Results for Stage III melanoma peeps who recurred after adjuvant targeted therapy

The positive benefits noted in yesterday's update on adjuvant therapy for Stage III melanoma - utilizing immuotherapy as well as targeted therapy in the form of BRAF/MEK inhibitor combos - have been practically miraculous in preventing many melanoma patients from advancing to Stage IV and even death.  Despite the benefits, there are still those whose melanoma does recurr.  This report addresses outcomes of melanoma peeps who advanced after taking BRAF/MEKi as adjuvant targeted therapy.

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.

So - in folks who were given targeted therapy as adjuvant treatment for their Stage III melanoma - 22% recurred.  Recognizing the small numbers in this break down - responses to treatment that they were given at that relapse point follows:

anti-PD-1 garnered a 63% response rate

ipi/nivo  = 62% RR

targeted therapy rechallenge = 25% RR

ipi as a single agent = 10% RR

33% of the relapsed patient died of melanoma.  

The two year overall survival for those treated with anti-PD-1 = 84%, ipi/nivo = 92%, targeted therapy = 49%, ipi alone = 45%.

Pretty clear to me.  If you relapse, go for the ipi/nivo combo.  Not that we didn't already know that! - c

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

ASCO 2021 - NEOadjuvant treatments - immunotherapy vs targeted and nivo plus relatlimab (anti-LAG3)

Having covered adjuvant therapy yesterday, today I turn to NEOadjuvant treatments.  In 2018 I wrote -

"Adjuvant therapy, is when a treatment is given AFTER signs of obvious disease have been removed, usually with surgery.  And we have very good data that adjuvant treatments, both with targeted and immunotherapy, work in melanoma to prevent progression in many of those patients.  After all, that is what the NED Stage IV ratties in my nivo trial proved from 2010 - 2013!!!!  NEO-adjuvant therapy, is when a treatment is given BEFORE melanoma has been removed. "

Here are a zillion Neoadjuvant reports.  Now, there are these:

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

Hmmm....  While targeted therapy is almost magical in BRAF positive melanoma peeps for melting away tumors and those responses have proven at times to be durable, that durability can be fickle.  This report (while not necessarily about neoadjuvant administration) is similarly illuminating:

First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: a real-world analysis.  Pavlick, Zhao, Lee, et al.  Future Oncol. Feb 2021.

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. 

Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. 

Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Then there's this, from ASCO....

Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.  Amaria, Postow, Tetzlaff, et al.  ASCO 2021

Background:  Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen.

Methods:  We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses.

Results:  A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( less than10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (greater than/= to 50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1-year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts. There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment.

Conclusions:  Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Perhaps neoadjuvant care will become the way of the future.  Thanks ratties.

best - 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

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

What the Melanoma Big Dogs are working on in 2017!!!

Immunotherapy!  Targeted therapy!  TIL!  CARs!  Intratumoral therapies!  Here we go!!!!

Novel Checkpoints and Cosignaling Molecules in Cancer Immunotherapy.  Giuroiu, Weber. Cancer J. 2017 Jan/Feb.

The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.

Novel Targeted Therapies for Metastatic Melanoma.  Iams, Sosman, Chandra.  Cancer J.  2017 Jan/Feb.

Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.

Adoptive Cell Therapy for Metastatic Melanoma.  Merhavi-Shoham, Itzhaki, Markel, et al. Cancer J. 2017 Jan/Feb.  

Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.  Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.

Intratumoral Approaches for the Treatment of Melanoma.  Bommareddy, Silk, Kaufman.  Cancer J. 2017 Jan/Feb.

There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.

Sounds good!  I like a multi-faceted approach.  Now!  Let's make it so!  Double time!!!! - c

Mo' Money....Mo' Bettah....Melanoma's Therapies (B-RAF, MEK, ipi, anti-PD1) and Their Cost and Availability

 Melanoma:  From Impossible to Treat to Poster Child for Targeted Therapies

AJMC.com  Published online:  October 23, 2013. Produced by Nicole Beagin.  In September, Mark Fendrick, MD, co-editor-in-chief of The American Journal Of Managed Care, led a discussion of experts about advances in the treatment of metastatic melanoma, which examined both the promise offered by new therapies and the issues surrounding cost, payment, and delivery.

