall survival (OS) and relapse-free-survival (RFS) in the intergroup S1404 phase III randomized trial comparing either high-dose interferon (HDI) or ipilimumab to pembrolizumab in patients with high-risk resected melanoma. Grossmann, Othus, Patel, et al.  ASCO 2021. 

Background:   We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved adjuvant treatments for high risk resected melanoma at the time of study design.

Methods:  Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. [SO OVER THIS!!!!!!!!!!!!!!]  At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm [(1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465)], or the experimental arm [pembrolizumab 200 mg IV q3w for 52 weeks (n=648)]. The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. 

Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically significant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%.

Conclusions:  Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10.  Clinical trial information: NCT02506153.

See study below! 

Propensity weighted indirect treatment comparison of nivolumab (NIVO) versus placebo (PBO) as adjuvant therapy for resected melanoma: A number needed to treat and overall survival analysis.  Weber, Poretta, Stwalley, et al.  ASCO 2021.

Background:  The CheckMate 238 trial demonstrated that NIVO improved recurrence free survival (RFS) vs. ipilimumab (IPI). The EORTC 18071 trial demonstrated that IPI improved RFS and overall survival (OS) vs. PBO. The current study pooled data from these two trials to indirectly assess the RFS and OS of NIVO vs. PBO and the numbers needed to treat (NNTs) for one additional recurrence-free survivor and survivor over 4 years.

Methods:  Patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma from CheckMate 238 (NIVO vs. IPI) and EORTC 18071 (IPI vs. PBO) were pooled together with inverse probability weighting to balance between-trial differences in baseline characteristics. NNTs were calculated for RFS and OS comparing NIVO vs. IPI and PBO over 4 years. To account for improved post-recurrence survival over time, a sensitivity analysis that adjusted for post-recurrence survival in the PBO arm of EORTC 18071 was performed.

Results:   A total of 278, 643, and 365 patients treated with NIVO, IPI, and PBO, respectively, were included. In the weighted samples, patients treated with NIVO had consistently higher RFS rates than those treated with IPI (HR [95% CI]: 0.69 [0.56, 0.85]) and PBO (HR: 0.49 [0.39, 0.61]). NIVO was associated with similar OS as IPI (HR: 0.80 [0.60, 1.08]) and superior OS compared to PBO (HR: 0.45 [0.33, 0.60]). At 4 years, the weighted RFS rate was 53.1% for NIVO, 41.8% for IPI, and 29.1% for PBO. The NNT to achieve one additional recurrence-free survivor was 4.2 for NIVO vs. PBO and 8.9 for NIVO vs. IPI. The NNT to obtain one additional survivor was 4.8 for NIVO vs. PBO and 22.2 for NIVO vs. IPI. The OS rate for PBO after adjusting for differences in post-recurrence treatments at 4 years was 64.1%, and the corresponding NNT of OS comparing NIVO vs. adjusted PBO was 8.5.

Conclusions:  In patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma, this indirect comparison showed that NIVO improved RFS and OS vs placebo, with OS improvement maintained after adjustment for post-recurrence therapy.

Like so much in melanoma, adjuvant therapy is not a sure thing.  Still, I am certain adjuvant nivo saved my life as a Stage IV patient spiraling into met after met in untenable physiologic locations.  

Thanks to all the mice and ratties who light our way.  I continue to hold ever so many, to whom my debt of gratitude will never be repaid, in my heart.  A few are remembered here ~ Oh, the people you'll meet...

And here:  Artie...a beautiful soul, an amazing knight. Merde!

And here:  Heavy heart, heavy lifting ~ for he was all of us...

I sill think of Steven, Joshie and all the others.  And today, news that I will never meet our dear Julie in person.  Even so, I will love her still, forever in appreciation of her wide smile, her incredible goodness and common sense.  I imagine she is looking down on us, from a beautiful vista, alongside her beloved camper that will never need repairs, on trips unspoiled by earthly troubles.  Be at peace, my dear friend.  We will always love you. Shalom. ~ les

Neo-adjuvant care for melanoma patients with BRAFi or immunotherapy continues to show good results!

