Circulating DNA - predicting survival in patients with resected Stage II/III melanoma

Wouldn't if be wonderful if a simple blood test could tell us if we have melanoma, what type of melanoma, and quantify the "amount" of melanoma...thereby giving us specific reports about whether our disease status is progressing, resolving, or stable?  Just think, with a test like that, we could quickly determine if we are responding to a particular therapy....or not!

I have posted data on this topic many times!  This link will take you to my last post and includes many more within:  ASCO 2017: Circulating DNA to measure response in melanoma

Now there's this:  

Circulating tumor DNA predicts survival in patients with resected high risk stage II/III melanoma. Lee, Gremel, Marshal, et al.  Ann Oncol. 2017 Nov 3.

Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma.

We performed droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial.

Mutant BRAF or NRAS ctDNA was detected (greater than/= to 1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval and distant metastasis-free interval versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status (PS) and disease stage. Five year overall survival (OS) rate for patients with detectable ctDNA was 33% versus 65% for those with undetectable ctDNA. OS was significantly worse for patients with detectable ctDNA and remained significant after adjustment for PS.

CtDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy.

Soon!!  I hope, soon...this test (or something like it) will be refined and readily available for melanoma patients of all stages!!! - c

Sew Chaotically! - The Basic InstincT t-shirt by Sasha!!!!!!!!!!!!!!

I have learned a great deal from many sewists through their blogs, tutorials, and other posts on various social media.  Some I simply watch, trying desperately to absorb all their tips and techniques.  Luckily, others have become peeps!!!  Amazing people...who touch my heart, make me laugh and teach me about life...not just sewing.  For a start there's Oonaballoona - aka Marcy Harriell who, via her blog, provided many tips for fabric shopping in NY, inspo and advice for the use of African Wax Prints, creates beautiful, personally authentic garments, and makes me laugh out loud!  There's Tilly, of Tilly and the Buttons, who inspired much of my London fabric shopping.  There's Rochelle, of Lucky Lucille who endlessly inspires me with her art, beautiful garments, work ethic and personal strength in not only enduring, but triumphing over personal challenges. I adore all the women who make up Mix and Sew.  French style is for real, y'all!!  I would be thrilled to be part of such a sewing group!  I adore their exuberance, willingness to admit flaws, and lovely sisterhood!

But, today -  I would like to introduce you to Sasha!!!  Her blog is Secondo Piano (that would be 'Second Floor' in Italian). I love her style, her passion!  Her dedication to authentic, sustainable fabric, fashion, and the way we look at garments, interpret, and make choices as "makers" inspires me daily!  If that is not enough, she MAKES great patterns!!!  AND....they are free!!!  Just subscribe to her amazing site!!!

Sew.....I happily embarked on making her Basic InstincT t-shirt!  To quote Sasha:
"I chose the relaxed cut because I think it’s a more contemporary silhouette and I personally do not like so much having my bra line showing. The crew neckline I just adore for its boyish, nonchalant look in a woman’s garment. I think it looks great under a blazer or a cardigan and can easily be lowered. I wanted this pattern to be a sort of I wanted this pattern to be a sort of blank canvas you could potentially transform into your own beautiful painting."

Great thanks to my B for printing and putting together another pattern.  (If you want, you can print only the size you prefer!  But, when you've got a helper willing to continually print and put together patterns for you...he can do it any way he wants!!!)

Here we go!

I used a drapey cotton knit from Mood I picked up a bit ago...

...and yes, one should make a muslin...but, I can't - be bothered!!!  I made the "small" with no changes, and luckily...the fit is fabulous!!!

I did ALMOST mess up my AMAZING t-shirt by being stubborn!!!  I was set on having my stripes go opposite to the body of the shirt on the neck band, and there was less stretch in that direction....but....I made it work!!!  

The Basic InstincT t-shirt  easily dresses up or down.  It plays well with skirts or pants, alone or with a jacket.  (Here I've added my Morris Blazer!) I can see this pattern becoming the wardrobe staple Sasha envisioned!  I am looking forward to other t's and dresses using this pattern!

Thanks, Sasha. And not just for this t-shirt!  Thanks for being you!!!  Sew chaotically! - les

Melanoma patients continuing Nivo after having adverse reactions to the ipi/nivo combo??? Yes, you can!

Though management can be tricky, docs have been saying from some time that folks CAN tolerate anti-PD-1 if you have previously had adverse reactions to ipi or a pre-existing autoimmune process.

Here's a report from ASCO 2016: Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders (AD) or major toxicity with ipilimumab (IPI).

And another post that includes several sources from this year:  Patients with preexisting immune disease, melanoma, and treatment with Anti-PD-1? Yes, this can be done. Yes, autoimmune flares should be treated with immunosuppressive therapy while on immunotherapy. And YES!!!! These patients can still attain a response!