Jeffrey Weber, MD, PhD, Moffitt Cancer Center, Tampa, Florida
Antonio Ribas, MD, PhD, Johnson Comprehensive Cancer Center, Los Angeles, CA
Jennifer Malin, MD, PhD, Manager and medical director of Oncology, Well-Point


(Quoted, but edited, by me!)

Weber:  Melanoma has gone from being regarded by many oncologists as an impossible to treat and hopeless malignancy to a disease...that is the poster child for new targeted and immunologic therapies...  That being said, there are major unmet needs in our field because...we still have a pretty narrow repertoire of drugs...[with] pretty serious toxicities, and we are a long way from curing a significant proportion of our patients.

Ribas:  Having seen this remarkable change in a short period of time...is a remarkable benefit to patients...but we are still faced...with many patients who are either not responding, responding for a short time and progressing, or having side effects.

Patients who were treated 2-5 years ago [with immunotherapies]...continue to respond and patients with T24 blocking antibodies, the longest...for 12 years...but we need to make it more efficient for everyone... The B-RAF inhibitors, vemurafenib...then the B-RAF that is called dabrafenib, which is a very recent approval. ....when we select patients with the B-RAF mutation, which is around 50% of melanomas, we are close to guaranteed to have some...patient benefit.

Over 80% of patients have some shrinkage of disease....but the majority - not all of them, but the majority - will progress...and the median duration of response is around 6-7 months, although there are some patients from the Phase 1 trial of vemurafenib who are now going beyond 4 years and are continuing to respond, but that is the minority.

These are targeted therapies that block the driver oncogene which leads to cell cycle arrest and response in the majority of patients... Around two-thirds of the progression mechanisms go through reactivation of the same pathway and a signal through an immediate downstream, a factor which is called MEK, which is a kinase under B-RAF... Then we have the MEK inhibitor trametinib that has been approved to use as a single agent in B-RAF mutant melanoma. But that is not where we are going to be using it because by itself, trametinib is less effective...and more toxic, so it is probably one of the only approvals by the FDA that we know from the start that we are not going to be using in the way the current label is written.  You can use it in combination with the B-RAF inhibitor and you can use it in patients who progress on the B-RAF inhibitor because there is actually no activity there. But there is a lot of activity when you put it together, ...it is one of the examples that I...know in medicine where you have 2 effective drugs, that you put them together and they are not only more effective but they are less toxic...which should impact on the cost-benefit ratio because even though...2 drugs are more expensive than 1, the side effects are decreased and the benefits of the drugs is markedly improved...  I think most of us would agree that this will be a drug that is cost-effective.

Weber:  I think everyone agrees...the expectation certainly is that the Phase II study results...with those 2 drugs are going to show serious benefit and major prolongation of survival, but again we don't have the data and they won't be out probably for another year...

Dabrafenib, trametinib, vemurafenib, and a lot of these drugs are...oral, you take them once or twice a day.  Whereas, virtually all of the immunologic agents that are in development are given intravenously.  Ipilimumab, for example is given every 3 weeks and to be honest, ...we haven't settled on the optimal dose.  There is a big trial of the standard approved dose of the 3mg/kg vs 10. Ten may be better...what implications [might this have] for the cost, because it is not a cheap drug?  If it turns out that the FDA will now approve 10 instead of 3 are they going to triple the price? 

I should add...that the excitement at ASCO...was because there was a combination trial of one of the PD-1 drugs, nivolumab, with the CTLA-4 blocking drug, ipilimumab...where you see in a graph the bars up or down indicating shrinkage or growth, it looked like it was a targeted drug, it was so good.  Toxicity, on the other hand, was not so trivial...Now, not only are we thinking about how do you combine the targeted drug, now you think about how to combine the immunologic drugs, so that is 5 more years of work at least, to work that out, and that will be impressive.

