Combination therapies for melanoma

New Combinations and Immunotherapies for Melanoma, Latest Evidence and Clinical Utility
Menzies and Long, Ther Adv Med Oncol. 2013;5(5):278-285.

Despite being a little over a year old, and most of the studies referenced - I've already posted, this article still presents a very good overview of the combination therapies with some clear explanations.  Here are the highlights:

Combination BRAF and MEK Inhibitors

Several trials have combined BRAFi and MEKi for patients with V600 BRAF-mutant melanoma.
1.  Dabrafenib with trametinib (CombiDT)
2.  Vemurafenib with cobimetinib
3.  LGX818 with MEK 162

The reason for the combinations is twofold:  to prolong the progression-free survival by delaying or preventing the development of MAPK-dependent resistance and to reduce BRAFi related toxicities as a result of the paradoxical activation of the MAPK pathway in non-melanoma BRAF wild-type cells.

In normal cells, growth factors bind to the cell surface receptor tyrosinekinases (RTKs).  There they trigger signals down various pathways:  RAS-RAF-MEK-ERK(MAPK) and P13K-AKT-mammalian target of rapamycin (mTOR).  This [normal] signaling creates regulated cell proliferation, growth and survival.  Melanoma causes abnormal activation of the MAPK pathway, and include activation of mutations in BRAF (40-50%), NRAS (20%), and KIT (less than 5%).

1.  Dabrafenib with trametinib (CombiDT)
Initial data showed that response rates were higher with CombiDT than with dabrafenib alone, BUT, only 19% of patients who had failed prior BRAFi therapy got a response.  The randomized section of the trial showed a higher response rate (76% vs 54%), longer median progression free survival (9.4 vs 5.8 months), and fewer toxicities in MAPK inhibitor naive patients compared with dabrafenib monotherapy.  All BRAFi toxicities:  hyperkeratosis, alopecia, arthralgia and rash were less frequent.  Cutaneous squamous cell carcinoma with CombiDT was 1/3 of that with dabrafenib alone (7% vs 19%).  Fever was the most common AE and occurred in 70% of patients on CombiDT, but was found in only 26% of dabrafenib only patients.  Mechanism is not understood.  Fevers occur early, are often repetitive, can be managed with brief dose interruption, or if recurrent...with corticosteroid prophylaxis.

2.  Vemurafenib with cobimetinib
In the phase 1 trial, 70 patients with Cobas-positive metastatic melanoma, of which 38 (54%) had failed to respond to prior vemurafenib.  {The Cobas 4800 BRAF V600 mutation test by Roche, is a polymerase chain reaction based test that is very sensitive and specific for V600E BRAF mutation, but only detects 40-70% of V600K and no other V600 mutations.}  All 25 BRAFi naive patients had a reduction in tumor size.  In 32 patients previously treated with BRAFi, the response was only 19%.  Squamous cell carcinoma, rashes, arthralgia, and fatigue were decreased with the combo compared to vemurafenib alone.  MEK inhibitor AE's:  creatine kinase elevation, diarrhea and chorioretinopathy were reported in 4-6% of patients.

3.  LGX818 with MEK 162
The phase 1 trial of the BRAFi, LGX818 and the phase 1/11 trial of the combo, LGX818 and the MEKi, MEK162 allowed any V600 BRAF mutation, including rare variants like V600R.  The phase 1 trial of the BRAFi LGX818 monotherapy enrolled 26 BRAFi naive and 28 BRAFi pretreated patients.  Results showed a confirmed response rate of 58% in BRAFi naive and 11% in BRAFi pretreated patients.  Unlike vemurafenib and dabrafenib - photosensitivity, liver enzyme elevations, and fever were rare.  In the combo trial - 9 BRAFi naive and 14 BRAFi pretreated patients were studied.  There was a confirmed response rate of 88% in naive patients and an 18% response in pretreated patients.  No fever, photo-sensitivity, nor squamous cell carcinoma reported thus far.

