Five year survival reports in melanoma after various targeted and immunotherapies

Five years.  I think every doc or researchers who touts "5 year survival" as the cat's meow really needs to think about how that would feel if applied to their life.  Now, when you are coming from a prognosis of "6 months to live" - a sentence once levied directly at me personally - five years to live certainly has a better ring to it.  Still, it is pretty sucky to have to look at five year survival as something to cheer about. But, in the crazy land that is melanoma - we'll take it.

From as early as 2016 there was this report on nivolumab (Opdivo) in advanced heavily pre-treated melanoma patients:  Nivolumab Shows Impressive OS in melanoma

This report from 2018 looked at the survival of patients on targeted therapy:  Long term outcomes with Dabrafenib/Trametinib (BRAF/MEK combo)

This abstract from last year examined survival data with the ipi/nivo combo:  Ipi/Nivo combo 5 year overall survival report for peeps with advanced melanoma!

The Keynote-001 study has put out data many times.  This link includes an abstract from Jan 2019 and links to previously published data:  KEYNOTE-001: Melanoma patients treated with Pembrolizumab (Keytruda) - 5 year survival outcomes

This report was published in April of last year:

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.  Hamid, Robert, Daud, et al.  Ann Oncol. 2019 Apr;30

Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.

Patients aged greater than/= to 18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).

KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months and 38.6 months, respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months and 16.9 months, respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.

This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.

Then, there is this report on outcomes in melanoma patients when anti-PD-1 or ipi/nivo is combined WITH surgical removal of the lesion:

Survival Outcomes After Metastasectomy in Melanoma Patients Categorized by Response to Checkpoint Blockade.  Bello, Panageas, Hollmann, et al.  Ann Surg Oncol. 2019 Dec 17.

Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear.

Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions.

Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months).

Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease

Melanoma sucks great big green hairy stinky wizard balls.  So do the treatments.  But knowledge is power and perhaps these reports can help shed some light for those facing tough decisions.  For what it's worth. - c

Advanced Melanoma - A smattering of 2020 literature for Stage IV peeps

Unfortunately, though some promising trials are underway, no major breakthroughs have occurred in melanoma research of late.  Still, there are studies and data that are meaningful.  Here is a collection of reports that may be valuable to Stage IV melanoma peeps.  (My comments in red.) -

Overall Survival Improved for Contemporary Patients with Melanoma: A 2004-2015 National Cancer Database Analysis.  Farrow, Turner, Salama, Beasley.  Oncol Ther. 2020 Dec.

Introduction: Since 2011, encouraging clinical trial results have led to approval of multiple new therapies for advanced melanoma, but the impact of these therapies outside of trial populations is largely unknown. This study examines use of novel therapies and survival in contemporary patients with melanoma.

Methods: Stage I-IV melanoma patients were identified in the 2004-2015 National Cancer Database and grouped into historic (2004-2010) and contemporary (2011-2015) cohorts. Overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard modeling adjusting for patient, tumor, and facility characteristics.

Results: Of 268,668 patients, 136,828 were classified as historic and 131,840 as contemporary. Among all stages, immunotherapy utilization was significantly higher among contemporary patients. Adjusted OS was improved in the contemporary cohort. There was no difference in OS among stage I/II patients between groups, while OS was significantly improved for contemporary stage III/IV patients. Among stage III/IV patients who received immunotherapy, OS was improved for the contemporary cohort.

Conclusions: Adjusted overall survival for contemporary melanoma patients is improved. This effect is driven by improvements for those with advanced stage disease, particularly those that received immunotherapy and BRAF/MEK targeted therapies.

Confirmation of what we already know - targeted therapy (BRAF/MEK combo's) for BRAF positive melanoma patients and immunotherapy - have made a world of difference for melanoma peeps.  

Systemic Therapy for Melanoma: ASCO Guideline.  Seth, …Kirkwood, Kudchadkar…Weber, Agarwala, Ascierto, …, Faries… Robert,…Sondak, et al.  J Clin Oncol, 2020 Nov 20.

Purpose: To provide guidance to clinicians regarding the use of systemic therapy for melanoma.

Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature.

Results: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma.

Recommendations: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. 

YEP!

Five-Year Outcomes With Nivolumab in Patients With Wild-Type BRAF Advanced Melanoma.  Robert, Long, Brady, et al.  J Clin oncol.  2020 Nov.

Purpose: The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated BRAF wild-type advanced melanoma. Five-year results are presented herein.

Patients and methods: In this multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type BRAF melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m2 every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Results: Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.

Conclusion: Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.

So over comparing any melanoma treatment with dacarbazine.  At the onset of this study, I suppose it was okay - but hopefully we are well past that now!!!  At any rate - important points are just relative to nivo only treatment and survival.  Overall response rate was 42%.  Of patients alive at five years ORR was 81%.  Of the patients on nivo with a complete response, 88% were alive at 5 years.  Of nivo treated patients alive at 5 years - 83% had needed no additional treatment, 23% were still on treatment, and 60% were treatment free.

Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218).  Hodi, Chapman, Sznol, et al.  Melanoma Res.  2020 Nov.

CheckMate 218, a North American expanded access program (EAP), investigated nivolumab plus ipilimumab in patients with advanced melanoma. Safety and efficacy, including 2-year survival in clinically relevant patient subgroups, are reported. Eligible patients were aged greater than/equal to18 years with unresectable stage III/IV melanoma, an Eastern Cooperative Oncology Group performance status of 0/1, and no prior checkpoint inhibitors. Patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction) followed by nivolumab 3 mg/kg every 2 weeks (maintenance) until progression or unacceptable toxicity or a maximum of 48 weeks. Safety and overall survival (OS) data were collected. This EAP included 754 treated patients from the USA (n = 580) and Canada (n = 174). Median follow-up time was 17.8 months. All-grade and grade 3-4 treatment-related adverse events were reported in 96% and 53% of patients and led to treatment discontinuation in 36% and 26% of patients, respectively. OS rates at 12 and 24 months were 82%  and 70%, respectively. Twenty-four-month OS rates were 63% in patients aged ≥75 years, 56% in patients with elevated lactate dehydrogenase levels, 73% in patients with BRAF wild-type tumors, 70% in patients with BRAF mutant tumors, and 56% in patients with mucosal melanoma. In this EAP, nivolumab plus ipilimumab demonstrated high survival rates and safety outcomes consistent with those from randomized clinical trials, further supporting the use of this combination for advanced melanoma across multiple subgroups.