Now there's this:

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Pollack, Betof, Dearden, et al.  Ann Oncol. 2017 Oct 11.

Combined CTLA-4 and PD-1 blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known.
We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs.

Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids, and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (6 grade 1-2, 7 grade 3-4, 1 grade 5 Stevens-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% vs. 28%). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2, 6 grade 3-4). Duration of steroid taper, severity of initial irAEs, and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% vs. 31%).

Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in select patients.

Clearly, not a walk in the park for some...but a return to nivo alone after a reaction to the ipi/nivo combo proved doable for about 60% of these patients with significant reactions requiring immunosuppression therapy for their side effects!  

Take care ratties!!  It's a tough world at NIMH!!!! - c

Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!!

Those who have read this blog for half a minute know that I have been yelling about the need for adjuvant treatment in melanoma that is NOT interferon....and after the response rates we know we can attain with anti-PD-1 products and BRAF/MEKi...NOT ipi either!!!  Here is a recent post with links to more within:

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

Now there's this:

Dabrafenib/Trametinib Combination and Nivolumab New Adjuvant Treatment Options for Stage III Melanoma. Prime Line, October 5, 2017.

The current adjuvant treatment options for high-risk patients with resectable melanoma include interferon and the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab. Compared to placebo, ipilimumab (10 mg/kg) prolonged relapse free survival (RFS) and showed significant 5-year survival benefit in high-risk patients with melanoma, but at the cost of serious toxicity. In the metastatic setting, combinations of BRAF/MEK inhibitors in patients harboring BRAF mutations, and immunotherapy with programmed death receptor 1 (PD-1) inhibitors (± ipilimumab) regardless of BRAF status are standard of care based on evidence of survival benefit and manageable toxicity. The efficacy of these regimens has, thus, been investigated in the adjuvant setting, and results from two of these studies presented at the third Presidential Session at the 2017 European Society for Medical Oncology (ESMO) Congress are practice changing.

The COMBI-AD trial (N = 870), presented by Axel Hauschild, MD, PhD (University Hospital Schleswig-Holstein, Kiel, Germany), compared the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg daily) to placebo in patients with resected, high-risk, stage IIIA-C melanoma with BRAF V600E/Kmutation. At 2.8 years follow-up, the combination of dabrafenib and trametinib had significantly improved RFS compared to placebo (not reached vs 16.6 months). The 3-year RFS rate was 58% with the combination compared to 39% with placebo. The benefit of dabrafenib plus trametinib adjuvant therapy was seen across all patient subgroups, regardless of disease stage or risk factors. Furthermore, combination therapy significantly improved overall survival (OS), with 3-year OS rates of 86% with combination versus 77% with placebo. Dabrafenib plus trametinib was associated with an increase in adverse events (AEs) compared to placebo (grade 3/4: 41% vs 14%), but there were no deaths due to AE. A greater number of patients receiving the combination discontinued treatment due to AE (26% vs 3%), with the most common reasons being pyrexia and chills. In his conclusion, Dr Hauschild highlighted the RFS and OS benefits of dabrafenib plus trametinib, along with the manageable safety profile, indicating that this combination should become a new treatment option for patients with resected, stage III, BRAF-mutated melanoma. Results from the COMBI-AD trial were simultaneously published in The New England Journal of Medicine.

Jeffery Weber, MD, PhD (New York University, New York, New York, United States), presented results from the phase III CheckMate-238 trial (N = 906), which compared one year of adjuvant therapy with nivolumab (3 mg/kg IV every 2 weeks) to ipilimumab (10 mg/kg IV every 3 weeks for 4 doses, then every 12 weeks) in patients with resected stage III/IV melanoma. Significantly more patients treated with nivolumab remained relapse-free at 18 months compared to ipilimumab (66% vs 53%). Relapse-free survival benefit favored nivolumab regardless of PD-L1 expression level, disease stage, or BRAF mutation status. Adjuvant treatment with nivolumab was more tolerable than ipilimumab. There were fewer grade 3/4 treatment-related AEs in the nivolumab arm (14% vs 46%), and fewer patients treated with nivolumab experienced a treatment-related AE leading to discontinuation (8% vs 42%). There were no treatment-related deaths in the nivolumab group, while 2 patients in the ipilimumab group died due to AE. Dr Weber concluded that nivolumab should be considered as a new standard treatment option for patients with resected stage IIIB/IIIC/IV melanoma, regardless of BRAF mutation status. Results from this trial were also simultaneously published in The New England Journal of Medicine.