...The key question....is, what is the best sequence of a targeted drug and an immunologic drug?...and it is not just a (single) drug.  It is what combination of targeted drugs and what combination of immunologic drugs, what should be the proper sequence? ...  That is a major unanswered question...

Fendrick:  What can you say about a standard of care, or a lack thereof, in metastatic melanoma...?

Weber:  ...There are the NCCN guidelines...

Malin:  ...before this call, I checked how...NCCN was recommending use of the 2 new B-RAF inhibitors...FDA approved in May, and NCCN hasn't updated its guideline...there is a little bit of lag...

Weber:  I think practices will vastly vary at an academic center like mine where you have 25 melanoma trials.  At UCLA I'm sure it's the same. It is going to be a little different than if you are in Albuquerque, New Mexico, at a good private practice with 5 other oncologists.  It is going to be very, very different as to what you can offer the patient.

Malin:  This brings up the issue of access.  These therapies are very exciting and the benefits that some patients have are really tremendous.  It is exciting to see someone go into a complete remission following 4 treatments with ipilimumab and stay in remission...for a year...  But, the wholesale cost of just the drug...is $120,000... Most small, independent practices (are) concerned about...taking on the financial risk of a drug that is that expensive without knowing whether the patient's insurance is going to cover it, whether the patient can afford whatever their copay might be.  If they have a 10% copay, that is $12,000 right there, so the cost of these drugs, at least in combining them, is going to bring new questions regarding access for people...

People can have long remissions...and some...benefit from retreatments...Does it mean someone is going to need to repeat treatment every couple of years?  ....When someone gets treated in the outpatient setting, usually the cost is double or triple, so just for ipilimumab, we are looking at a cost to the patient's payer....of $240,000 - $360,000...

Weber:  I think this is something that is at the top of everybody's consciousness...just about every professional group is going to emphasize the idea of trying to have biomarkers to select the right patients.  You can't just treat 100 patients and benefit  8 of them.  It is not going to happen in the future, the FDA has made it very clear how important they think biomarkers are.  ...  I predict that you are not going to get the (Oncologic Drugs Advisory Committee) and the FDA to approve drugs or push forward unless there is clear significant value; a 5 week prolongation of survival is not going to cut it in the next 10-20 years, not when the drug costs $120,000 for the wholesale price....

I suspect if you graph the price of current drugs over the last 20 years, you would see at least a linear increase with a doubling every 5 years and eventually what is it going to be, $300, $400, $500 or $600,000 to treat someone?  That is not practical....I'm not an economist, but I find it hard to believe that for [drug companies] to stay in business they need to charge $200,000 a year for dabrafenib and trametinib.

Ribas:  ...In places like the county hospital, it is hard to find any patient who has been on ipilimumab because it has not been approved for administration even though it is an FDA-approved drug and there are randomized trials that demonstrated approval and survival.  Those randomized trials showed improvement that is based on a small percentage of patients, around 10-15%...  We don't have a marker and possibly we will not have a marker, because it is an agent that is activating the immune system very far away from the tumor, so there are several thousand genes that are involved... It is unrealistic to think that there is going to be one biomarker that says this works or doesn't work in patients... We have dedicated over 5 years of research...and we are back to where we were...we give it to everyone because we don't want to miss those patients that can go on to have decades worth of life...free of metastatic melanoma. That is something I have trouble putting a price on, but the worst case is when we don't even have the chance to give it, and that is what is happening with the price of ipilimumab being so high....it is not only the wholesale price, it is the total bill that I see, and I am outraged every time a patient comes and says, this is what your clinic charged my insurance to give 4 doses of ipi.

Weber:  We have...the occasional referral...a charity patient who has either Medicaid from another part of the state, like someone from Miami, and the University of Miami will not treat them....and Moffitt will eat the cost of some percentage [for] those patients, or BMS will make the drug essentially free... A lot of companies have these programs where if you can't get anybody to pay for it, they will give you the drug for free...so eventually it happens, but it can be a huge hassle...