Again - ipi/nivo with better survival than nivo alone, though with a more significant side effect profile.

PD-1 inhibitors might limit the development of brain metastases in patients with advanced melanoma.  Marcaillous, Linder, Chaltiel, et al.  Melanoma Res. 2020 Dec.

Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017. Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy [immune checkpoint inhibitor (ICI)] vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group and 27.26% in the other group. The cumulative incidence was 9.49% in the anti-PD-1 group vs 30.11% in the other group . In multivariable analysis, anti-PD-1 reduced the risk of brain metastases by almost 70%. The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.

Yep.  Been yelling it for over 10 years!!!  Immunotherapy works in the brain.  Folks treated with anti-PD-1 had an incidence of brain met development of 9.49% vs 30.11% in patients not treated with anti-PD-1.  Analysis found that anti-PD-1 reduced the risk of brain mets by almost 70%.

PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Ribas, Algazi, Ascierto, et al.  Nat Commun.  2020 Dec.

Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

In this trial of either Durvalumab (anti-PD-L1) combined with dabrafenib/trametinib or just with trametinib or given sequentially - patients given the combination of the three drugs had a 69.2% response rate, of the 2 a response rate of 20% and in the sequential group (not clear, but I suspect that they got the three drugs) a response rate of 31.8%.  For comparison here is a report on atezo and pembro when combined with a BRAF/MEK therapy from 2019 that includes links to other reports of results when immunotherapy was combined with targeted therapy - Treating melanoma by COMBINING targeted therapy AND immunotherapy!!  When atezo and pembro were combined with a BRAF/MEK combo - responses rates were 70+%.  Of course, this treatment option is only available to about half of us as patients need to be BRAF positive.

Chemotherapy combined with antiangiogenic drugs as salvage therapy in advanced melanoma patients progressing on PD-1 immunotherapy.  Wang, Weiran, Zhihong, et al.  Transl Oncol. 2020 Nov.

Background: This study aimed to evaluate the effect of salvage therapy with nab-paclitaxel (nab-p) or temozolomide (TMZ) combined with antiangiogenic drugs in programmed death 1 (PD-1) inhibitor-resistant patients with unresectable metastatic melanoma.

Methods: We conducted a retrospective review of 69 metastatic melanoma patients who received nab-p or TMZ combined with antiangiogenic drugs after developing PD-1 inhibitor resistance and were treated at the Beijing Cancer Hospital between 2016 and 2019. The disease control rate (c-DCR) and progression-free survival (c-PFS) of salvage CA (chemotherapy combined with antiangiogenic drugs) regimens were investigated. Univariate and multivariate analyses were performed to evaluate the clinical pathological factors affecting the outcomes. Then, a nomogram was formulated to predict the probability of 3-month and 6-month c-PFS based on the multivariate analysis results.

Results: The c-DCR was 63.8%, and the median c-PFS was 3.0 months. In the univariate analysis, factors associated with the c-DCR were included the melanoma subtype, baseline platelet-to-lymphocyte ratio (PLR) and best response status to PD-1 inhibitors. Factors influencing c-PFS included age, baseline lactic dehydrogenase, PLR, neutrophil-to-lymphocyte ratio (NLR), PFS duration of anti-PD-1 therapy (p-PFS), and the best response and progression pattern of PD-1 inhibitors. In the multivariate analysis, age <65 years, heterogeneous progression pattern and baseline PLR<200 were significantly associated with improved c-PFS. The concordance index (C-index) of the nomogram was equal to 0.65.

Conclusions: CA regimens demonstrated promising effects in PD-1 inhibitor-resistant patients. The nomogram could be a valuable predictive module for salvage therapy choice in PD-1 inhibitor-resistant patients.

So these peeps created a fancy scale to determine whether a chemo cocktail would provide 3 vs 6 months of progression free survival in unresectable Stage IV melanoma folks who had become unresponsive to anti-PD-1.  Sad thing to face.  But, if this formula works, perhaps it can provide patients with knowledge that may inform their decision to accept or decline such therapy.

So there you have it.  Final 2020 reports in review for advanced melanoma patients - my take, anyway.  Over the coming days, I will plow through some other 2020 research on other topics pertinent to melanoma.  Stay safe.  Wear a mask.  Get a COVID vaccine when you can.  - c

Ipi/Nivo combo 5 year overall survival report for peeps with advanced melanoma!

As a convenient follow-up to my September report Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then? in which I addressed the latest survival data for both targeted and immunotherapy, a report coming from some Melanoma Big Dogs on the 5 year OS of the ipi/nivo combo was just released. 

This ASCO 2019 report, linked my previous post noted:  Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.  2019 ASCO.  Akins, Kirkwood, Wolchok, ..., Postow, ...Sznol.  J Clin Oncol 37, 2019. 

"Results: At a median follow-up of 43.1 months in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57%. The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% versus 49%; for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% and 61%, respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74%, 65%, and 56%, respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84%, 75%, and 65%, respectively, and in pts who discontinued for disease progression (n = 30), these were 52%, 34%, and 24%, respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. "

Now, there's this ~

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.  Larkin, ..., Lebbe, ..., Ascierto, ...Long, ...Hodi, Wolchok.  N Engl J Med. 2019 Sep 28. 

Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.

We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.

At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group. Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.

Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab.

So - the ASCO report broke various factors down a bit, but generally noted:  "overall post-treatment 1-, 2-, and 3-year OS rates were 74%, 65%, and 56%, respectively".  In this new report the OS at 5 years for the ipi/nivo combo = 52%, for nivo alone = 44%, and ipi alone = 26%.  Given what we have been seeing in the research these numbers are pretty consistent with expectations.  The ipi/nivo combo peeps didn't quite hold onto the 3 year survival number of 56%, the data point where those who are fond of kaplan meier curves note things flatten out, but it is pretty close.  I do want to reiterate from the ASCO report, "pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84%, 75%, and 65%, respectively.   I think it is reasonable to assume that while the 5 year OS in that group may well decrease a bit, that would still be a good number! (Considering we are talking melanoma world y'all!!!)  