In their discussions of these studies, Alexander Eggermont, MD, PhD (Gustave Roussy, Villejuif, France), and Reinhard Dummer, MD, PhD (Cancer Center Zurich, Zurich, Switzerland), indicated that these trials represent the death knell for both ipilimumab and interferon as adjuvant therapies for melanoma. Moving forward, either nivolumab or dabrafenib plus trametinib will be the adjuvant therapy of choice for stage III melanoma, with treatment choice dependent on BRAF mutation status and physician and patient preference.

Additional reiteration (if you're into redundant redundancy) was noted in an editorial by Lynn Schuchter M.D. in The New England Journal of Medicine, published today:

Adjuvant Melanoma Therapy - Head-Spinning Progress

There she states, in part:

"Every year in the United States, approximately 87,000 patients receive the diagnosis of melanoma. Although most of these patients are cured with simple excision, those with node-positive, stage III melanoma are at increased risk for distant metastasis and death. To date, the Food and Drug Administration (FDA) has approved three adjuvant therapies for such patients, all of which are immunotherapies: high-dose interferon alfa-2b, pegylated interferon alfa, and high-dose ipilimumab (10 mg per kilogram of body weight).  Concerns about the marginal efficacy of these drugs (especially the interferon-based agents) and considerable toxicity (all three drugs) have limited their use. Therefore, the current standard of care for patients with node-positive melanoma includes observation without therapy, the use of one of the approved adjuvant therapies, or participation in a clinical trial."

She goes on to note the approval of "8 new drugs for the treatment of melanoma, seven of which have improved survival" - noting specifically the use of BRAF/MEK inhibitors and immunotherapy over the past 5 years - continuing:   "With these new approaches, some patients have been cured and many have seen remarkable improvements in symptoms...and duration of life.  The median overall survival of patients with disseminated melanoma has increased from 9 months before 2011 to 2 years or more."

As does the report above, she notes the results of the Weber presentation of the CheckMate 238 trial and the COMBI-AD trial.  Stating further:   "How do these results compare with those currently approved adjuvant therapies in patients with node-positive melanoma?  High-dose interferon...was approved more than 20 years ago and has been extensively studied...and showed no benefit in overall survival.  [It] has been associated with substantial toxic effects...the majority of patients... [fail to complete] 1 year of therapy, and the frequency of Grade 3/4 events has been more than 65%. 

Adjuvant high-dose ipilimumab was approved by the FDA 2 years ago on the basis of the results of EORTC 18071, which compared ipi with placebo...[and] significant benefit of overall survival was reported [with ipi]...Although high dose ipi has been shown to be effective, the toxicity of ipi at a dose of 10 mg/kg continues to pose a major challenge as an adjuvant therapy.

...Adjuvant therapy with nivo in patients with node-positive melanoma may now be considered a new standard of care, regardless of BRAF status.  On the basis of efficacy and safety, nivolumab, unequivocally, is a better choice than interferon or high-dose ipilimumab.  Adjuvant combination therapy with dabrafenib and trametiib is also an option for patients with node-positive BRAF-mutated melanoma.  Testing of melanoma tumors for the presence of BRAF mutations may now become standard in patients with node-positive, stage III melanoma.  There is no longer a role for adjuvant interferon in patients with  node-positive melanoma."

So, there!!!

Come on, FDA peeps!!!  If you or your loved one were affected...these therapies...not the crap you approved years ago....are the ones YOU would want!!! - c

A look back - ipi and pembro

Here are couple of review papers looking at ipi and pembro ~

Real world treatment patterns and outcomes among metastatic cutaneous melanoma patients treated with ipilimumab. Mohr, Ascierto, Arance, et al.  J Eur Acad Dermatol Venereol. 2017 Oct 17. 

There is a scarcity of real-world data on treatment patterns and outcomes among advanced melanoma patients treated with immunotherapies including ipilimumab, an anti-CTLA-4 antibody approved since 2011.  To evaluate ipilimumab and post-ipilimumab treatment patterns and outcomes among patients with advanced melanoma in Australia, Germany, Italy and Spain following regulatory approval.  Retrospective multicentre, multinational, observational chart review study. Data were extracted from the start of ipilimumab therapy until the end of at least 40 weeks of follow-up, or death.
Data from 371 patients (Australia, 103; Germany, 152; Italy, 76; Spain, 40) were analysed. Mean age was 65 years; 62% were male. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 or 1 for 94%. In 67%, ipilimumab was initially received as second-line or later therapy. Patients received on average 3.4 ipilimumab doses. The ipilimumab-refractory cohort comprised of 226 patients. Of these, 17% in Australia, 47% in Germany, 29% in Italy and 14% in Spain received another anti-melanoma treatment after ipilimumab including chemotherapy in 26% and BRAF/other kinase inhibitors in 11%. Ipilimumab-refractory patients who received post-ipilimumab treatment showed a 40% reduced hazard of dying than those not receiving treatment after ipilimumab, after adjustment for potential confounders.

