Radiation and ipi = better responses than either alone!!! (AGAIN!!!)

Hopefully, this will soon become routine info and thereby treatment for melanoma patients!!!   Prior posts on the topic:  Better responses when immunotherapy is combined with radiation    

Now this:

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Hiniker, Reddy, Maecker, et al.  Int J Radiat Oncol Biol Phys. 2016 Nov .

Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.

In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.

Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.

This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T-cells.  Tang, Welsh, de Groot, et al.  Clin Cancer Res. 2016 Sep 20.

Little prospective data is available on clinical outcomes and immune correlates from combination radiation and immunotherapy. We conducted a phase I trial (NCT02239900) testing stereotactic ablative radiation therapy (SABR) with ipilimumab.

SABR was given either concurrently (1 day after the first dose) or sequentially (1 week after the second dose) with ipilimumab (3 mg/kg every 3 weeks for 4 doses) to 5 treatment groups: concurrent 50 Gy (in 4 fractions) to liver; sequential 50 Gy (in 4 fractions) to liver; concurrent 50 Gy (in 4 fractions) to lung; sequential 50 Gy (in 4 fractions) to lung; and sequential 60 Gy (in 10 fractions) to lung or liver. Maximum tolerated dose was determined with a 3+3 dose de-escalation design. Immune marker expression was assessed by flow cytometry.

Among 35 patients who initiated ipilimumab, 2 experienced dose-limiting toxicity and 12 (34%) grade 3 toxicity. Response outside the radiation field was assessable in 31 patients. Three patients (10%) exhibited partial response and 7 (23%) experienced clinical benefit (defined as partial response or stable disease lasting {greater than or equal to}6 months). Clinical benefit was associated with increases in peripheral CD8+ T-cells; CD8+/CD4+ T-cell ratio; and proportion of CD8+ T-cells expressing 4-1BB and PD1. Liver (vs. lung) irradiation produced greater T-cell activation, reflected as increases in the proportions of peripheral T-cells expressing ICOS, GITR, and 4-1BB.  Combining SABR and ipilimumab was safe with signs of efficacy; peripheral T-cell markers may predict clinical benefit; and systemic immune activation was greater after liver irradiation.  

If these latest posts seem like we melanoma patients have been singing the same tune...for YEARS....regarding liquid assays for tumor eval and progression, PD-L1 staining, and radiation COMBINED with immunotherapy....WE HAVE BEEN!!  Come on melanoma researchers, general oncologists and the FDA!!!  This should not be hard to figure out!!! - c

Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma!

Also from the Boston Conference, Society for Melanoma Research -

And as I said earlier this year:   A valid and specific blood draw that could help diagnose, determine the presence of a response to therapy, and be used as follow-up (instead of scans!) would be sooooooooooo  awesome!!!!  Now there's this: 

Non-invasive monitoring of treatment response to immunotherapy in patients with metastatic melanoma.  Gray, Pereira, Calapre, et al.

Current methods for monitoring melanoma dynamics during treatment are limited to LDH levels and imaging to estimate tumour burden. In particular, responses to immune checkpoint inhibitors vary greatly in timing and extent, and may not be accurately reflected through radiological examination. The analysis of circulating tumour DNA (ctDNA) through sensitive methods can provide a rapid, accurate and quantitative method to determine therapeutic effect as early as possible. In this study mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF, NRAS and TERT variants in 47 patients with advanced metastatic melanoma before commencing treatment with the immune checkpoint inhibitors pembrolizumab (N=30) or ipilimumab (N=17). Tumour-associated ctDNA was detected in 32/47 (68%) plasma prior to treatment, in 76% (N=17) of BRAF mutant and 100% (N=2) of NRAS mutant melanomas. In addition, TERT promoter mutations were detected in the plasma of 61% (N=28) of BRAF/NRAS wild-type cases. Monitoring of ctDNA levels in patients positive at baseline, showed a decrease in ctDNA in response to therapies prior to or concurrently with radiographic response. However, a delayed pattern of response was observed in comparison with our previous data in patients treated with MAPK inhibitors, and consistent with clinical measures of response in ipilimumab and pembrolizumab clinical trials. In conclusion, this study demonstrates the utility of ddPCR assays to monitor ctDNA in the plasma of melanoma patients undergoing immunotherapy.  
Yep!  Been yelling about this for some time:

Here's a post about BRAF testing via a blood draw with lots of previous links to liquid biopsy info:  BRAF testing via blood draw....and more

Here's another demonstrating the value of such non-invasive monitoring:  Melanoma antigens in blood are prognostic of OS and correlate with response to ipi

C'mom man!!!  Let's get this going....for everybody!!! -  c

Chaotic Cookery! - From Someone Else's Table: I am thankful....

It begins....with family, fun, laughter, and food!

Stuffing a pre-roasted pumpkin with bread and cheese...recipe to follow!

Yes, there are always flashlights!!!! 

Turkey breast...roasted on a bed of celery, onion, lemon slices and thyme...with sage leaves tucked under the skin, a little olive oil massage, salt and pepper!!  No more complicated than that.  Roast at 350 for 20 minutes per pound!

And then there was.....Roast DUCK!!!  Clean, prick skin (without pricking flesh) and boil for 10 minutes.

Then, drain and pat dry. (You should let it cool...but we ain't got time for that!!!)  Stuff with one whole garlic bulb (de-papered and halved), celery, and orange pieces.  Smear with mixture of salt, pepper, and smoked paprika.  Roast at 350:  breast side up for 45 minutes, remove from oven...

...drain fat and turn breast side down, return to oven and bake 30 minutes, remove, drain any fats, turn breast side up again, and cook another 30 minutes or so...until leg/thigh has temp of 175.  Rest 10-15 minutes.

It takes team work!!!

Ta dah!!!!

Green bean casserole.  Baked sweet potatoes plain.  And some dolled up by Roo with marshmallows, butter, cinnamon, and nutmeg!  See below for the best dressing recipe....E'VAH!!!

Canned "cranberry sauce" for some people (always in special bowl from Frankie!!!).  And Ruthie/Rosie/Jamie cranberry relish:  One bag fresh cranberries, 4 'cuties' (3 peeled, one not - probably one orange whole), 1 apple with peel - but cored, 1 tablespoon of sugar, 1 teaspoon salt....all grated together!

Greens!!!  Very large bag of kale and another of turnip greens.  Saute one onion in olive oil, add about a cup of chopped ham - brown a little.  Add one cup chicken broth, the greens, and water to cover.  Salt and pepper. Cook an hour or so.  Easy to do the day before.

Roast Pumpkin with cheese "fondue"!  B found this recipe some years ago via NPR and gourmet.com.  We have made several iterations of it.  I think this year's was best.  A smallish pie pumpkin, seeds removed.  Rubbed nicely with olive oil.  Roasted empty at 350 for 30 min to one hour....until pumpkin is tender, but at no risk of falling apart or caving in. (Time will vary depending on size of pumpkin. Can be done ahead.) After roasting...layer toasted bread (slices or bite size pieces) alternating with grated Gruyere cheese within the pumpkin until filled.  Pour cream with a bit of grated nutmeg over bread and cheese, until full.  Roast another 30 min or so at 350.  Serve by scooping out servings of bread and cheese with the pumpkin flesh out the top...or as we did with our small pumpkin, just cut in half and serve wedges to everyone!!

Duckie goodness!

Pumpkin fondue!!!

 Vallie Leslie's Dressing

     As written from my cookbook years ago:  I was 'adopted' by a wonderful lady who looked after me as a young nurse living alone in the big city of Chattanooga when I was barely 19 years old.  She took great care of me and made me feel at home.  Not the least of her gifts was this recipe for dressing.  Thanks Ms. Leslie.  You'll never know how much you meant to me.

1 medium onion, chopped           2 stalks celery, chopped      Saute both in 1 stick of butter seasoned with 1/4 teaspoon of pepper, 1 tsp sage, and 1 tsp thyme until tender.  Add about 2 cups chicken broth.  Pour this mixture over crumbled cornbread.  Place in baking dish and bake about 30 minutes at 350.  Serve with the gravy and meat dish of your choice.