Pretty hopeful stuff when you consider that in 2010, NONE of the current therapies attaining these survival results for melanoma patients were FDA approved.  Not even ipi.  NOW!  Let's get some help for that other 50% of our melanoma peeps!!! - c

Adjuvant treatments in melanoma - They WORK!!! Now, let's make sure people can get them!!!!!

It was certainly good news when the FDA (FINALLY!!!) approved ipi as an adjuvant treatment for melanoma.  And....it works!  ASCO 2017: Ipi 3 mg vs 10 mg in advanced melanoma and as adjuvant

We also KNOW that anti-PD-1 works EVEN BETTER, with fewer side effects, as an adjuvant treatment in melanoma. The trial that I and my fellow ratties started in 2010 proved that...and so have other studies since:  Nivo better than ipi as adjuvant treatment for melanoma! Surprise, surprise, surprise!!!

We also KNOW that BRAF/MEK inhibitors are extremely effective as an adjuvant therapy in patients with BRAF positive melanoma:  2016: Straight Outta Boston!!! Latest melanoma research ~
One abstract included in that link notes:

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.  

Now...there's this:  

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long, Hauschild, Santinami, et al. N Engl J Med. 2017 Sep 10. 

Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. 

In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety. 

At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group. The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group, but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. 

Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects.

Relapse free survival...58% with treatment, 39% with placebo!  Sounds good to me...of course you have to be BRAF positive....but it's something!!!

Now this is something "new"....and VERY old!!!  Remember this post:  Immunotherapy....The Original Super Heroes and Ratties!!!!  When you talk about CpG-B - Coley's toxin comes to mind, who, in the 1890's, injected bacteria into tumors and found that they would GO AWAY!!!  In 1983 an underlying DNA component of the bacteria, responsible for the effect, was discovered.  And in 1995, the specific DNA molecules (CpG) were found to be the component that specifically stimulated the immune response, with the B group in particular, causing B cell and monocyte maturation.  And since some of the patients were also given GM-CSF in the study below, here's a reminder about what that is:  Sargramostim ~ aka GM-CSF or leukine (and other related posts)  Here's the latest:

Local Adjuvant Treatment with Low-Dose CpG-B Offers Durable Protection against Disease Recurrence in Clinical Stage I-II Melanoma: Data from Two Randomized Phase II Trials. Koster, Van den Hout, Sluijter, et al. Clin Cancer Res. 2017 Oct 1.  

Although risk of recurrence after surgical removal of clinical stage I-II melanoma is considerable, there is no adjuvant therapy with proven efficacy. Here, we provide clinical evidence that a local conditioning regimen, aimed at immunologic arming of the tumor-draining lymph nodes, may provide durable protection against disease recurrence (median follow-up, 88.8 months).

In two randomized phase II trials, patients, diagnosed with stage I-II melanoma after excision of the primary tumor, received local injections at the primary tumor excision site within 7 days preceding re-excision and sentinel lymph node (SLN) biopsy of either a saline placebo (n = 22) or low-dose CpG type B (CpG-B) with (n = 9) or without (n = 21) low-dose GM-CSF.

CpG-B treatment was shown to be safe, to boost locoregional and systemic immunity, to be associated with lower rates of tumor-involved SLN (10% vs. 36% in controls), and, at a median follow-up of 88.8 months, to profoundly improve recurrence-free survival, even for patients with histologically confirmed (i.e., pathologic) stage I-II disease.

Potentially offering durable protection, local low-dose CpG-B administration in early-stage melanoma provides an adjuvant treatment option for a large group of patients currently going untreated despite being at considerable risk for disease recurrence. Once validated in a larger randomized phase III trial, this nontoxic immunopotentiating regimen may prove clinically transformative. 

What's not to like????? 

And there's this....  Here, CancerVax (canvaxin) was given along with BCG.  

Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. Faries, Mozzillo, Kashani-Sabet, et al.  Ann Surg Oncol. 2017 Oct 10. 

This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma.  After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test.  Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group. Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group. Positive DTH skin testing correlated with increased survival.  In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.

So...that adjuvant therapy is a big NO!!!  As much as I love the idea of a vaccine (peptide vaccines - 6 of them actually - were included in my trial and DID NOT HELP!!!!) as treatment for melanoma, and have hope that someday....  Well, so far - it has been a no go!!!  But...we have all the options noted above that DO WORK!!!

I have been yelling about melanoma adjuvant treatment options since 2003!!!!!!!!!!!!!!!  Could we please take some action?????

The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients. Eggermont, Dummer.  Eur J Cancer. 2017 Sep 28.  

The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. [No shit!!!!] In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. [No shit!  And...ABOUT TIME!!!] In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

"Important paradigm shifts in the management of high-risk melanoma patients are upon us." I hope so!!!  It is more than time!  So many ratties have done the work.  Let's make this so!!!! - c

Brain Mets - A mixture of recent reports

I've covered the data related to brain mets in melanoma for a long time - A few zillion relative reports  

Unfortunately, some older posts are at the top of that list, so scroll through for newer posts if you are interested.  Also unfortunately, not a lot has changed since many of those postings, but here are some reports published over the past year (my comments in red as ever) ~

Tumor Control Probability of Radiosurgery and Fractionated Stereotactic Radiosurgery for Brain Metastases.  Redmond, Gui, Benedict, et al.  Int J Radiat Oncol Biol Phys.  Dec 2020.

Purpose: As part of the American Association of Physicists in Medicine Working Group on Stereotactic Body Radiotherapy, tumor control probability (TCP) after stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for brain metastases was modeled based on pooled dosimetric and clinical data from published English-language literature.

Methods and materials: PubMed-indexed studies published between January 1995 and September 2017 were used to evaluate dosimetric and clinical predictors of TCP after SRS or fSRS for brain metastases. Eligible studies had greater than/= to10 patients and included detailed dose-fractionation data with corresponding greater than/= to 1-year local control (LC) data, typically evaluated as a greater than 20% increase in diameter of the targeted lesion using the pre-SRS diameter as a reference.

Results: Of 2951 potentially eligible manuscripts, 56 included sufficient dose-volume data for analyses. Accepting that necrosis and pseudoprogression can complicate the assessment of LC, for tumors less than/= to 20 mm, single-fraction doses of 18 and 24 Gy corresponded with greater than 85% and 95% 1-year LC rates, respectively. For tumors 21 to 30 mm, an 18 Gy single-fraction dose was associated with 75% LC. For tumors 31 to 40 mm, a 15 Gy single-fraction dose yielded ∼69% LC. For 3- to 5-fraction fSRS using doses in the range of 27 to 35 Gy, 80% 1-year LC has been achieved for tumors of 21 to 40 mm in diameter.