Ribas:  There are patients who don't get to our clinics.....when I talk to doctors [in county hospitals], they tell me that it is very seldom [they] are able to give ipi to a patient because of the cost.

Weber:  I can see that being an issue for the poorest patients....this was a huge topic...at [an] Advisory Board I recently attended at ASCO....the question was, what if the price were $300,000 or $400,000 to get treated with some regimen lasting a year, would that be realistic? 

Fendrick:  ...I want to ask one thing that comes up a lot...what [do you think] about the idea of a situation where patients would get better coverage...if they went to Centers of Excellence for specific types of cancers?  Do you think it would be a good idea or a bad idea for particularly rare cancers to follow a model that we've had in place for transplants for decades?

Weber:  ...I wouldn't have a problem with seeing more patients and bring more business to places that excel at what they do.  To be honest, if I had metastatic melanoma...I would probably go to the big center, no question...

Ribas:  I would agree.  Sometimes we see patients on a second opinion, coming from the community. The data the community doctor has are the same as we have, the drugs are the same, but the usage may be wrong because they are not thinking about melanoma every day.  My thinking is that regardless of the cost, if we treat, it is cheaper than if we don't treat.  I mean treat...a medical condition and the medical condition improves...

...With all of this discussion I wanted to bring up one thing...I know is going to change even further...the PD-1 and PDL-1 antibodies are going to change...the treatment of melanoma again within the next 2 years...   If we look at the data right now, [it] suggests that we will get a significant fraction of patients with metastatic melanoma to have durable responses with therapies that are basically non-toxic or [with] serious side effects that need [intervention] and will leave the patient in the hospital....There are 7 of those PD-1, PDL-1 antibodies in the clinic [under] development right now....  3 of them...positioned to have licensing potential in melanoma and maybe many other cancers.

Malin:  ...Clearly the cost of these new drugs is a challenge...in just a few years...the cost will be half of the median family income.  So, clearly, it is not conceivable that costs can continue to go up...  The good news is we think that 30% of what we spend on health care is waste, so if we can figure out how to stop doing the things that don't help people, we can insure that we can continue to make sure to make new therapies that are highly innovative available to people, but figuring out where that waste is, and getting people to stop doing things that don't provide value is challenging...

...You look at the fact that there are 3 aromatase inhibitors that have gone generic, in 2 of them the price dropped to $20 per month [yet] one of them is still $300 per month, but most oncologists don't even realize there is a difference in price, that either the patient...or the employer is paying...a difference in cost for a very active therapy that is equally effective...

Fendrick:  ...on the issue of clinical nuance, [it] is critically important to...identify...services that differ in the value that they create and the current benefit designs that patients see.  They pay the same out of pocket for lifesaving drugs as they do for drugs that I wouldn't give my dog... [We need to make] those services on which the evidence is strong accessible to patients and profitable to providers, and hopefully turn the corner and no longer make it profitable or easily accessible to patients,...services for which the evidence is weak, or in some cases, where there is true evidence of harm.

Audio link to discussion between Weber, Ribas, and Malin

Money, money, money!  My current working theme, huh?  Makes me tired.   - c

BRAFi as neoadjuvant - Now we're talk'n!!!

BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma:  a potential neoadjuvant strategy.  Sloot, Zager, Kedchadkar...Weber, Sondak, Gibney.  Melanoma Res. 2/2016.

"Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months. Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival."

Adjuvant treatment provides positive benefits!  Here's more adjuvant trial results:  From my NED nivo/Opdivo trial as well as one with ipi!

Here are a few amazing quotes:  

 From the Nivo trial (published Dec 2014!!!) ~ "Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up."

And this from the ipi ~ "Adjuvant ipi significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma."