Anti-PD1 and Anti-PD-L1 Antibodies [immunotherapy]  (Note:  what follows is pretty old news but a good summation of data, especially from the early trials.)


Unlike CTLA-4 antibodies, the PD-1 and PD-L1 antibodies aim to potentiate the antitumor T-cell response at a tumor-specific level, by impairing the interaction of the inhibitory receptor PD-1 on T cells with PD-L1 expressed on tumor cells.  T cells interact with tumor cells in peripheral tissues.  Tumor cells can present antigen to the T-cell receptor, resulting in a stimulatory signal to the T cell.  Tumor cells may also express PD-L1, which interacts with PD-1 on activated T cells, and results in inhibition of the antitumor T-cell response.  (See below)

Nivolumab (BMS-936558, MDX-1106, ONO-4538, Opdivo)  Anti-PD1
A fully human immunoglobulin monoclonal PD-1 antibody and was first of its class to be tested in a phase 1 trial with 107 patients with metastatic melanoma with no exclusions. Approximately 25% of patients had received 3 or more lines of systemic therapy, responses were seen throught the range of doses given every 2 weeks, with an overall response rate of 31% (41% in the 3mg/kg group).  Median duration of response was over 2 years.  Well tolerated generally.  Toxicities were immune related and were less frequent and less severe than with ipi.  Common toxicities were: fatigue, rash, diarrhea, and itching.  Grade 3/4 AE's occurred in 21% of patients = lymphopenia, fatigue, diarrhea, nausea and anemia.  Pneumonitis was a rare but significant side effect, resulting in the death of three patients.  There was no association between drug dose and efficacy or toxicity.

Lambrolizumab (MK-3475, Pembrolizumab)  Anti-PD1
A humanized monoclonal PD-1 antibody, studied in phase 1 trial that included 132 patients with metastatic melanoma.  67% of patients had BRAF wild type, 9% had brain mets.  Overall response rate was 51% in the 85 patients dosed at 10mg/kg.  Ipi naive patients had a response rate of 55%. Patients who had progressed on ipi had a 41% response rate.  15.9% of entire cohort had immune related AE, only 5.3% of those were grade 3/4.  All grade 3/4 toxicities were at the 10mg/kg dose and included: nephritis, pleuritic pain, pancytopenia, pneumonia, v/d, thyroiditis.  Pneumonitis occurred in 3% of patients, all grade 1/2 and was managed with dose interruption, and in once case, steroids.

BMS-936559 - PD-L1
A fully human PD-L1 antibody, was tested in 55 patients with metastatic melanoma.  56% of the patients had received prior immunotherapy and 9% had had BRAFi.  Overall response rate was 17%.  Highest response rate was in the 3 mg/kg dosage. Of the 9 who responded, 5 had an ongoing response for over a year, and overall, 27% of patients had stable disease for over 6 months.  Toxicity was mild.  9% of patients had grade 3 AE's, 39% had immune adverse event of any grade - rash, hypothyroidism, hepatitis, sarcoidosis, endophthalmitis, DM, and myasthenia gravis.