Conclusions: TCP for SRS and fSRS are presented. For small lesions less than/= to 20 mm, single doses of ≈18 Gy appear generally associated with excellent rates of LC; for melanoma, higher doses seem warranted. For larger lesions greater than 20 mm, local control rates appear to be ≈ 70% to 75% with usual doses of 15 to 18 Gy, and in this setting, fSRS regimens should be considered. Greater consistency in reporting of dosimetric and LC data is needed to facilitate future pooled analyses. As systemic and biologic therapies evolve, updated analyses will be needed to further assess the necessity, efficacy, and toxicity of SRS and fSRS.

Not stuff that we as melanoma patients have a lot of control of or say in - but there you go.

Long-term disease outcome and volume-based decision strategy in a large cohort of multiple brain metastases treated with a mono-isocentric linac-based Stereotactic Radiosurgery technique.  Alongi, Nicosia, Figlia, et al.  Clin Transl Oncol.  August 2021.

Purpose: Radiosurgery (SRS) is an effective treatment option for brain metastases (BMs). Long-term results of the first worldwide experience with a mono-isocentric, non-coplanar, linac-based stereotactic technique in the treatment of multiple BMs are reported.

Methods: Patients with multiple BMs, life expectancy greater than 3 months, and good performance status (less than/= to 2) were treated with simultaneous SRS with volumetric modulated arc technique. Data were retrospectively evaluated.

Results: 172 patients accounting for 1079 BMs were treated at our institution from 2017 to 2020. The median number of treated metastases was 4 (range 2-22). Primary tumor histology was: lung (44.8%), breast (32%), and melanoma (9.4%). The 2-year LPFS was 71.6%, respectively. A biological effective dose (BED) greater than/= to 51.3 Gy10 correlated with higher local control. Uncontrolled systemic disease and melanoma histology were independent prognostic factors correlated with decreased iPFS. Patients with greater than 10 BMs had a trend towards shorter iPFS. 31 patients received multiple SRS courses (2-7) in case of intracranial progression. The median iOS was 22.4 months. Brainstem metastases and total PTV greater than 7.1 cc correlated with shorter iOS. The 1- and 2-year WBRT-free survival was 83.2% and 61.1%, respectively.

Conclusion: Long-term results in a large patient population treated with a mono-isocentric, dedicated technique demonstrated its effectiveness and safety also in the case of multiple courses. The shortened treatment time and the possibility to safely spare healthy brain tissue allows the safe treatment of patients with a large number of metastases and to deliver multiple courses of SRS. In selected cases, the administration of WBRT can be delayed.

Not all melanoma patients here.  But good to know that multiple rounds of SRS were effective and well tolerated in some of these patients.

Time from stereotactic radiosurgery to immunotherapy in patients with melanoma brain metastases and impact on outcome.  Wegner, Abel, D’Amico, et al.  J Neurooncol.  Mar 2021.

Background: The role of immunotherapy for metastatic melanoma has expanded over the past decade triggering questions regarding the combination and timing of immunotherapy and radiation for brain metastases. We used the National Cancer Database (NCDB) to see if the time from radiation to immunotherapy in patients with melanoma brain metastases had an impact on survival.

Methods: We queried the NCDB from 2010 to 2015 for patients with melanoma brain metastases treated with immunotherapy and stereotactic radiosurgery (SRS). Receiver operator characteristic (ROC) curve analysis was done to determine a timepoint associated with outcome. Cox regression was used to identify predictors of survival. Propensity matching was done to account for indication bias.

Results: We identified 247 patients meeting the above criteria. The median patient age was 62 years (27-90) and the vast majority were Caucasian (99%). The median SRS dose was 22 Gy (18-24 Gy).The median time to SRS was 39 days (0-344) and the median time to immunotherapy was 56 days (6-454). The ROC analysis revealed 8 days from SRS to immunotherapy as associated with outcome. Fifty-six patients had immunotherapy prior to SRS, 30 patients had immunotherapy within 0-7 days of SRS, and the remaining 161 had immunotherapy greater than 7 days from SRS. Three year survival rates were 21%, 55%, and 35% for those timeframes, respectively. Propensity matching of the 0-7 day and greater than 7 day groups yielded 28 pairs and Kaplan Meier analysis showed 3 year overall survival of 55% and 35%, in favor of immunotherapy within 7 days of SRS. Multivariable Cox regression identified lack of extracranial disease, more recent year of treatment, and time from SRS to immunotherapy of 0-7 days as predictors of improved survival.

Conclusions: Immunotherapy within 7 days of SRS shows a possible association with improve outcomes in patients with brain metastases from melanoma.

Many other studies have already demonstrated this fact - outcomes are better when you DO NOT delay immunotherapy!!!!!!!!!!!!!!!!!!!!!!!!!!!!  Again = a zillion reports:  Radiation AND immunotherapy

Management of melanoma brain metastases: Evidence-based clinical practice guidelines by Cancer Council Australia.  Hong, Waldstein, Shivalingam, et al.  Eur J Cancer.  Jan 2021.

Introduction: The brain is a common site of metastatic disease for patients with advanced melanoma. Brain metastasis portends a poor prognosis, often causing deterioration in neurological function and quality of life, and leading to neurological death. Treatment approaches including surgery, radiotherapy and systemic therapy can lead to better control of this problem. Therefore, appropriate guidelines for the management of melanoma brain metastases need to be established, with regular updating when new treatment options become available.

Methods: A multidisciplinary working party established by Cancer Council Australia has produced up-to-date, evidence-based clinical practice guidelines for the management of melanoma. After selecting key clinical questions, a comprehensive literature search for relevant studies was conducted, followed by systematic review of those studies. Data were summarized and the evidence was assessed, leading to the development of recommendations.

Main recommendations: Symptomatic lesions are best treated with surgery, when possible; this provides safe and effective local control. For patients with single or a small number of asymptomatic brain metastases, stereotactic radiotherapy is recommended, but in asymptomatic patients who have not previously received systemic treatment, drug therapy can be considered as a first-line treatment option. Whole brain radiotherapy may provide palliative benefits in patients with multiple brain metastases. Whenever possible, melanoma patients with brain metastases should be managed by a multidisciplinary team of melanoma specialists that considers the optimal combination and sequencing of surgery, radiotherapy and systemic therapy.