During the time observed, ipilimumab was mainly used as second-line or later therapy. A significant proportion of patients received post-ipilimumab therapy, most of which was chemotherapy. Nevertheless, overall survival following progression on ipilimumab treatment remained poor, highlighting the need for research to develop more effective end-of-life treatment options.

Sadly, yep.  We knew that.  There is also this:  

Efficacy and Safety of Pembrolizumab in Patients Enrolled in KEYNOTE-030 in the United States: An Expanded Access Program. Gangadhar, Hwu, Postow, Hamid, Daud...O'Day, Hodi, Pavlick, et al.  J Immunother. 2017 Nov/Dec.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAF mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% in the treated population (n=947) and 22.1% in patients who had greater than/= to1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced greater than/= to 1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced greater than/= to 1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Remembering that this was back in the day, when in order to attain pembro, you had to have "progressed after standard-of-care therapy" (meaning ipi and BRAFi - if BRAF positive) - a circumstance which we now know provides a LESSER response to immunotherapy like pembo and nivo - Yep.  We knew this, too!!

While a look back is essential for progress and incredible strides have been made in treatments available for melanoma patients in the past 5 years,  a best case 40-50% response rate leaves far too many in need of effective therapy.  Come on researchers!!!  Ratties are counting on you.  Let's move forward....FAST! - c

Copper Chelation to inhibit BRAF V600E melanoma growth and decrease resistance to BRAF/MEK inhibitors???

I've actually reported on Copper Chelation and melanoma before.  Here is this from 2015:  CDK4/6 inhibitors, PLX8394, or copper chelation?????

Now there's this:

Copper Chelation Inhibits BRAFV600E-driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors. Counter, Crowe, Greenberg and Brady.  Cancer Res. 2017 Oct 6.

MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacological reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended towards an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAFV600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma.

Sounds good to me!  Hang in there ratties!  -  c

I've repeated it endlessly. If you have melanoma - you need an EXPERT!!!!

I have long ranted about the need for a melanoma expert if you are dealing with melanoma.  And holy crappy wizard balls!  Was I ever right!!! ~

Variance between experts and community practitioners in the use of immune checkpoint inhibitors for advanced melanoma.  Quill, Agarwala, Atkins, Daud, Flaherty, Weber, Obholz.  Society for Melanoma Research 2016 Congress.  Published 29 January 2017. 

Immune checkpoint blockade has revolutionized the care of patients (pts) with melanoma; however, treatment guidelines lack specific recommendations on the use of these agents for individual pt cases. We developed an interactive, online treatment (Tx) decision tool to assess whether expert Tx recommendations based on specific disease and pt characteristics would affect the planned Tx decisions of community practitioners. In January 2016, 5 experts provided Tx recommendations for 90 case variations based on key factors they considered important to guide Tx choice and then an online tool was developed to provide this guidance to clinicians. To use the tool, specific pt and disease characteristics along with the intended Tx for that pt were entered. Then Tx recommendations from 5 experts for that scenario were provided and users were prompted to indicate whether this online consultation would change their Tx plan. An analysis of 432 cases entered into the tool found variation between the intended use of immunotherapy among tool users versus Tx recommendations from the experts. For example, compared with the experts who all chose immune checkpoint blockade as frontline Tx for BRAF wild-type disease, 44% of tool users planned to use a different Tx or were unsure. For BRAF^V600-mutant disease with a good PS and normal LDH, all of the experts recommended frontline immunotherapy whereas 55% of users selected combination BRAF/MEK therapy for this scenario. In total, 59% of tool users whose planned Tx differed from the experts indicated that the expert recommendations from the tool would subsequently change their Tx plan. An analysis of specific first- and second-line agent and combination choice along with Tx variance in other case scenarios will be presented. 

What the hell is wrong with these community oncologists????  I have been providing care to children for over 30 years.  Not only does maintenance of my license REQUIRE continuing education training on an annual basis, but I REQUIRE keeping up with changes in standards of care for my little patients of MYSELF!!!!  How in the world these providers could insert the particulars of their patient's melanoma data into a program designed by melanoma experts and PURPOSELY CHOOSE to provide a "treatment" NOT recommended is beyond me!!!  But...they did.

This report highlights a sad state of medicine and a seriously scary situation for folks with melanoma.  All I can tell you is:  learn from more than half of these 432 ratties (and these are just the ones we know about in this particular study) who were given treatment that was NOT recommended by melanoma experts by their local oncologist.  RUN, don't walk...even if it takes more effort than a trip to a local onc...to a melanoma expert if you are dealing with melanoma.  Your life may depend on it!  - c