Spring Fling....Across Six Aprils!!!

Yep, 6 years ago today I had the upper lobe of my right lung removed to get rid of melanoma that had decided to make a nest in my bronchus after SRS to a brain met 3 days prior.

 Here are several April and Melanoma posts that explain: Across Five Aprils

To enjoy another April is precious to me. My peeps and Mother Nature know how to do a Spring Fling right!!!!

There is Bentie's DELICIOUS fresh baked Challah!  That's khggggghallah...don't 'cha know????

Spring's flora and fauna were beautiful at home.....

Johnny White's Irises that have moved with me to three different homes.

Knock Outs!

B's beautiful peonies!

Mischievous chive blossoms.

 My own wild flowers here at home:

Some of the few star grass blossoms the critters allowed me to have.

Appropriated Columbine!

More!

Trina's Trillium!

More!

Appropriated wild azalea.

And a bit more...

Variegated Solomon's Seal

 ...and abroad...in Cades Cove...Spring brought....

A beautiful hike with Pals/Poppies!

Trillium edged streams.

Wild Oats

Showy Orchis

Obstacles that were a bit high for a little donkey!!!

The most beautiful, sweeping patches of crested iris I have ever seen!

Gigantic Dog Wood blossoms, floating among the branches.

An incredible show of Silver Bells, in the trees and as a carpet below.

A special stream with my best boy.

And yes!  We had bears!!!  One on the trail.  4 in Cades Cove.  

Across Six Aprils.  A lucky girl indeed!!  Thanks to all of you who helped me through and brighten my days.  Wonder what summer will bring.  love, c

Sew Chaotically! - Cute little summer dress ~ McCall's 7242

There's always a story!!!  (And boys...Mat, Ed, Josh, Paul...you guys...I know this is not your thing...but...keep reading...you'll like it....)  Here's the inspiration:

The pattern:

Initially, I was planning to make View C...the sleeveless longer version.  I know...not in keeping with the inspiration, now was it?  So, fate intervened and somehow (I think I had not paid attention to the width of my fabric when purchasing) I didn't have enough material for the maxi length.  No worries...make view A...more like the vision anyhow!  That was not as easily done either, since I found a long random flaw in the fabric!!!!  A very soft washable cotton, perfect for the vision, in color, print and drape....by Jo-Ann's from Jo-Ann's.  It turned out to be both easy to work with and....well...'FLIMPY'!  Not familiar with the word?  Here's THAT story:

Brent and I went to Greece, about a year after getting married, in 1989.  We had a wonderful time.  Years later...we went back with the kids when they were in their early teens.  We were catching a flight out of Nashville and spending the night there before take-off.  Rosie and I carefully packed for the trip and made a special 'Nashville Bag'.  One we wouldn't have to take with us that would have all we needed for Nashville and the flight over.  It was Athleisure before the term was coined!  Comfy but cute for the trip, usable for workouts and jogs once there.  It was AWESOME!!!!  Along about Manchester...it has been reported that I let out a huge gasp!  Three startled faces stared at me confused about the problem.  Suddenly, one face crumpled and erupted in a bit of a scream!  (Roo!!!)  The two male faces remained utterly confused.  We did not have the well-prepared, perfectly curated, "Nashville Travel Bag" with us!!!  Explanations were given and demands to return to Chattanooga to  fetch it were made (by two of us)!  Responses were a polite, but a little excessively firm, "No!!!!  We'll stop at Walmart!"  OMG!!!!  Never, never, ever, ever shop at Walmart in Manchester, TN!!!!  The sizes range from large to huge!!!  Rosie and I finally managed to find some exercise capri's, cami's and sweaters.  Fred was tricked out in red, gigantic, nylon of the worst sort, basketball shorts (that he could have sagged with ease) and some sort of t-shirt.  But, B!!!  He went all out:  Faded Mom-Jean-SHORTS, with a Western-wear plaid shirt, replete with pearlized snaps, and flimpy socks!  There it is again ~ 'flimpy'. Yep, flimpy socks are made of very thin nylon (black in this case) that could easily be made to reach ones thigh, but that he preferred to roll down, much as your great aunt or grandma did her hose, somewhere along mid calf.  Flimpy as they were, they were constantly being "eaten" by his shoes, necessitating many adjustments in airports across the globe and were accordingly dubbed: FLIMPY!