All conclusions seem true based on current data.  There is even this confirming report from 2019 regarding immunotherapy as first line treatment (without radiation) for folks with melanoma brain mets - IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma  However, as I noted in that post - with the vast preponderance of evidence showing that responses are better when immunotherapy is COMBINED with radiation, you would have a hard time convincing me to roll with immunotherapy alone.  But, maybe that's just me!

Sustainable responses in metastatic melanoma patients with and without brain metastases after elective discontinuation of anti-PD1-based immunotherapy due to complete response.  Dimitriou, Zaremba, Allayous, et al. Eur J Cancer.  Jul 2021.

Background: Anti-PD1-based immunotherapy is currently used in most patients with advanced melanoma. Despite the remarkable data regarding overall survival, the optimal treatment duration is still unknown.

Methods: We evaluated the outcome of 125 patients with advanced melanoma with and without brain metastases (MBM), treated either with anti-PD1 monotherapy (N = 97) or combined with anti-CTLA4 (N = 28) after elective treatment discontinuation due to complete response (CR) (group A, N = 86), or treatment-limiting toxicity (N = 33) and investigator's decision (ID, N = 6) (group B) with subsequent CR.

Results: For group A, median duration of treatment (mDoT) was 22 months (range 5-49) and median time to CR 9 months (range 2-47). Accordingly, mDoT for group B was 3 months (range 0-36) and median time to CR 7 months (range 1-32). Seven patients from group A and three from group B experienced disease recurrence. Off-treatment survival was not reached. Median off-treatment response time (mOTRt) was 19 months (range 0-42) and 25 months (range 0-66), respectively. For MBM, mOTRt was 17 months (range 7-41) and 28 months (range 9-39), respectively. After a median follow-up of 38 months (range 9-70), seven (5.6%) patients had deceased, one (0.8%) due to melanoma.

Conclusions: Treatment discontinuation is feasible also in patients with MBM. Efficacy outcomes seemed to be similar in both groups of patients who achieved CR, regardless of reason for discontinuation. In patients who experienced disease relapse, treatment re-challenge with anti-PD1 resulted in subsequent renewed response.

Deciding when to stop therapy - esp when there has been no complete response, remains hard.

First line immunotherapy extends brain metastasis free survival, improves overall survival, and reduces the incidence of brain metastasis in patients with advanced melanoma.  Wang, Haaland, Hu-Lieskovan, et al.  Cancer Rep.  June 2021.

Background: Recent advances in targeted therapy and immunotherapy have improved the prognosis of melanoma patients but brain metastasis remains a major challenge. Currently, it is unclear how existing therapies can be best used to prevent or treat brain metastasis in melanoma patients.

Aims: We aimed to assess brain metastasis free survival (BMFS), overall survival (OS), incidence of brain metastases, and sequencing strategies of immunotherapy and targeted therapy in patients with BRAF-mutated advanced melanoma.

Methods and results: We retrospectively analyzed 683 patients with BRAF-mutated advanced melanoma treated with first line (1L) immunotherapy (N = 266) or targeted therapy (N = 417). The primary outcome was BMFS. Secondary outcomes included OS of all patients and incidence of brain metastases in patients without documented brain metastases prior to 1L therapy. The median BMFS was 13.7 months among all patients. The median BMFS for patients receiving 1L immunotherapy was 41.9 months and targeted therapy was 11.0 months. Median OS results were qualitatively similar to BMFS results. The cumulative incidence of brain metastases for patients receiving 1L targeted therapy was higher than for patients receiving 1L immunotherapy. Patients receiving 1L anti-CTLA4 plus anti-PD1 combination immunotherapy only or followed by second line (2L) targeted therapy had better BMFS, improved OS, and reduced incidence of brain metastases, than patients receiving 1L combination BRAF and MEK targeted therapy followed by 2L immunotherapy.

Conclusion: Patients with advanced BRAF mutant melanoma treated with 1L immunotherapy have significantly longer BMFS and OS, and reduced incidence of brain metastases, compared with those treated with 1L targeted therapy. Further studies evaluating the ability of immunotherapy and targeted therapy to improve OS and prevent brain metastases are warranted.

Interesting.

Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies.  Bander, Yuan, Carnevale, et al.  Cancer.  June 2021.

Background: Historically, the prognosis for patients who have melanoma brain metastasis (MBM) has been dismal. However, breakthroughs in targeted and immunotherapies have improved long-term survival in those with advanced melanoma. Therefore, MBM presentation, prognosis, and the use of multimodality central nervous system (CNS)-directed treatment were reassessed.

Methods: In this retrospective study, the authors evaluated patients with MBM who received treatment at Memorial Sloan Kettering Cancer Center between 2010 and 2019. Kaplan-Meier methodology was used to describe overall survival (OS). Recursive partitioning analysis and time-dependent multivariable Cox modeling were used to assess prognostic variables and to associate CNS-directed treatments with OS.

Results: Four hundred twenty-five patients with 2488 brain metastases were included. The median OS after an MBM diagnosis was 8.9 months. Patients who were diagnosed with MBM between 2015 and 2019 experienced longer OS compared to those who were diagnosed between 2010 and 2014 (OS, 13.0 months vs 7.0 months). Prognostic multivariable modeling significantly associated shortened OS independently with leptomeningeal dissemination, increasing numbers of brain metastases at diagnosis, earlier MBM diagnosis year, higher serum levels of lactate dehydrogenase, receipt of immunotherapy before MBM diagnosis, and the presence of extracranial disease. The use of different CNS-directed treatment modalities was associated with presenting symptoms, diagnosis year, number and size of brain metastases, and the presence of extracranial disease. Multivariable analysis demonstrated improved survival for patients who underwent craniotomy.

Conclusions: The prognosis for patients with MBM has improved within the last 5 years, coinciding with the approval of PD-1 immune checkpoint blockade and combined BRAF/MEK targeting. Improving survival reflects and may influence the willingness to use aggressive multimodality treatment for MBM.

