Circulating tumor DNA in melanoma - Yep. AGAIN!!!

If you've hung around this space for half a minute, you know that I've long been yelling about "liquid assays" (including ctDNA) that can diagnose, predict, and evaluate progression or response in melanoma patients.  Perhaps more importantly, despite the clear benefit of these tests, they remain pretty much unavailable to most melanoma patients.  Here are only a zillion reports: Melanoma and circulating tumor DNA

Now there are these:

Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA.  Tan, Sandhu, Lee, et al.  Ann Oncol.  2019 May 30.

The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma.

Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n=29).

ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative time point relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline and postoperatively. ctDNA detection at baseline and postoperatively was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status.  Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.

Circulating tumor cells and early relapse in node-positive melanoma.  Lucci, Hall, Patel, et al.  Clin Cancer Res. 2020 Feb 3. There is a need for sensitive, reproducible biomarkers for stage III melanoma patients to guide clinical decision making. Circulating tumor cells (CTCs) can be detected in melanoma patients; however, there is limited data regarding their significance in stage III disease. The aim of this study was to determine if CTCs are associated with early relapse in stage III melanoma. We prospectively assessed CTCs at first presentation in clinic (baseline) for 243 stage III melanoma patients. CTCs were measured using the CellSearch System. Relapse-free survival (RFS) was compared between patients with one or more baseline CTC versus those with no CTCs. Log-rank test and Cox regression analysis were applied to establish associations of CTCs with RFS. At least one baseline CTC was identified in 90/243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. CTC detection was not associated with sub stage, or primary tumor characteristics. Multivariable analysis demonstrated that the detection of greater than/= to 1 baseline CTC was significantly associated with decreased 6 month RFS and 54 month RFS. Greater than/= to 1 CTC was independently associated with melanoma relapse, suggesting that CTC assessment may be useful to identify patients at risk for relapse who could derive benefit from adjuvant therapy.

Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.  Khola, Lorigan, Dive, et al.  Ann Oncol.  2019 Dec 4.

Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.

Despite very convincing data and a desperate need in the patient population these tests remain unavailable to the average patient.  Will the desire of firms to make a buck, make a difference?

This report from CNBC tech, 2/2020 :  These start-ups are racing to help doctors detect cancer early with a simple blood test

Which states, in part:  "Getting a blood test to screen for cancer in the earliest stages might seem like a pipe dream. But a group of biotech entrepreneurs say they’re close to making it a reality. If Gabriel Otte’s start-up, Freenome, is successful, millions of people could get a blood test to screen for early-stage colorectal cancer. Freenome looks for two major biomarkers in the blood. It’s simultaneously hunting for tiny fragments of DNA that are shed into the bloodstream from a tumor, as well as early signals that the patient’s immune system is starting to respond.  The medical industry has known for years that that blood-based “liquid biopsies” can find signatures of cancer. But the tests on the market today focus on monitoring the progression of the disease once a patient has been diagnosed with cancer, including how it’s responding to treatment.  The next generation of companies want to detect cancer while it’s early and often easier to treat."

We know these tests work.  We know they could provide a great deal of helpful information for melanoma patients facing hard choices.  It is past time that they be made available.  For what it's worth. ~ c

Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice

The length of time melanoma patients should remain on immunotherapy and what happens to them after they come off has been a huge point of interest for researchers and patients since these drugs were first determined to be an effective treatment for melanoma.  In my Phase 1 nivolumab trial, begun in 2010, unless we progressed or developed untenable side effects, we were all allowed 2 1/2 years of therapy.  Period.  The end.  I was happy to be off it at the end.  However, that was certainly colored by the fact that I was NED.  Had I had lesions - stable or otherwise - I don't know that I would have been so at ease.  No matter, by the time I was reaching the end of my participation in 2013, Dr. Weber, lead investigator for the trial, was already postulating that we had been given the medication "too long".  His thinking ran along the lines that only a "certain amount" of the medication would do a patient any good and to give the medication longer would only increase the risk of side effects.  Still, determining the "certain amount" that does a body good has been hard to define.  In fact, I posted this in 2018:  Awesome news regarding how and when to stop immunotherapy in melanoma patients.  Now, seven years later, there is this...