Cornbread

     You can bake this in a glass baking dish (especially if using in dressing) but, it is even better in a cast iron skillet with a little oil heated hot and sizzling before you add the batter!

1 c flour      1 c cornmeal       2 T sugar       3/4 tsp salt        2 t baking powder
1/4 t baking soda       2 beaten eggs        1 c buttermilk        1/4 c vegetable oil

Preheat oven to 425.  Put cast iron skillet with enough vegetable oil to coat the bottom in to heat if that is what you are using.  Sift dry ingredients together.  Mix wet ingredients together.  Stir wet and dry together without over mixing.  Pour into heated skillet or baking dish coated with non-stick spray.  Bake for 20 minutes or until golden brown on top.

Substitution tip:  Don't have buttermilk?  No worries.  Use 1/2 quantity of sour cream or yogurt and 1/2 milk to make up the portion needed.  Or - add 1 tablespoon vinegar to enough milk to make one cup and let sit for 10 minutes...then use as needed.

Yes....I am thankful.  I am thankful to be able to share such an abundance of delicious food with my dear ones.  Thankful to have seen another beautiful crop of fall leaves.  Thankful for chaotic adventures with B.  Thankful to be done with PAL's for another 2 years!!  HA!  Thankful that my kiddo's are busy working, playing and living their own lives on their own terms.  Thankful that Jeannie, Allyson, Stevie, Susan, Jonathan, Francoise, Kerri, Eric, Joshie, Ed, Mat, Paul, Gary, Sue, Lucy, and so many others are part of my chaotic world.  I am thankfully looking forward to more chaotic food and fun with those I love.  But, most of all, I am thankful to each and every one of you who take time to laugh and play with me.  Much love and appreciation to you all! - c

Sew Chaotically! - One more afghan...

...more of a throw, really - for me!!! And with hate crimes on the rise across our beautiful country - forest fires, smoke and the horrific loss of beautiful young children in my home town - a quiet, warm evening on the couch with those I love, has never seemed more appealing.

Take time to have a sit and a hug with those you love. - c

PD-L1 expression by tumor and response to Pembro - more expression = more response

Not really news here.  We're known this for sometime.  Patients with greater PD-L1 expression on their tumors respond better to anti-PD1, though those with lesser expression can still gain a response.

Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.  Daud, Wolchok...Weber, Ribas, Hodi,... Hamid, et al.  J Clin Oncol. 2016 Dec;34.  

Expression of programmed death-ligand 1 (PD-L1) is a potential predictive marker for response and outcome after treatment with anti-programmed death 1 (PD-1). This study explored the relationship between anti-PD-1 activity and PD-L1 expression in patients with advanced melanoma who were treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Six hundred fifty-five patients received pembrolizumab10 mg/kg once every 2 weeks or once every 3 weeks, or 2 mg/kg once every 3 weeks. Tumor response was assessed every 12 weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent central review. Primary outcome was objective response rate. Secondary outcomes included progression-free survival (PFS) and overall survival (OS). Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5 by one of three pathologists who were blinded to clinical outcome; a score greater or = to 2 (membranous staining in greater or = to 1% of cells) was considered positive. Of 451 patients with evaluable PD-L1 expression, 344 (76%) had PD-L1-positive tumors. Demographic and staging variables were equally distributed among PD-L1-positive and -negative patients. An association between higher MEL score and higher response rate and longer PFS and OS  was observed. Objective response rate was 8%, 12%, 22%, 43%, 57%, and 53% for MEL 0, 1, 2, 3, 4, and 5, respectively. Conclusion PD-L1 expression in pretreatment tumor biopsy samples was correlated with response rate, PFS, and OS; however, patients with PD-L1-negative tumors may also achieve durable responses.

So....when are we going to actually USE this information?????  PD-L1 positive???? Which treatment is best???  This is from 2015 y'all...with links within to other posts from 2012! And, no....I still don't know the results of my tumor testing.