Lay summary: Historically, melanoma brain metastases (MBM) have carried a poor survival prognosis of 4 to 6 months; however, the introduction of immunotherapy and targeted precision medicines has altered the survival curve for advanced melanoma. In this large, single-institution, contemporary cohort, the authors demonstrate a significant increase in survival of patients with MBM to 13 months within the last 5 years of the study. A worse prognosis for patients with MBM was significantly associated with the number of metastases at diagnosis, previous exposure to immunotherapy, spread of disease to the leptomeningeal compartment, serum lactate dehydrogenase elevation, and the presence of extracranial disease. The current age of systemic treatments has also been accompanied by shifts in the use of central nervous system-directed therapies.

Yep.  Things are better.  But, not yet good enough.  Still, we know - if you have melanoma brain mets - hit 'em hard with everything you've got!  No waiting.  No pussy footing around!!!

Immune checkpoint inhibitor therapy may increase the incidence of treatment-related necrosis after stereotactic radiosurgery for brain metastases: a systematic review and meta-analysis.  Kim, Suh, Kim, et al.  Eur Radiol.  June 2021.

Objectives: To compare the incidence of treatment-related necrosis between combination SRS+ICI therapy and SRS therapy alone in patients with brain metastases from melanoma and non-small cell lung cancer (NSCLC).

Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed up to August 10, 2020. The difference in the pooled incidence of treatment-related necrosis after SRS+ICI or SRS alone was evaluated. The cumulative incidence of treatment-related necrosis at the specific time point after the treatment was calculated and plotted. Subgroup and meta-regression analyses were additionally performed.

Results: Sixteen studies (14 on melanoma, 2 on NSCLC) were included. In NSCLC brain metastasis, the reported incidences of treatment-related necrosis in SRS+ICI and SRS alone ranged 2.9-3.4% and 0-2.9%, respectively. Meta-analysis was conducted including 14 studies on melanoma brain metastasis. The incidence of treatment-related necrosis was higher in SRS+ICI than SRS alone (16.0% vs. 6.5%). The incidence showed rapid increase until 12 months after the SRS when combined with ICI therapy (14%) and its pace of increase slowed thereafter. Histopathologic diagnosis as the reference standard for treatment-related necrosis and inclusion of only symptomatic cases were the source of heterogeneity in SRS+ICI.

Conclusions: Treatment-related necrosis tended to occur 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis showing high cumulative incidence within the first year. Treatment-related necrosis should be considered when SRS+ICI combination therapy is used for melanoma brain metastasis, especially in the first year.

Key points: • Treatment-related necrosis occurred 2.4 times more frequently in the setting of combination SRS+ICI therapy compared with SRS alone in melanoma brain metastasis. • Treatment-related necrosis more frequently occurred in brain metastases from melanoma than NSCLC. • Reference standard for treatment-related necrosis and inclusion of only symptomatic treatment-related necrosis were a significant source of heterogeneity, indicating varying definitions of treatment-related necrosis in the literature need to be unified.

First of all, melanoma sucks.  Melanoma brain mets suck even more.  Yes, treatment necrosis is a real thing.  Yes, it seems to happen in melanoma brain mets more than in brain mets caused by other cancers.  BUT!  What 'cha gonna do?  Not treat and risk more mets and less survival?  Plus, this is a meta-analysis - NOT a real report with full intel on every rattie studied.  There are studies with real ratties that show this:  Immunotherapy with SRS does NOT increase risk of radiation necrosis in melanoma brain mets!!!

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis.  Jessurun, Hulsbergen, Wit, et al.  Neuro Oncol.  August 2021.

Background: Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.

Methods: A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.

Results: After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS and systemic progression-free survival in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS.

Conclusions: Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.

This article is proof that I share all the data that I find - even if it doesn't jive with most of the previous data.  To whit - steroids do NOT diminish response in melanoma patients - and are often in fact,  REQUIRED in order for melanoma patients to continue their life saving treatment!!!  While there may be some truth in the conclusion that folks who have to undergo steroids while on immunotherapy have a decreased response compared to those who do not - I think the REASON for that may not be the one first concluded - ie steroids themselves diminished the response.  RATHER, patients who must use steroids to tolerate immunotherapy often are unable to complete a sufficient quantity of immunotherapy to treat their disease effectively because they could not tolerate it.  The lack of knowledge about the specific patients in this review of 14 other studies demonstrates the severe limitations that this kind of compiled data in meta-analysis contains.  My opinions about the abstract of this study are much like those I discussed in a similar report from September of this year:  What to do about immunotherapy if you - take steroids or infliximab for side effects? Have a pre-existing autoimmune disease?????  If you are interested in the effects of steroids on immunotherapy, it is worth your time.  With repeated thanks to the Edster for help in analysis and provision of the complete article.

The studies in this post were all retrospective meta-analysis studies.  While reports like these can give a useful overview of the state of the science they are decidedly lacking in REASONS for outcomes.  For instance, there are absolutely NO elephants in Chattanooga, TN at this moment.  Further, I just clapped my hands three times.  Are those two things related?  Probably not!!!  Concurrent events and causative events are not the same.  Counting up a tally from some carefully chosen studies can be informative.  But, the results must be considered in the light of how they were attained and with recognition of the limited specifics known about the individual ratties in each of the studies, multiplied by how many studies and ratties there were.

See, Bentie?  All those crazy doctoral level statistic courses at UAB were worth the price of admission and tears of confusion, right????  BAHAHAHA!!!

Hang tough, ratties.  Melanoma isn't easy.  But there is hope. - c

Ipi for melanoma...the data keeps pouring in...and it's pretty good!

Since the FDA in all its wisdom has required ipi failure (given ipi's response rate of 10-20%) as a prerequisite to the use of anti-PD1 drugs (with their 40% response rate), we need all the data we can get on ipi.  Here's some of the latest...and it's not too bad!  Especially when looking at some of the durability numbers.....

Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme.  Chiarion, Pigozzo, Ascierto, et al.  J Exp Clin Cancer Res. April 2014.

Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients.  However, data suggest ipi confers a consistent survival benefit and has a similar safety profile.  Patients older than 70 years with pretreated melanoma were given ipi 3mg/kg every 3 weeks for 4 doses.  Immune related disease control rate (usually referred to as 'clinical benefit') among 188 patients was 38%, with 4 patients with an immune-related complete response, 24 with an immune-related partial response, and 44 with immune-related stable disease.  Median progression-free survival was 4 months and the 1 and 2 year progression free survival rates were 21% and 12% respectively.  Median overall survival rates was 8.9 months.  1 and 2 year overall survival rates were 38% and 22% respectively.  Adverse effects generally resolved within a median of 2 weeks.  Ipi was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated in Italy.