As I mentioned in regard to adjuvant therapy in melanoma a couple of posts ago - initially, CLND (complete lymph node dissection - the removal of all lymph nodes in the area of a positive node) was recommended for melanoma patients.  Gradually, we learned that such a procedure merely increased the rate of complications like lymphedema, but did NOT extend overall survival in patients.  (Review the posts and articles that pop up when you enter 'CLND' in the search bubble at the top right if you want to check out tons of research that went into that decision over time.)  As the data was revealed, changes in the standard of care followed.  Today, SLND (sentinel lymph node dissection - the removal of only the node - occasionally 2 or 3 - that 'light up' nearest the initial lesion when the area is injected with radiographic material) is the recommended procedure.  Standard of care also recommends that these patients are then treated with adjuvant therapy (treatment provided once all gross evidence of tumor has been removed) utilizing either targeted or immunotherapy.  This standard of care, led to the approval of immunotherapy for adjuvant use in 2017 and for targeted therapy in 2018.  

That said - there is a "new" methodology in town!  NEO-adjuvant therapy ~ Therapy for melanoma patients with either targeted or immunotherapy when affected nodes are left IN PLACE!  I began reporting the data on this method in 2015. Find reports addressing it here:  Neoadjuvant treatment in melanoma 

Now, there's this:

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).  Menzies, Amaria, Rozeman, et al.  Nature Medicine.  Feb 2021.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%,) and OS (pCR 2-year OS 95% versus no pCR 83%). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.

The positive nature of this data is even making it to the lay press for medical advances.  This link takes you to - Melanoma breakthrough: New treatment saving lives - Published in Medical X-press today.

It seems data collected for over 6-plus years indicates that if you find yourself in the position of a Stage III melanoma patient, consideration of leaving any positive node(s) in place and availing yourself of treatment with either BRAFi or immunotherapy BEFORE that node is removed is one worth discussing with your oncologist. 

For what it's worth.  Perhaps a new way of looking at melanoma treatment, especially for Stage III patients, may be in the offing. - 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

CLND in melanoma patients is NOT associated with survival benefit

As effective therapies were developed for melanoma patients, folks began to take a harder look at whether or not the removal of all the lymph nodes in the nodal basin, after a positive sentinel lymph node, provided benefit.  With no effective treatment for melanoma, the argument for CLND made more sense.  These days, as ratties have proved the value of both targeted and immunotherapy as treatment for advanced disease as well as adjuvant (BRAFi and Yervoy were FDA approved for metastatic melanoma in 2011, anti-PD-1 was approved for same in 2014, and nivo was approved for use as adjuvant only in 2017) and are now furthering the examination of NEO-adjuvant treatments, we have learned better.  The research and recommendations have vacillated back and forth over the years and the topic has been more than covered in this space with a zillion articles and discussions.  Here's a brief review of the value and difference between SLNB (sentinel lymph node biopsy) and CLND (complete lymph node dissection) written in 2016:

I have long said that sentinel lymph node removal and testing in melanoma seems like a complete no-brainer to me!!!  It is done when you return for the needed wide excision around the tumor that was removed.  It is minimally invasive considering you're going to have the wide excision anyway.  It is the only way to know what stage you really are.  You may have only cutaneous disease and therefore are categorized as Stage 1 or 2....based on how thick your lesion was, the presence of ulceration, etc.  BUT....if you have a positive node to go with that....you are then Stage 3....and that is a very different place to be.  

1.  It's important to know that's where you are in melanoma land.

2.  It makes a world of difference in recommended follow up.

3.  It makes a world of difference in what insurance companies will cover for your follow-up.

4.  AND....it makes a world of difference in potential treatment options.

NOW....do NOT confuse sentinel node removal and biopsy with a complete lymph node dissection (CLND).  CLND is different.  A CLND is when, usually after having one or more positive nodes, all the lymph nodes are removed from the nodal basin (the area in which the positive node was located).  This IS invasive surgery and has the potential to cause nerve damage and/or lymphedema, among other things.  IF you had a positive sentinel node, this would be one of the things you would have to decide about doing or not.  The science and data surrounding whether this is helpful or not, worth the potential damage or not, is murky.  There are studies that say it helps and others that say is does not.  BUT whichever way you decide to go with this...this is a decision made AFTER the sentinel node dissection and separate from it!!!

The difference between the two procedures and reasons for them remains on point.  And while there are still occasional valid reasons to consider a complete lymph node dissections - now there's this:

Completion lymphadenectomy for a positive sentinel node biopsy in melanoma patients is not associated with a survival benefit.  Kleman, Han, Leong, ..., Sondak, et al.  J Surg Oncol. 2019 Mar 18. 