Hang in there ratties!!  The ride sometimes lasts longer than we wish....but we ARE getting there! - c 

Chaotic Cookery! - From Someone Else's Table: Pork Chops and Roasted Onions

I like the combo of sweet and salty.  And for me...pork chops with roasted sweet potatoes or apples or onions...always seems right....especially in the fall.  My family, especially the kiddo's and their  friends have always raved about my everyday pork chops, often requesting "Momma's Pork Chops"!  With such good reviews and their ease of cooking.....thought you might like them yourself.

Momma's Pork Chops

Super easy.  Sear pork chops seasoned on both sides with salt, pepper, and paprika, in a hot skillet.  If it ain't sizzling, it ain't right!!  After all are nicely and quickly browned on both sides.  Splash each chop with a hefty dose of Worcestershire sauce.  Turn down to simmer.  Cover and let simmer as long as you like...at least one hour...more is better....turning occasionally.  Only requirement...DON'T LET THE PAN GO DRY!!!  Add splashes of water as needed until chops are so tender you can cut them with a fork!!  Enjoy.

Roasted Sweet Potatoes

No recipe here really.  Wash and pat dry taters.  Rub with oil.  Poke a couple of holes with a sharp knife.  Roast in 400 degree oven until soft when jabbed with a knife.  Large taters take longer...but about an hour.

Roasted Onions

Another easy, delicious dish from a simple vegetable.  The real cheater's method is to peel medium sized onions, any type, place on a fairly large piece of foil, drizzle with olive oil, salt, pepper, and add one ice cube.  Wrap into a packet and bake until tender.  For a slightly fancier and a bit tastier version.....

Roughly quarter, peeled, red onions.  Place in heavy baking dish.  Cover bottom of pan in white wine (broth would do).  Drizzle onions with olive oil, paprika, salt, pepper and fresh thyme (dried works too!).  Bake covered at 350 for about 30 min.  Then uncover and bake til most of the liquid has evaporated and onions are nicely roasted....about 15 more minutes.  Such a great side dish.

Enjoy your cookery - From Someone Else's Table! - c

BRAF/MEK combined with immunotherapy!!!

I thought this was a very informative article regarding BRAF inhibitors, MEK inhibitors...what we've learned and where research is looking with those drugs.

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.  Eroglue and Ribas.  Ther Adv Med Onc. Jan 2016.

 Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents.

The article goes on to report:  "About one half of melanoma patients carry the BRAF V600E mutation.  BRAF inhibitors illicit 48-59% response rates in those patients. However, duration of response is limited in most patients with a median PFS of 5-7 months “although a minority can last for over 5 years”.  BRAF inhibitors combined with MEK inhibitors improved things further with decreased side effects and increased PFS, amounting to 11-12 months depending on the combo.  It also reviews the importance of intermittent dosing as opposed to continuous therapy with BRAFi in order to delay resistance.  Other drugs combined with BRAF/MEK , like heat shock protein 90 (HSP90) inhibitors, like XL88 can overcome resistance.  There are also plans for additional studies using a triple therapy approach.

NCT01657591:  (Active, not recruiting) - Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma

NCT01902173:  (stopped for assessment) - Akt Inhibitor GSK2141795, Dabrafenib, and Trametinib in Treating Patients With Stage IIIC-IV Cancer

NCT02110355:  (recruiting) - A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma

BRAF/MEK has provided response rates of up to 70% in trials but with limited durability of that response, researchers are looking at combining those drugs with checkpoint inhibitors like ipi, anti-PD1, or anti-PD-L1.  When dabrafenib, trametinib and ipi were combined patients experienced colitis with perforation.  So that arm was stopped, though the ipi and dabrafenib arm is ongoing.  Another trial is currently looking at dabrafenib, trametinib and anti-PD-L1 (MEDI4736).  So far, the ratties are demonstrating a 69% ORR and 16 of 18 patients have an ongoing response."