Three year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy, Phase II study.  Di Giamcomo, Ascierto, Queirolo, et al.  Ann Oncol. Dec. 2014.

Ipi and fotemustine (an old time typical chemo) was given to patients with metastatic melanoma, with or without brain mets. 86 patients, including 20 with asymptomatic brain mets,...pre-treated with radiotherapy in 7 subjects, were enrolled.  With a median follow-up of 39.9 months, median OS and 3 year survival rates were 12.9 months and 28.5% for the whole study population, and 12.7 months and 27.8% for patients with brain mets, respectively.  BRAF status did not correlate with outcome.

Survivorship in immune therapy:  assessing chronic immune toxicities, health outcomes, functional status among long-term ipilimumab survivors at a single referral center.  Johnson, Friedman, Berry, et al.  Cancer Immunol Red. Feb. 2015. 

Ipi is associated with long-term survival in more than 20% of advanced melanoma patients and is being evaluated in the adjuvant setting. Vanderbilt researchers looked at 90 patients given ipi for metastatic melanoma or as adjuvant therapy between Jan 2006 and September 2012.  33 patients survived more than 2 years with a median survival of 60.1 months.  Of these, 24 were alive at last follow-up (73%) with 14 patients free of disease (42%).  GI and derm adverse events were frequent but largely transient.  Hypophysitis universally required ongoing corticosteroids although largely remained asymptomatic with appropriate hormone replacement.  Surviving patients had excellent performance status.  Chronic neuro toxicities caused problems for 2 patients who received whole brain radiotherapy more than 5 years before analysis and in one patient with chronic, painful peripheral neuropathy.  No previously undescribed cardiac, pulmonary, gi, hematologic, or neoplastic safety signals were id'd.  Ipi was associated with excellent functional outcomes among long-term survivors.  

Pooled analysis of long-term survival data from phase II and phaseIII trials of ipilimumab in unresectable or metastatic melanoma.  Schadendorf, Hodi, Robert, Weber, Hamid, Chen, Wolchek, et al.  J Clin Oncol.  Feb. 2015.

This primary analysis pooled OS data for 1, 861 patients from 10 prospective and 2 retrospective studies of ipi.  Patients were previously treated (n=1,257) or treatment naive (n=604) and the majority of patients were given ipi 3mg/kg or 10 mg/kg.  We also conducted a secondary analysis of OS data with an additional 2,985 patients from an expanded access program.
Among 1,861 patients, median OS was 11.4 months, which included 254 patients with at least 3 years survival follow-up.  The survival curve began to plateau around year 3, with follow-up of up to 10 years.  3 year survival rates were 22%, 26%, and 20% for: all patients, treatment naive patients, and previously treated patients, respectively.  Including data from the EAP, median OS was 9.5 months, with a plateau at 21% in the survival curve beginning around year 3.  These data add to the evidence supporting the durability of long-term survival in ipi-treated patients with advanced melanoma.

Gauging the long-term benefits of ipilimumab in melanoma.  Ribas, Flaherty. J Clin Oncol.  2015.

....interest in cancer immunotherapy is based on the premise that it could provide responses with long duration that may translate into true cures... ...high-dose IL-2 [was FDA approved] on the basis of a 6% durable complete response rate.  [The usefulness of this] is limited to relatively young patients who could endure the severe physiologic stress induced by this therapy.  By using IL-2 in asymptomatic patients with limited disease burden of metastatic disease, the fraction of responding patients can be increased but not the absolute number of long-term survivors.

Anticytotoxic T-lymphocyte-associated antigen 4 antibody (ipilimumab) .... studies [have] response rates...in the range of 10-15% and are typically manifested only after 3 months or more...from initiation of therapy.  The progression free and overall survival curves separated after several months and stayed separated by approximately 10% beyond 2 years.  In [the Schadendorf article noted above] the authors document a plateau in the survival curve at 21% starting at 3 years and maintained thereafter, suggesting that patients...treated with ipi who survive to 3 years are highly likely to have a good long-term outcome.

While pooled analysis of large numbers of patients treated with a single agent...[is helpful]...inclusion of patients on uncontrolled trials loses benefit...Schadendorf et al do not provide info on long-term outcomes in control arms...  Patients who participated [in these trials were] unlikely to have had access to new...targeted and second-generation immunologic therapies.  Therefore, it is reasonable to consider that [outcomes of control arm patients were the same] as cohorts from the preceding era.  [A review of stage IIIc/IV overall survival Kaplan-Meier curves in 2009] suggest that these curves may have a plateau in patients not treated with ipi, but [it occurs beyond 8 years].  The updated data...provides survival rates at 19%, 13%, and 9% at 3, 5, and 10 years, respectively for stage IV melanoma.  Therefore, [this suggests] the long-term benefit of ipi at 3 years may not be too different from what could be expected, but...it improves by 10% over the [treatments offered at the time] these studies were conducted. Notably, this difference aligns with the percentage of patients who achieve objective responses.

....It is notoriously difficult to assess response rate and progression-free survival in patients treated with ipi because there are well-documented instances of patients who meet the criteria for disease progression early [on] but...go on to have a durable tumor response. ...it would have been useful to query this large database of patients...to determine how many of the patients in the 21% plateau after 3 years were disease-free or stably maintaining response at that time.  This would represent firmer evidence of the long-term benefits of ipi, even if it did overestimate the small percentage of patients who may have benefited from subsequent therapy.

...despite the generalized belief that ipi is highly toxic, the great majority of patients have no serious adverse effects with [ipi]... However, 10-15% had grade 3/4 adverse effects that may require hospitalization to manage, leading to a 2.1% of deaths as a result of toxicity.

Since 2011...5 additional agents have been approved in the US...for patients with advanced melanoma...BRAF-mutated patients can derive benefit from the use of BRAF and MEK inhibitors.  Because of the frequent development of acquired resistance within months and relatively shorter follow-up available for these agents compared to ipi, it is less clear that BRAF inhibitor based therapies will have a tail in the survival curve that can be maintained for years. Though on the basis of a small fraction of patients now beyond 3 years from the initiation of single-agent BRAF inhibitors and improved...outcomes with combined BRAF/MEK, it is certainly possible...  Anti-PD-1 antibodies [have proven] to improve overall survival compared to dacarbazine and...[extend responses in patients] previously progressed on ipi...[and the fact that] anti-PD-1 and anti-PD-L1...are being tested in...combination therapies...[their] impact on outcomes may be far greater.