So, yes this fabric was indeed flimpy.  Quite maneuverable when putting in sleeves, but less than stable when working on a collar or hem.  Indeed....once you have dealt with 'flimpy' you will know it forever.

There you have it.  A flimpy little summer dress.  I think it lived up to the vision rather well.  Wore it to work this week with a woven leather belt at the waist.  Lots of compliments.  But only you, dear readers, got to know about.....FLIMPY!!!!

Sew and travel chaotically!!!!! - c

Celecoxib (Stuff that's in NSAID's like ibuprofen and aspirin!!!) and anti-PD1 work synergistically

I put this post up a while ago: An aspirin a day keeps melanoma at bay and makes immunotherapy work better???   As I noted in that post....I figure all us immunotherapy peeps have pretty much been living on advil in order to deal with our arthralgias!!!  But, this was republished recently:

Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity.  Li, Fang, Zhang, et al.  Oncoimmunology. 2015 Aug 12;5(2):e1074374. eCollection 2016. 

Two major challenges facing cancer immunotherapy are the relatively low therapeutic efficacy and the potential side effects. New drug delivery system and efficient drug combination are required to overcome these challenges. We utilize an alginate hydrogel system to locally deliver 2 FDA-approved drugs, celecoxib and programmed death 1 (PD-1) monoclonal antibody (mAb), to treat tumor-bearing mice. In two cancer models, B16-F10 melanoma and 4T1 metastatic breast cancer, the alginate hydrogel delivery system significantly improves the antitumor activities of celecoxib (CXB), PD-1 mAb, or both combined. These effects are associated with the sustained high concentrations of the drugs in peripheral circulation and within tumor regions. Strikingly, the simultaneous dual local delivery of celecoxib and PD-1 from this hydrogel system synergistically enhanced the presence of CD4⁺inteferon (IFN)-γ⁺ and CD8⁺IFN-γ⁺ T cells within the tumor as well as in the immune system. These effects are accompanied with reduced CD4⁺FoxP3⁺ regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the tumor, reflecting a weakened immuosuppressive response. Furthermore, this combinatorial therapy increases the expression of two anti-angiogenic chemokines C-X-C motif ligand (CXCL) 9 and CXCL10, and suppresses the intratumoral production of interleukin (IL)-1, IL-6, and cycloxygenase-2 (COX2), suggesting a dampened pro-tumor angiogenic and inflammatory microenvironment. This alginate-hydrogel-mediated, combinatorial therapy of celecoxib and PD-1 mAb provides a potential valuable regimen for treating human cancer.

Hmmmm.... "reduced myeloid derived suppressor cells (MDSCs)"....  Now that could be something!!  Remember this?   Increased Myeloid Suppressor cells = not so good.

And for what it's worth....there was also this back in the day:  
Nonsteroidal anti-inflammatory drugs and the risk of skin cancer:  A population-based case-control study. Johannesdottir, Chang, Mehnert, et al.  Cancer, 2012, May 29.

Knowing that Nonsteroidal anti-inflammatory drugs (NSAIDS....like aspirin, ibuprofen, etc.) may prevent the development of cancer by inhibiting cyclooxygenase (COX) enzymes, these folks from Denmark looked at NSAID use and the risk of squamous cell carcinoma, basal cell carcinoma, and melanoma.  They looked at all cases of those diseases from 1991 through 2009 in northern Denmark. (Squamous = 1,974, basal = 13, 316, and melanoma = 3,242).  They matched 10 population controls (n=178,655) to each case by age, gender, and county of residence.  Use of NSAIDs was noted via a prescription data base.  FINDINGS:  After a great deal of incidence rate ratios and confidence interval statistical shenanigans....they determined that "NSAID ever use compared with nonuse was associated with a decreased risk of squamous cell and melanoma, especially for long-term use and high-intensity use.  NSAID use was not associated with a reduced risk of basal cell.  All estimates of reduced risk were driven primarily by the use of nonselective NSAIDs and older COX-2 inhibitors."

Just putting it out there.  Best - c

Pembro's (Keytruda's) overall tumor response and OS in melanoma patients....

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.  JAMA. 2016 Apr 19.  Ribas, Hamid, Daud, Hodi, Wolchok, Kefford, Joshua, Patnaik, Hwu, Weber, et al.

The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.

Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision.

Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33%) and in 60 of 133 treatment-naive patients (45%). Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35% in the total population and 52% among treatment-naive patients. Median overall survival in the total population was 23 months, with a 12-month survival rate of 66%, and a 24-month survival rate of 49%. In treatment-naive patients, median overall survival was 31 months, with a 12-month survival rate of 73%,  and a 24-month survival rate of 60%. Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths.

Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

Once again it is clear that treatment naive patients do better on anti-PD1 than those who are pretreated...particularly with ipi.  Here is a post and link to the report from the Checkmate 064 trial in which folks who got nivo first followed by ipi had slightly more side effects (roughly 50 vs 43%) but they also had objective response rates of 41.2% vs only 20% in the ipi first group!!!!!!!!!!!!!!!! - Sequential nivo then ipi vs Sequential ipi then nivo

Here is a recent report on OS with nivo - Nivolumab shows impressive OS in melanoma
The data here is further out.  All patients were "heavily pre-treated", so none were treatment naive, but none had been treated with ipi.

We never can compare apples to apples, can we?  But...still....good news overall!  Way to go, Ratties! - c

Hope after standard melanoma immunotherapies fail

Omid Hamid, MD, discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option.

 http://www.onclive.com/web-exclusives/novel-checkpoints-offer-hope-after-standard-melanoma-immunotherapies-fail  

Determining the next step for a patient with melanoma who has failed or is not a candidate for existing targeted therapies or immunotherapies can be a challenge.  However, there is hope, says Omid Hamid, MD, chief of Translational Research and Immunotherapy, and director of Melanoma Therapeutics at The Angeles Clinic.

“There are times when you throw your hands in the air and say, ‘I’ve run out of options,’” he says. “But, all you need to do is look in another direction, open another cabinet, and realize that there are a ton of new options for our patients. These are nontraditional agents that maybe would not come to mind, but can be very effective in first-line, second-line, or any line.”

Currently, several new checkpoint inhibitors and costimulatory molecules are being explored. These include those that target glucocorticoid-induced tumor necrosis factor receptor (GITR)—which is expressed on CD4- and CD8-positive T cells—in addition to T-regulatory cells, NK cells, and dendritic cells.  GITR binds to its ligand on antigen presenting cells (APCs) and endothelial cells to promote T-cell activation. A number of GITR agonists are in clinical trials, including TRX518, developed by the biotech startup GITR Inc.  OX40, also known as CD134, is another option for patients with melanoma, says Hamid.  This targets the tumor necrosis factor (TNF) receptor, which is primarily found on the surface of activated cytotoxic and regulatory T cells. MedImmune is developing 3 different OX40-targeting agonists: MEDI6383, MEDI0562, and MEDI6469.  Combination regimens also offer an additional option for patients, says Hamid. Often, agents that do not have much activity alone in a patient may work well with something else.

In an interview with OncLive, Hamid discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option. 

OncLive: What new agents are available that are showing great potential?

Hamid: There are newer checkpoint agents such as GITR, OX40, and 4-1BB. These new checkpoint inhibitors are showing response after failure with traditional checkpoints. Adaptive T-cell therapeutics, which used to be considered “boutique drugs,”—meaning they were difficult for physicians to find—are now transitioning into normal centers like ours, thanks to collaborations. Antibody-drug conjugates have a role in melanoma, as well. These are phase II options, and some of them will be in phase III soon. 

What should a community oncologist know about these newer agents?

They need to have an understanding of the approved drugs and combinations, the toxicities of these agents, and how to mitigate those toxicities so patients can get back on therapy and get the proper dose intensity. These agents are going to go through clinical trials and will be in their clinics soon.  Community oncologists need to refer patients to enroll in clinical trials. There are a lot of pressing questions that we can answer through clinical trials. What breeds resistance? What are the biomarkers that predict response? How do we treat toxicities, and where do go from here?  There are newer toxicities out there, and physicians need to keep up with the literature in order to understand these and how to treat them. 

Is there potential for these newer agents to be used in combination with existing ones?

Absolutely. Some of these new drugs will be great companion agents. As a single agent, we may see a low response rate; however, in combination, we may see improved response rates because the agents are synergistic.  In the course of 2 or 3 years, we have gone from single-agent trials, to combination trials, to triplet trials.  The future is going to be adding more tolerable regimens, and discussing whether we should be stopping treatment earlier if we get early responses. All of these are going to move forward on a PD-1 backbone, BRAF backbone, or a CTLA-4/PD-1 combination backbone. There is no doubt that, by this time next year, we are going to be talking about triplet trials.

Are there particular combinations being investigated that you are excited about?