Completion lymph node dissection (CLND) for sentinel lymph node (SLN) disease in melanoma patients is debated. We evaluated the impact of CLND on survival and assessed for predictors of nonsentinel node metastasis (positive CLND).

Positive SLN melanoma patients were retrospectively identified in the Sentinel Lymph Node Working Group database. Clinicopathological factors were correlated with CLND status, overall survival (OS), and melanoma-specific survival (MSS).

There were 953 positive SLN patients of whom 831 (87%) had CLND. Positive CLND was seen in 141 (17%) cases and was associated with worse OS and MSS . CLND was not performed (No-CLND) in 122 of 953 positive SLN cases (13%), of whom 100 had follow-up and 18 (18%) developed a nodal recurrence (NR). No significant differences in OS and MSS were seen comparing CLND with No-CLND and comparing positive CLND with No-CLND NR patients. Gender, primary site, ulceration, and number of positive SLNs were correlated with nonsentinel node metastasis.

Performance of CLND provides prognostic information but is not associated with a survival benefit. Clinical variables can predict a positive CLND in patients who may be at high risk of recurrence.

In reviewing the records of 953 melanoma peeps with positive SLN, researchers found that there was no impact on overall survival or melanoma-specific survival, no matter if the CLND was done or not.  The usual risk factors of "gender, primary site, ulceration, and number of positive SLNs" were noted to coordinate with metastasis as studies I've reported on previously corroborate.  

As someone who has had two CLND's (to both axilla), the first in 2003 and the second in 2007, yet still progressed to Stage IV in 2010, watching the research on the topic unfold has been interesting to say the least.  However, given the advances in melanoma therapy, it is probably time to move on! - les

Melanoma madness links!! ASCO and others....

Hey guys! Don't have the time or energy to give you my usual print out and assessment on these just now!  However, in the spirit of access and knowledge, I still wanted you to have them.

So....here you go:

Galectin's GR-MD-02 Positive in Phase Ib Study With Keytruda

Why Yervoy's Resurgence Will Gain Momentum

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Lifestyle Modifications and Policy Implications for Primary and Secondary Cancer Prevention: Diet, Exercise, Sun Safety, and Alcohol Reduction