What are we waiting on???  Come on researchers!  FDA?!!!  Drug companies????!!!!  Hang in there, Ratties.  You rock! - c 

Old Stuff from the newest ASCO - NLR association with response and survival in advanced melanoma, SRS with targeted or immunotherapy for melanoma brain mets, COX2 inhibitors (NSAID's) and improved response to anti-PD-1 therapy in melanoma

Yeah.  Most of this jazz, is NOT news.

I have been yelling about NLR and its relationship to response in melanoma patients FOREVER!!!  Here are only a million prior reports:  Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...) Now, this:

Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.  2019 ASCO.  Hemadri, Lin, Lin, et al.   J Clin Oncol 37, 2019 (suppl; abstr 9571)

Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR greater than/= to 2 to NLR greater than/= to 5) with NLR greater than/= to 5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR greater than/= to 1 (ORR 64%), NLR greater than/ = to 2 (ORR 61%), NLR greater than/= to 3 (ORR 52%), NLR greater than/= to 4 (ORR 43%), NLR greater than/ = to 5 (ORR 43%). Elevated NLR was associated with poorer PFS (median 21.5 mos vs. 5.2 mos) and OS (median 35.4 mos vs. 10.6 mos). In a multivariate model, elevated NLR  was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR greater than/= to 3 to NLR greater than/= to 5), although NLR greater than/+ to 5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.

Once again, elevated NLR was associated with worse outcomes across the board, including PFS, OS, and ORR - in melanoma patients treated with immunotherapy - even when separated from ulceration, patient status, and elevated LDH.  This is a cheap and easy test that might aid patients and docs in their selection of treatment options!  

When dealing with brain mets, we have learned that when systemic therapy (targeted or immunotherapy) is combined with radiation (SRS) the response is better than with either treatment option alone.  Here are a zillion reports: Radiation combined with systemic therapy in melanoma treatment - 2015 forward  Now, this:

First-line stereotactic radiosurgery combined with systemic targeted and immune checkpoint inhibitor therapy in melanoma patients with newly diagnosed brain metastases.  2019 ASCO.  Heumann, Wu, Ye, ..., Weber, Pavlick, et al.  J Clin Oncol 37, 2019 (suppl; abstr e13577)

Background: Of solid tumors, melanoma has the highest propensity for central nervous system spread with historic median survivals of 5-8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. Results: Among 123 newly diagnosed MBM patients:  65% were male, 24% were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis. Locally, 73% received SRS as first-line treatment.Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With median follow up of 11 months (mo), total cohort median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS) when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS) when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither systemic therapy. SRS and BRAF targeted therapy were associated with improved OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant prognosticators for OS.At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. Conclusions: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line brain radiosurgery combined with BRAF targeted therapies and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM. 

Wait for it...  Folks with melanoma brain mets did better when they were treated with targeted therapy or immunotherapy combined with radiotherapy, than with either of the treatments as single agents!

COX inhibitors, your basic NSAID's ~ think aspirin or advil ~ have long been a topic of discussion as they relate to responses from immunotherapy.  In this post from 2015, An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!, I noted, "...here's the deal:   To back up a step -  NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2).  Blocking those enzymes, blocks the production of prostaglandins.  Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors.  Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab).  Researchers note:

• Prostaglandins in tumors interferes with immune cell function.
• Blocking cyclooxygenase in tumors restores immune cell function.
• The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
• This mechanism is shared by mouse and human tumor systems.

My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!"

Then there was some back and forth in this composite of many posts and articles in 2018:  Aspirin, NSAID's, and melanoma  Now, there's this:

Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.  2019 ASCO.  Ferreira, Krybaeva, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14114)

Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a-/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups. Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.

Well, okie dokie then!  Not sure just taking anti-PD-1 with an aspirin is going to work for folks who failed anti-PD-1 in the first place, especially since I think it would be a hard task to find a melanoma peep on anti-PD-1 who hasn't had to dip into the NSAID bottle of choice in order to survive the assorted aches and pains that come with that therapy!  But what do I know?????

There is beauty still...

... even if we come through the storm looking something like a Dr. Seuss flower!  - c