I presented data at the 2015 Society for Melanoma Research Congress on the triplet combination of a BRAF inhibitor, a MEK inhibitor, and an anti–PD-L1 agent that showed significant response, good tolerably, and a good duration of response. That is what is up and coming. It is currently being looked at in 3 major trials.  I hope we can get past the idea that, “we need to select from one agent or another” and find a combination regimen that has a higher efficacy, initially.

Here's a link to some of that data:  Combos looking good...

And a more recent discussion:  Weber and Agarwala discuss combination therapies for melanoma 

Wishing you all my best - c

Determining the next step for a patient with melanoma who has failed or is not a candidate for existing targeted therapies or immunotherapies can be a challenge.

However, there is hope, says Omid Hamid, MD, chief of Translational Research and Immunotherapy, and director of Melanoma Therapeutics at The Angeles Clinic.

“There are times when you throw your hands in the air and say, ‘I’ve run out of options,’” he says. “But, all you need to do is look in another direction, open another cabinet, and realize that there are a ton of new options for our patients. These are nontraditional agents that maybe would not come to mind, but can be very effective in first-line, second-line, or any line.”

Currently, several new checkpoint inhibitors and costimulatory molecules are being explored. These include those that target glucocorticoid-induced tumor necrosis factor receptor (GITR)—which is expressed on CD4- and CD8-positive T cells—in addition to T-regulatory cells, NK cells, and dendritic cells.

GITR binds to its ligand on antigen presenting cells (APCs) and endothelial cells to promote T-cell activation. A number of GITR agonists are in clinical trials, including TRX518, developed by the biotech startup GITR Inc.

OX40, also known as CD134, is another option for patients with melanoma, says Hamid.

This targets the tumor necrosis factor (TNF) receptor, which is primarily found on the surface of activated cytotoxic and regulatory T cells. MedImmune is developing 3 different OX40-targeting agonists: MEDI6383, MEDI0562, and MEDI6469.

Combination regimens also offer an additional option for patients, says Hamid. Often, agents that do not have much activity alone in a patient may work well with something else.

In an interview with OncLive, Hamid discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option.

OncLive: What new agents are available that are showing great potential?

Hamid: There are newer checkpoint agents such as GITR, OX40, and 4-1BB. These new checkpoint inhibitors are showing response after failure with traditional checkpoints. Adaptive T-cell therapeutics, which used to be considered “boutique drugs,”—meaning they were difficult for physicians to find—are now transitioning into normal centers like ours, thanks to collaborations. Antibody-drug conjugates have a role in melanoma, as well. These are phase II options, and some of them will be in phase III soon.

What should a community oncologist know about these newer agents?

They need to have an understanding of the approved drugs and combinations, the toxicities of these agents, and how to mitigate those toxicities so patients can get back on therapy and get the proper dose intensity. These agents are going to go through clinical trials and will be in their clinics soon.

Community oncologists need to refer patients to enroll in clinical trials. There are a lot of pressing questions that we can answer through clinical trials. What breeds resistance? What are the biomarkers that predict response? How do we treat toxicities, and where do go from here?

There are newer toxicities out there, and physicians need to keep up with the literature in order to understand these and how to treat them.

Is there potential for these newer agents to be used in combination with existing ones?

Absolutely. Some of these new drugs will be great companion agents. As a single agent, we may see a low response rate; however, in combination, we may see improved response rates because the agents are synergistic.

In the course of 2 or 3 years, we have gone from single-agent trials, to combination trials, to triplet trials.

The future is going to be adding more tolerable regimens, and discussing whether we should be stopping treatment earlier if we get early responses. All of these are going to move forward on a PD-1 backbone, BRAF backbone, or a CTLA-4/PD-1 combination backbone. There is no doubt that, by this time next year, we are going to be talking about triplet trials.

Are there particular combinations being investigated that you are excited about?

I presented data at the 2015 Society for Melanoma Research Congress on the triplet combination of a BRAF inhibitor, a MEK inhibitor, and an anti–PD-L1 agent that showed significant response, good tolerably, and a good duration of response. That is what is up and coming. It is currently being looked at in 3 major trials.

I hope we can get past the idea that, “we need to select from one agent or another” and find a combination regimen that has a higher efficacy, initially.
- See more at: http://www.onclive.com/web-exclusives/novel-checkpoints-offer-hope-after-standard-melanoma-immunotherapies-fail#sthash.nJwR9a1R.piv8iAUe.dpuf