Future Implications

• MAPK inhibitors in combination result in response in almost every patient and are more durable than single agent responses, but acquired resistance is still an obstacle, and most patients relapse within a year.  However, there is a subgroup of patients that may benefit for a prolonged period.
• PD-1 and PD-L1 immunotherapies provide faster and more frequent responses than ipi, but durability remains unknown {though we are gaining more info daily!!}.
• Combining MAPK inhibitors and immunotherapy seems to have a real possibility of greater success.  However, the first combo trial tried (vemurafenib and ipi) had to be terminated due to liver toxicity, a known side effect of both drugs.  Trials with dabrafenib and ipi with/without trametinib are underway.
• IPI and nivo combined, and ipi combined with radiation, are producing good results.
• Though not compared head-to-head, anti-PD1 and anti-PDL1 are probably more active and have fewer toxicities than ipi.  Also, the possibility that tumor PD-L1 expression may be a biomarker to predict response is appealing. In one nivo trial, no responses were seen in 17 patients with tumors that did not express PD-L1, while 9 of 25 patients with PD-L1 expression had a response.  Pretreatment biopsies have been collected for all patients on the lambrolizumab trial and results are awaited.
• The greatest role for systemic treatments may be in the adjuvant setting.  The risk of distant relapse and death in patients with high-risk early stage melanoma (11C/111) is approximately 50%.  The only approved adjuvant, interferon, is toxic and has little impact on survival.  Several drugs ipi, MAGE-A3, vermurafenib, and CombiDT are in ongoing trials as adjuvants vs placebo....so.....

We've come a long way, baby!!!  But, we still have a long way to go!!!! - c

Believe in good....

I have been touched by this video for some time.  When a friend re-posted it, I knew it was really worth sharing.  (Thanks, David!)

Yes, it's an ad....but.....

Witness happiness.  Feel love. Receive what money can't buy.  Make the world more beautiful.  Believe in good.

And...for a bit of fun.....another ad...

Laugh. Enjoy the silly, the beautiful, the grand, the small.  Much love - c

Strength and beauty = Chantelle Brown-Young....and me???

So very proud of a lovely young woman and those who accept her beauty, though strength of spirit is her most impressive attribute!!!  Read her story in the link below.

Chantelle Brown-Young

Not as dramatic given my fair skin tone in the first place, but....sometimes gives a girl pause.

May we all find the strength to be our best selves each day. Love, c

SUMMER READING, Part 3

Cutting for Stone  By:  Abraham Verghese
     A truly beautiful book of love, heartbreak, and medicine that begins in an Ethiopian Mission hospital, populated by locals, an Indian nun, two Indian doctors and a British surgeon.  I adored the characters Hema and Ghosh and the medical aspects. (Do not be alarmed....you needn't know a thing about medicine to appreciate them!)  I was touched that some of the characters' love for one another came through in their ease of working side by side, as if of one mind, assisting one another while caring for patients with no strain or confusion.  Just a simple flow and intuitive knowledge of what the other needed.  It reminded me of working with B!  My only criticism was a stretch into the symbiosis of twin-dom that got a little carried away, but was still very much worth the reading.  I was very glad I had eaten Ethiopian food, their bread in particular...

     Injera is served just as you see here...in rolls alongside (Incredibly similar in appearance to ACE wraps, unfortunately!!), and as the "plate" for the communal meal.  The food is deliciously seasoned and doesn't taste like Indian food despite the appearance.  The bread...is something you probably need to develop a taste for!  It is a sourdough flat bread made from teff (a tiny iron rich grain) flour, mixed with water, that is allowed to ferment for several days.  The liquid batter is poured onto the baking surface resulting in flat bread with one smooth and one porous side that is then used both as your plate and your fork!

     Passages I loved:
"Sound Nursing Sense is more important than knowledge, though knowledge only enhances it. [It] is a quality that cannot be defined, yet is invaluable when present and noticeable when absent."

"Hema's style was precise and careful - a living example...of why more women should be surgeons."

"My VIP patients often regret so many things on their deathbeds.  They regret the bitterness they'll leave in people's hearts.  They realize that no money, no church service, no eulogy, no funeral procession no matter how elaborate, can remove the legacy of a mean spirit."

"But a few lucky men...never have such worries; there was no restitution he needed to make, no moment he failed to seize."