Despite...exciting developments...we are still far from the goal of benefiting most patients over the long term. ...  Ipi was the first agent to demonstrate overall survival, a benefit that we now know can be sustained even when measured in years.  We look forward to...continuing improvement in long-term outcomes of patients with advanced melanoma.

Thought it was a little interesting that 2 melanoma big dogs NOT included in the pooled analysis by Schadendorf put together a response gunning for the ones who collected and put out the data...though they make a couple of reasonable points.  It seems we've finally discovered most all the side effects ipi can cause...and pretty good ways of dealing with them.  Thanks, ratties!!!  Older patients can tolerate ipi and attain benefit.  These articles reiterate the ability of some patients to attain durable responses to immunotherapy generally, and ipi specifically.  Remember the data already posted here:  Review of immunotherapy and durable benefit in melanoma!!!  As noted we know there have been complete and durable responses to IL2.  It is looking as though ipi can do the same, for some.  And while similar time frames have not passed since the utilization of anti-PD1 products, durable effects look possible there as well.  It will be interesting to see if there is a difference in the duration of response among immunotherapies.  Will durable response be proportional to the percentage of initial responses across all drugs?  Time will tell, ratties.  Time will tell.  - c

Melanoma patients want to know! What do I choose? Targeted or immunotherapy? What happens then?

We melanoma patients all want to know!  Should I opt for targeted or immunotherapy?  What happens to me during treatment?  What happens after?  While there are no absolutes, here are some reports that attempt to provide a few answers.

TARGETED THERAPY:

The first addresses outcomes in Stage III/IV patients treated with the targeted therapy combo, Dabrafenib plus trametinib:

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.  Robert, Grob, Stroyakovskiy, et al.  N Engl J Med. 2019 Jun 4. 

Patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival and overall survival when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients remain undefined. To determine 5-year survival rates and clinical characteristics of the patients with durable benefit, we sought to review long-term data from randomized trials of combination therapy with BRAF and MEK inhibitors.

We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.

A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (17 to 24) at 4 years and 19% (15 to 22) at 5 years. The overall survival rates were 37% (33 to 42) at 4 years and 34% (30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (62 to 79) at 5 years.

First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Here are some links to earlier posts on the subject:
2014:  BRAF inhibitors for melanoma: Dabrafenib, Vemurafenib, Dabrafenib/trametinib combo. Answers!!!!!

2015:  BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?

2016:  Factors predictive of response, progression and OS with dabrafenib and trametinib

Also from 2016:  ASCO 2016 - Cobimetinib and Vermurafenib - coBRIM study

IMMUNOTHERAPY:

For comparison to the targeted therapy outcomes above, here's a report on immunotherapy from the dark ages of 2014:  Review of immunotherapy and durable benefit in melanoma!!!

This report documents the 4 year outcomes for ipi/nivo vs nivo alone for melanoma patients from December 2018:  CheckMate 067 - 4 year outcomes for nivo/ipi combo vs nivo alone in melanoma patients 

2019:  IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma

LOS DOS:

Here is a report from this year (with many links within) on combining targeted and immunotherapy:
Treating melanoma by COMBINING targeted therapy AND immunotherapy!!

HOW RATTIES REPORT THEY WERE AFFECTED BY EITHER TREATMENT:

Here are the results of a survey of 105 melanoma patients treated with either immunotherapy or BRAF/MEK who had an "objective response or stable disease" and were asked about the impact of said treatment on their lives:

The survivorship experience for patients with metastatic melanoma on immune checkpoint and BRAF-MEK inhibitors.  Lai-Kwaon, Khoo,Lo, et al.  J Cancer Surviv. 2019 Jun 4. 

Immune checkpoint inhibitors (ICI) and BRAF and MEK inhibitors (BMi) have improved survival in metastatic melanoma (MM). However, the experience of long-term responders remains undescribed. This study characterised survivorship issues faced by long-term responders to ICI or BMi.

Patients with MM, aged greater than/equal to 18 years old, greater than/= to 6 months post-ICI or BMi initiation with an objective response or stable disease. A 72-question survey assessed physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports.

One hundred and five of 120 (88%) patients completed the survey (ICI 69/BMI 36). For the ICI cohort, 39 (57%) were receiving ongoing treatment, 17 ceased due to toxicity and 13 due to a sustained response. For the BMi cohort, 31 (85%) were receiving ongoing treatment, 4 ceased due to toxicity and 1 due to a sustained complete response. At data cut-off on 18 December 2018, median PFS (range) was 2.5 years (1.3-8.5) for ICI and 3.1 years (0.6-7.3) for BMi. Long-term toxicities included dry/itchy skin (ICI 51, 74%/ BMi 25, 69%), arthralgias (ICI 30, 58%/ BMi 23, 64%) and fatigue (ICI 62, 90%/ BMi 33, 92%). Psychological morbidity was common, including anxiety awaiting results (ICI 50, 72%/ BMi 29, 81%), fear of melanoma recurring or progressing (ICI 56, 81%/ BMi 31, 86%) or death (ICI 44, 64%/ BMi 26, 72%).

MM survivors experience chronic treatment toxicities and frequently report psychological concerns.  Survivors may benefit from discussions regarding long-term toxicities and tailored psychological supports

WHAT TREATMENT TO CHOOSE:

If you are lucky enough to be a BRAF positive melanoma patient (about 1/2 of us) you have the option of targeted therapy or immunotherapy.  But picking which therapy to utilize is really tough for melanoma patients.

Here is some advice from some Melanoma Big Dogs in 2015:  Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Some advice on sequencing from 2018:  ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

This post includes a report on what ratties have to consider re immunotherapy:  Balancing the Hype with Reality: What Do Patients with Advanced Melanoma Consider When Making the Decision to Have Immunotherapy?

Here is advice and thoughts from Weber and Allison this year:  Progress in the Treatment of Advanced Melanoma: Where We Are Now, and Why the Future Is So Promising 

Melanoma gives us no easy answers. Yet, we continue to learn more about the disease and more about how to survive it!!  Hang tough, ratties.  Hang tough. - c