When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?  Banks and Sullivan.  Am J Clin Dermatol.  2020 Feb 5.

Systemic therapy for metastatic melanoma has been revolutionized over the past decade with the development of highly effective immune checkpoint inhibition, specifically anti-Programmed Death 1 receptor (PD-1) therapy. However, even though one-third of patients will have durable response to single-agent or combination therapy, the optimal duration of therapy is unknown. Identifying the optimal duration of therapy is important, as exposure to anti-PD-1 therapy increases the risk of developing immune-mediated toxicities that can have significant morbidity and are, at times, fatal. It has long been understood that patients with complete responses to high-dose interleukin-2 and ipilimumab typically maintain their responses after a brief treatment course; thus, it is important to better understand the data to help understand the optimal management of melanoma patients treated with anti-PD-1 therapy. The clinical data with anti-PD-1-based therapy and published data on the duration of therapy suggest that patients may not require a full 2 years of anti-PD-1 therapy and that the risk of toxicity may be mitigated by further understanding the mechanisms and kinetics of response to therapy. Although novel markers to help guide therapeutic decision making are under investigation, there is an ongoing need to improve our tools to monitor response to therapy and disease activity.

{Note:  Those "novel markers"  they mention refer to the various blood tests that allow us a peek into the body's response that melanoma peeps STILL aren't routinely allowed to avail ourselves of though researchers keep mentioning it and I keep YELLING about it!!!  As in the zillions of reports here on bio-markers generally:  Biomarkers  And these on circulating DNA in particular:  ctDNA }

Apart from not being very clear about how long melanoma patents really should continue immunotherapy for the best result, there is the issue of what happens to patients when they do stop.  Is the outcome different for those who must stop due to side effects as opposed to those who complete the current recommended doses?  Well...  I have reported this data over and over and over ~

This from 2016:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!

And again in 2017:  40% of melanoma patients stop ipi/nivo due to side effects...BUT...efficacy is about the same!!!

Per this data, the difference made in response in those who "completed" the proposed therapy vs those who do not due to side effects is - NOT MUCH!!!!

I've also written posts that cover what happens to folks who choose to end their immunotherapy for whatever reason.  This link to a post in 2019 includes links to many others:  Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment

Now, there's this:

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity: clinical outcomes in advanced melanoma.  Jansen, Rozeman, Mason, et al.  Ann Oncol.  2019 Jul 30.

Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established.  This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia.

Median time on treatment was 12 months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18 months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12 months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response.

In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for greater of equal to 6 months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients.

For what it's worth - again. ~ c

The ipi/nivo combo - responses in melanoma patients ~

As with most things in melanoma land, this is a topic I've covered before!  Here are lots of reports from recent years that cover response rates and outcomes for melanoma patients treated with the ipi/nivo combo:  Results of the ipi/nivo combo in melanoma patients

Now there is a report breaking down those responses:

Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy.  Pires da Silva, Lo, Quek, et al. Cancer. 2019 Oct 4.  Patients with metastatic melanoma have variable responses to combination ipilimumab and nivolumab. The objectives of this study were to examine the patterns of response and survival in patients treated with combination ipilimumab and anti-PD-1 therapy (IPI + PD1) and to explore the nature of pseudoprogression and acquired resistance. Patients with metastatic melanoma who received treatment with first-line IPI + PD1 had all metastases ≥5 mm measured on computed tomography/magnetic resonance imaging studies. The lesional response rate (LRR) and the overall response rate (ORR) were determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 140 patients who had 833 metastases were studied. The ORR and the overall complete response (CR) rate decreased as tumor burden or the number of metastases increased. Metastases that had a CR (49%) were smaller than metastases without a CR (median, 13 vs 17 mm). Soft-tissue and lung metastases had the highest LRR (79% and 77%, respectively), whereas liver metastases had the lowest (46%). In multivariate analysis, patients with lung metastases had superior ORR and progression-free survival, whereas those with liver metastases had inferior ORR, progression-free survival, and overall survival. Pseudoprogression occurred in one-third of patients who had progressive disease as their best response, with an overall survival that was comparable to that of patients without disease progression. Acquired resistance occurred in 12% of responders after a median of 9.6 months, with an overall survival rate of 83% at 1 year from progression. Metastases in different anatomical locations display distinct response patterns and also are associated with overall response and survival with combination immunotherapy. Specific sites of disease may hold unique mechanisms of resistance and should allow for more personalized treatment.