New Era in the Management of Melanoma Brain Metastases

Combination Immunotherapy Development in Melanoma Practice-Changing Developments in Stage III Melanoma: Surgery, Adjuvant Targeted Therapy, and Immunotherapy Patterns of Response and Progression to Immunotherapy Emerging Strategies in Systemic Therapy for the Treatment of Melanoma Challenging Cases: Management of Immune-Related Toxicity The Role of Completion Lymph Node Dissection for Sentinel Lymph Node-Positive Melanoma. Hieken, Kane JM, Wong.  Ann Surg Oncol. 2018 Oct 3.  Completion lymph node dissection (CLND) for sentinel lymph node (SLN)-positive melanoma patients has been guideline-concordant standard of care since adoption of lymphatic mapping and SLN biopsy for the management of clinically node-negative melanoma patients more than 20 years ago. However, a trend for omission of CLND has been observed over the past decade, and we now have randomized, controlled clinical trial data to help guide treatment recommendations. Publication of these data prompted an American Society of Clinical Oncology-Society of Surgical Oncology 2018 clinical practice guideline update for these patients. Systematic review of current evidence supports a selective, individualized approach to CLND for SLN-positive melanoma. For low-risk, low-volume micrometastatic disease, SLN biopsy may be both diagnostic and therapeutic, and close clinical follow-up with imaging or CLND are reasonable options for appropriately selected patients. For higher-risk patients, omission of CLND requires careful consideration of risks versus benefits, relevant histopathology, and individualized patient discussion. This should address patient comorbidities and life expectancy, the predicted likelihood of additional positive nodes, availability of imaging surveillance, likelihood of adherence to imaging and clinical follow-up, consequences of regional recurrence, and the prognostic value of complete nodal staging and its impact on adjuvant therapy recommendations or clinical trial participation. Data on long-term outcomes, cost, and patient-reported quality of life measures are not yet available. Prognostic Value of Low Tumor Burden in Patients With Melanoma. Poklepovic, Carvajal.  Oncology (Williston Park). 2018 Sep 15. The therapeutic landscape for cutaneous melanoma has dramatically advanced in the last several years with the development, validation, and approval by the US Food and Drug Administration of several new therapies that have proven effective in treating metastatic disease. Considerable effort has been put into identifying prognostic and predictive markers of therapeutic response to better delineate the patient populations most likely to benefit from treatment. Baseline tumor burden has been described as a common clinical factor associated with treatment response: lower tumor burden at the time of therapeutic intervention is associated with improved responses and survival outcomes on several therapies. Some therapies have shown efficacy as adjuvant interventions in patients with subclinical disease following definitive treatment, further supporting their role in patients with minimal tumor burden. The increasing evidence that patients with lower tumor burden may be the ones who derive maximal benefit from several melanoma-directed therapies points toward the critical need for risk-tailored surveillance to permit early identification of melanoma metastasis in patients at high risk for recurrence.   Predictors of Sentinel Lymph Node Positivity in Thin Melanoma Using the National Cancer Database. Conic, Ko, Damiani, et al.  J Am Acad Dermatol. 2018 Sep 18.  Following melanoma excision, patients often receive sentinel lymph node biopsy (SLNB) for further staging. Limited data regarding predictors of SLNB positivity in thin melanoma are available.  To evaluate predictors of SLNB positivity in thin melanoma.  Patients with cutaneous melanoma, Breslow thickness great than/= to 1.00 mm who received a SLNB were identified from the National Cancer Database in the period from 2004-2014 (n=9,186). Predictors of SLNB positivity were analyzed using logistic regression.  In a multivariate analysis, patients with age less than 60 and Breslow thickness greater than 0.8mm were at increased risk for positive SLN. Moreover, on multivariate analysis, presence dermal mitoses increased odds of SLN positivity by 95%, ulceration by 63% and Clark level IV-V by 48%. Patients without ulceration but with dermal mitoses had 92% increased SLN positivity.  Limited survival data available.  Younger age, Breslow thickness greater than 0.8 mm, presence of dermal mitoses, ulceration and Clark level IV-V are positive predictors of positive SLN. While the new AJCC system has removed dermal mitotic rate from staging, continued evaluation of dermal mitotic rate could be valuable for guiding surgical decision making about SLNB.   Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. Wang, Salem, Cohen, et al.  JAMA Oncol. 2018 Sep 13. Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.  To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.  We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab). Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Systematic Review and Meta-analysis of the Prognostic Significance of miRNAs in Melanoma Patients.

Sabarimurugan, Madurantakam Royam, Das, et al.  Mol Diagn Ther. 2018 Sep 27. 

Melanoma is the most aggressive and deadly form of skin cancer. The molecular variability involving microRNA (miRNA) expression plays a significant role in melanogenesis, which leads to poor prognostic effects in melanoma. Since there is a scarcity of comprehensive data on the prognostic role of miRNAs in melanoma patients, this study focuses on filling this knowledge gap through a systematic review and meta-analysis.

The included studies were extracted from several bibliographic databases between 2012 and 2018 using multiple keywords according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) for different survival endpoints were compared to the high and low expression levels of miRNAs. The mean effect size of HR values was estimated using a random-effects model of meta-analysis. Inverted funnel plot symmetry was used to assess publication bias. Subgroup analysis was carried out individually for multiple miRNAs across different studies.

A total of 24 studies across eight countries were included, of which 16 studies were eligible for meta-analysis. Twenty-five miRNA expression levels were studied from 2669 melanoma patients to estimate the association between the prognostic role of miRNAs and survival outcome in these 16 studies. The overall pooled effect size (HR) for up- and downregulated miRNAs was 1.043, indicating that the miRNA expression increased the likelihood of death in melanoma patients by 4.3%. Subgroup analysis for miRNA10b, miRNA16 and miRNA21 showed a poor prognosis. The quality assessment revealed that 16 studies were good quality and eight studies were of fair quality. 

This is one of the first pooled meta-analysis studies on the role of miRNAs in the prognosis of melanoma. Our findings are inconclusive but suggest that miRNA expression could predict poor survival in melanoma patients. Therefore, miRNA expression could act as promising prognostic marker for melanoma.  

Induced Vitiligo due to Talimogene Laherparepvec Injection for Metastatic Melanoma Associated with Long-term Complete Response.