NCT02130466 is ongoing and recruiting:  A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

 Here's a link to the whole paper:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/ 

Hope that helps, for what it's worth - c

HDAC (Histone deacetylase) inhibitors for melanoma

HDAC inhibitors have been mentioned by melanoma experts previously as something that might aid melanoma patients in overcoming BRAFi resistance:  ASCO 2016 - Inhibitors that may overcome BRAFi resistance: Heat Shock Protein 90 (HSP90) and Ricolinostat (an HDAC6 inhibitor)

Now there is this:

Inhibition of histone deacetylases in melanoma-a perspective from bench to bedside.  Hornig, Heppt, Graf, et al.  Exp Dermatol. 2016 Nov 25.

Histone deacetylases (HDACs) are critically involved in epigenetic gene regulation through alterations of the chromatin status of DNA. Aberrant expression, dysregulation of their enzymatic activity or imbalances between HDACs and histone acetyltransferases are likely involved in the development and progression of cancer. Pharmacologic inhibition of HDACs shows potent antitumor activity in a panel of malignancies such as colon or gastric cancer and multiple myeloma. In this review, we summarize the current knowledge of HDACs in melanoma and evaluate the application of HDAC inhibition from an experimental and clinical perspective. The molecular functions of HDACs can be classified into histone and non-histone effects with diverse implications in proliferation, cell cycle progression and apoptosis. HDAC inhibition results in G1 cell cycle arrest, induces apoptosis and increases the immunogenicity of melanoma cells. Some studies proposed that HDAC inhibition may overcome the resistance of melanoma cells to BRAF inhibition. Several inhibitors such as vorinostat, entinostat and valproic acid have recently been tested in phase I and early phase II trials, yet most agents show limited efficacy and tolerability as single agents. The most frequent adverse events of HDAC inhibition comprise haematological toxicity, fatigue, nausea and laboratory abnormalities. Existing evidence supports the hypothesis that HDAC inhibitors (HDACi) may sensitize melanoma cells to immunotherapy and targeted therapy and hence bear therapeutic potential concurrent with immune checkpoint blockade or BRAF and MEK inhibition.

As noted here, studies of HDACs are proving helpful in multiple myeloma patients when combined with other drugs.  However, thus far, beneficial results for melanoma patients has been minimal.  Keeping my fingers crossed, though!!! - c

Travel Chaotically! - Blame Canada..... (and Seattle)....

....because it was so lovely....I just have to share ~

This is my picture book from our lovely trip traveling from Chicago - Glacier - Vancouver - Victoria - Seattle:  Skyscrapers!!!  Here are the artist's pics of the last 3 ports of call!!

Vancouver

All dressed up and ready for the Blue Water Cafe!

I TOLD you there were skunks!!!

I think their sign has a misprint! It should read:  PROTECTED by SSSS....SKUNKS!

The harbor and Granville Market!

Maiwa!!!  All the pretty things!!!

Atex

Stanley Park - Lost Lagoon - Such peace and beauty in the middle of the city!!!

Of course there were Dragonflies!!!!!

Final perfect evening sunset.  Thanks, Vancouver!!

Views from ferry to Victoria

Victoria

Such pretty flowers - EVERYWHERE!!!

I always love China Town....no matter the city I'm in!

Then there's ~ Butchart Gardens.  An incredibly beautiful place....especially when you consider that Jennie Butchart created it from a 55 acre, worked-out limestone quarry that had supplied her husband's nearby Portland cement plant!!  Amazing! Never have I seen such a lovely collection of begonias - all shapes, sizes and colors!

Seattle

Can you tell I adore markets, veggies, and those who grow them and...???  I do love Pike Place!

Thanks, Sally!

Thanks so much to all the folks we met and shared time with on our travels....the group of Women Marines on the train, the weird Russians vs Germans next to us in the hotel in Glacier where they believed in leaving the door open - no matter their state of undress (Oh, yeah!!!  I saw stuff!!), the taxi drivers in Vancouver, the police man there as well, Liberty at Maiwa, the lovely lady who runs Gala Fabrics...all the vendors at ALL the markets.  But most of all, thanks, B!!!  The best bunkie ever!!! - c