This report looked at 140 patients as well as their combined 833 lesions.  Smaller tumors responded better than big ones.  Lung and soft tissue tumors responded better than tumors in the liver, leading to greater overall response rates, progression free survival, as well as overall survival in patients with lung mets versus those with liver tumors.  Pseudoprogression is real, but only occurs in 1/3 of patients with progressive disease.  And finally, about 12% of responders stopped responding at about 9-10 months.

None of this is real news.  We know that patients with the lowest disease burden respond best to immuotherapy.  Sadly, we have also known for some time that folks with liver mets have a very tough go of it.  These reports go back to 2015:  Liver mets and response to immunotherapy  While researchers have long noted and worked to address resistance in targeted therapy, it is not often discussed in regard to immunotherapy.  But, this report does note that 12% of melanoma peeps on ipi/nivo may at first respond but stop doing so some months later.

We've come a long way, but there is still much we need to learn to improve the plight of melanoma patients.  For what it's worth. - c

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

Sew Chaotically! ~ Everyone needs a unicorn in their pocket! Purl Soho's City Gym Shorts

When I saw this unicorn flannel at JoAnn's I knew I had to get a bit of it for some pajama bottoms for Roo as an ode to the little girl I watched grow and who still hangs out within the awesome woman she has become!!  I used the FREE Purl Soho City Gym Shorts pattern and made the 38-40 inch size adding an inch of length as shown in the pattern piece below.  I did stitch above the elastic for a cute little paper-bag look not included in the pattern and added a back pocket just for fun.

Rather than a fiddly approach of folding bias tape that is meant to be visible over your edge and then trying to catch both edges in one seam - here's my method.

Stitch the right side of the unfolded tape even with the edge of the WRONG side of the piece you are binding along the tape's crease. 

Then press the tape around the piece to the RIGHT side and stitch that edge in place.  As you can see with close inspection of the inside leg visible in the pic Roo is holding on the table top, that line of stitching is visible on the inside - but, who's looking at that?  Besides, it looks neat anyway!  Using an edge stitching foot makes this even easier and the stitching that IS visible on the outside is PERFECT!!!

She loved them!  I loved the pattern as it goes together well and in a different fabric would make a great running short!  Check it out!  It's FREE!!!

Though on a day like today...

...running in shorts seems a little far away!!!  Sew Chaotically! ~ les

Do immune related side effects from immunotherapy in melanoma lead to better responses?

Do side effects suffered indicate a better rate of response to immunotherapy?  Or a longer period of recurrence free survival? The possibility of a connection has been pondered before.  There is this report from 2017:  Do melanoma peeps with side effects to immunotherapy have a better response?

Now, there's this:

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial.  Eggermont, Kicinski, Blank, et al.  JAMA Oncol.  2020 Jan 2.

Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.  To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.

A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.

Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.  The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.

Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE.

In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.

So, in this study they looked at 1019 Stage III patients who either got pembrolizumab (Keytruda) or placebo.  Not surprisingly, recurrence free survival was longer in the peeps who got pembro, than in those who were given the placebo.  Of the 509 who got pembro, 109 (37%) developed immune related adverse events.  Of the 502 who were given placebo, 45 (9%) acquired an irAE.  {I really hope that is just the natural incidence of immune related disease processes rather than the power of a placebo effect!!!!}  The researchers state that the development of these adverse side effects led to longer RFS in the pembro group, but the association was not significant in the placebo arm.  However, at least in this abstract, how long that RFS was extended is not stated.

For what it's worth. Ratties rule! - c

Chaotic Cookery! ~ Wild Rice and Blue Cheese Skillet Souffle'

B found  set a set of Williams-Sonoma cookbooks at a resale book shop and they are so good!  So far, everything we've tried has been at worst, quite good, and more often - absolutely delicious!!!  Here is a really yummy dish from ~ Williams-Sonoma Kitchen Library:  Beans and Rice ~ 

YUM!  Super easy too, especially if you have left over rice!!

Perfectly simple and cozy for a rainy day.  Enjoy your chaotic cookery! - les