Iglesias, Ribert, Barreiro,   Acta Derm Venereol. 2018 Oct 3. 

Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.

Huber, Vallacchi, Fleming  et al.  J Clin Invest. 2018 Sep 27.

The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and with resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs are increased in circulating CD14+ monocytes, plasma and tumor samples, where they correlate with the myeloid cell infiltrate. In plasma, their baseline level clusters with the clinical efficacy of CTLA-4 or PD-1 blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.  

Epacadostat Plus Pembrolizumab in Patients With Advanced Solid Tumors: Phase I Results From a Multicenter, Open-Label Phase I/II Trial (ECHO-202/KEYNOTE-037).

Mitchell, Hamid Smith, et al.  J Clin Oncol. 2018 Sep 28.

Tumors may evade immunosurveillance through upregulation of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. Epacadostat is a potent and highly selective IDO1 enzyme inhibitor. The open-label phase I/II ECHO-202/KEYNOTE-037 trial evaluated epacadostat plus pembrolizumab, a programmed death protein 1 inhibitor, in patients with advanced solid tumors. Phase I results on maximum tolerated dose, safety, tolerability, preliminary antitumor activity, and pharmacokinetics are reported.

Patients received escalating doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, patients received epacadostat (50, 100, or 300 mg) twice per day plus pembrolizumab 200 mg every 3 weeks.

Sixty-two patients were enrolled and received one or more doses of study treatment. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached. Fifty-two patients (84%) experienced treatment-related adverse events (TRAEs), with fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%) occurring in greater than/ = to 20%. Grade 3/4 TRAEs were reported in 24% of patients. Seven patients (11%) discontinued study treatment because of TRAEs. No TRAEs led to death. Epacadostat 100 mg twice per day plus pembrolizumab 200 mg every 3 weeks was recommended for phase II evaluation. Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non-small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck. The pharmacokinetics of epacadostat and pembrolizumab and antidrug antibody rate were comparable to historical controls for monotherapies.

Epacadostat in combination with pembrolizumab generally was well tolerated and had encouraging antitumor activity in multiple advanced solid tumors.

Predictive Biomarkers for Checkpoint Immunotherapy: Current Status and Challenges for Clinical Application.

Tray, Weber, Adams.  Cancer Immunol Res. 2018 Oct;6.

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation.

And because y'all know I've been yelling about biomarkers for years, here are links to my prior posts on the subject:  

Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...)  

MHC proteins and how they work if you are taking anti-CTLA4 (ipi) or anti-PD-1 (Opdivo or Keytruda) in melanoma  

Simple blood tests that tells us where we are with our melanoma....AGAIN (and again, and again, and again)!!!

And here is an update on the Columbus Trial....with my prior notes:

March 2018 - Encorafenib plus binimetinib better than vemurafenib or encorafenib alone in melanoma! Well, duh!!! We already knew that a BRAF/MEK combo is better than a single agent!!!!

Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Dummer, Ascierto, Gogas, et al.  Lancet Oncol. 2018 Sep 12.

Encorafenib plus binimetinib and encorafenib alone improved progression-free survival compared with vemurafenib in patients with BRAF^V600-mutant melanoma in the COLUMBUS trial. Here, we report the results of the secondary endpoint of overall survival.

COLUMBUS was a two-part, randomised, open-label, phase 3 study done at 162 hospitals in 28 countries. Eligible patients were aged at least 18 years with histologically confirmed, locally advanced, unresectable, or metastatic cutaneous melanoma, or unknown primary melanoma, BRAF^V600E or BRAF^V600Kmutation, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and were treatment naive or had progressed on or after first-line immunotherapy. In part 1 of the study, patients were randomly assigned (1:1:1) by use of interactive response technology to receive oral encorafenib 450 mg once daily plus oral binimetinib 45 mg twice daily (encorafenib plus binimetinib group), oral encorafenib 300 mg once daily (encorafenib group), or oral vemurafenib 960 mg twice daily (vemurafenib group). Randomisation was stratified by the American Joint Committee on Cancer stage, ECOG performance status, and BRAF mutation status. The primary outcome of the trial, progression-free survival with encorafenib plus binimetinib versus vemurafenib, was reported previously. Here we present the prespecified interim overall survival analysis. Efficacy analyses were by intent to treat. Safety was analysed in patients who received at least one dose of study drug. Part 2 of the study was initiated at the request of the US Food and Drug Administration to better understand the contribution of binimetinib to the combination therapy by comparing encorafenib 300 mg once daily plus binimetinib 45 mg twice daily with encorafenib 300 mg once daily alone. Results of part 2 will be published separately. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01909453, and EudraCT, number 2013-001176-38.

Between Dec 30, 2013, and April 10, 2015, 577 of 1345 screened patients were randomly assigned to receive encorafenib plus binimetinib (n=192), encorafenib (n=194), or vemurafenib (n=191). Median follow-up for overall survival was 36·8 months (35·9-37·5). Median overall survival was 33·6 months (24·4-39·2) with encorafenib plus binimetinib and 16·9 months (14·0-24·5) with vemurafenib. The most common grade 3 or 4 adverse events did not change substantially from the first report; those seen in more than 5% of patients treated with encorafenib plus binimetinib were increased γ-glutamyltransferase (18 [9%] of 192 patients), increased blood creatine phosphokinase (14 [7%]), and hypertension (12 [6%]); those seen with encorafenib alone were palmar-plantar erythrodysaesthesia syndrome (26 [14%] of 192 patients), myalgia (19 [10%]), and arthralgia (18 [9%]); and with vemurafenib the most common grade 3 or 4 adverse event was arthralgia (11 [6%] of 186 patients). One death in the combination treatment group was considered by the investigator to be possibly related to treatment.

The combination of encorafenib plus binimetinib provided clinically meaningful efficacy with good tolerability as shown by improvements in both progression-free survival and overall survival compared with vemurafenib. These data suggest that the combination of encorafenib plus binimetinib is likely to become an important therapeutic option in patients with BRAF^V600-mutant melanoma.

The ASCO Educational Book looks like it might be helpful to melanoma peeps...so you might keep that in mind as an additional resource in the future.  Remember to read critically.  Use your common horse sense.  Don't fall for everything everybody is selling.  Take good care and remember I love you.  - C

SLNB and CLND....in melanoma patients!! Again!

The topics of sentinel lymph node biopsy (SLNB) and complete lymph node dissection (CLND) have been more than covered here!!  But, melanoma is a scary world to say the least, and folks are most frightened right at the time they are having to make these decisions! So, there was this:

SLN biopsy. Delay of 40 days = WHAT???? (Plus some general guidelines)

And this:

CLND - Complete lymph node dissection in melanoma - the whole shmegegge!!!!!!!!!!!

Now there's this:

Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations. Verver, van Klaveren, van Akkooi, et al. Eur J Cancer. 2018 Apr 13.

In light of the evolving landscape of adjuvant therapy in melanoma and the recently confirmed absent survival benefit of completion lymph node dissection (CLND), it becomes important to explore possible consequences of omitting CLND, and whether it is possible to adequately stratify positive sentinel node (SN) patients solely based on information retrieved from the melanoma up to the sentinel lymph node biopsy (SLNB).

A retrospective cohort from nine European Organization for Research and Treatment of Cancer Melanoma Group centres was used. Patients were staged based on SLNB and CLND result according to the American Joint Committee on Cancer (AJCC) criteria and stratified by ulceration and SN tumour burden. These were incorporated in Cox regression models. Predictive ability was assessed using Harrell's concordance index (c-index) and the Akaike information criterion (AIC).

In total, 1015 patients were eligible. CLND led to upstaging in N-category in 19% and in AJCC stage in 5-6%. The model incorporating only ulceration and SN tumour burden performed equally well as the model incorporating substages after CLND. The model incorporating substages based on SLNB had the lowest predictive ability. Stratifying by ulceration and SN tumour burden resulted in four positive SN groups from which low-, intermediate- and high-risk prognostic classes could be derived.

Adequate stratification of positive SN patients was possible based on ulceration and SN tumour burden category. The identification of low-, intermediate- and high-risk patients could guide adjuvant therapy in clinical practice. Omitting CLND seems to have little consequences.  

This report simply reiterates what prior studies have shown.  SLNB is important for staging.  And looking at what the sentinel node shows as far as tumor burden, esp when you consider whether or not the initial lesion was ulcerated,  can be very helpful in evaluating risk and decision making regarding adjuvant treatment.  CLND did not really impact results.

Good luck, ratties!  You can do this! - c