The Thirteenth Tale  By: Diane Setterfield
     Offered to me by a nurse at work, this was a uniquely written mystery of sorts, in which the method of the telling lent a great deal to the story itself.  Surprisingly, after the symbiosis of twins was touched on in Cutting for Stone, it was part of this story too.  Interestingly, the author touched another chord....the question of seeing things as we choose to see them...whether we intend to or not...  "To guard against errors such as this, one would have to teach oneself to view everything without preconception, to abandon all habitual modes of thought.  There is much to be said in favor of such an attitude in principle.  The freshness of the mind!  The virginal response to the world!  So much science has at its root the ability to see afresh what has been seen and thought to be understood for centuries..."  Something researchers need to train themselves to do for certain....but it is not always that easy, is it?
Happy reading! - c

SUMMER READING, Part 2

And then there were none  By:  Agatha Christie

      The lady can tell a tale. It had been some time since my first reading, and this round hit me most profoundly. A little story with so much to say on right and wrong, responsibility, and living with your choices. Murder is often much more complicated than the 'simple' act of pulling the trigger.
     As planes are being shot down because of an uprising, supported by this faction, supplied by that power, with agreements signed by this man.  Did 'he' not ultimately shoot down that plane...and kill 298 people?
     Why are children (over 100 so far this year) dying and suffering with polio in Pakistan?  Is it due to the marauding Taliban followers who have killed 60 polio vaccination workers since the Pakistani Taliban banned polio vaccination in 2012? Does responsibility fall to the Taliban leaders who direct such tactics? Or does the fault lie with the genius in our own CIA who used a bogus hepatitis B vaccination campaign to collect information about the location of Osama bin Ladin?  I'm not against the process of espionage needed to find bin Ladin.  But, to connect those trying to protect and heal others from deadly diseases with our CIA surveillance in a culture that places little trust in our motives in the first place, thereby putting the lives of children, their parents, and healthcare workers at risk, is unconscionable!  So, who is killing and maiming those children and workers?  The ones who pulled the trigger?  The Taliban leaders?  Or did we do that?  Me and You?

10,000 Maniacs - Please Forgive Us

Lyrics:

"Mercy, mercy, why didn't we hear it?  Mercy, mercy, why didn't we read it, buried on the last page, of our morning papers?

The plan was drafted, drafted in secret.  Gunboats met the red tide.  Driven to the rum trade for the army, that they created.  But, the bullets were bought by us, it was dollars that paid them

Please forgive us, we don't know what was done.  Please forgive us, we don't know what was done in our name.

There'll be more trials like this, in mercenary hey days.  When they're so apt to wrap themselves up in the stripes and stars, and find that they are able to call themselves heroes, and to justify murder by their fighters for freedom.

Please forgive us, we don't know what was done.  Please forgive us, we didn't know.  Could you ever forgive us? I don't know, how you could.  I know this is no consolation.  Could you ever believe that we didn't know?

Please forgive us, we didn't know.  I wouldn't blame you if you never could.  Please forgive us.  And you never will."

To all the questions posed, I fear Dame Agatha would answer, "Yes! All of you." - c

eIF4F, the way to break resistance to anti-BRAF and anti-MEK in the future?

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies   Boussemart, et al.  Nature. 2014. July.

 Synopsis:

'In BRAF (V600)-mutant tumors, the resistance to the drugs that targets BRAF or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal pathway, on activation of the other PI(3)K-AKT-mTOR pathway, or on modulation of the caspase-dependent apoptotic cascade.  (WOW!!  But, basically - these three different 'pathways' can mess up a patient's response to BRAFi or MEKi treatment.)  All three of these pathways converge to regulate the formation of the eIF4F...complex, which binds to the...end of messenger RNA, thereby modulating the transcription of mRNAs...[and in this study they show] that the persistent formation of the eIF4F complex...is associated with resistance to anti-BRAF, anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF (V600)-mutant melanoma, colon, and thyroid cancer cell lines.  (Sooo, these smart peeps figured out the three main ways the eIF4F complex messes up the works.) [They developed a way to detect such interactions and showed] that the eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases... Strikingly, inhibiting the eIF4F complex...synergizes with [BRAFi] to kill the cancer cells.  eIF4f not only  appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target.  Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.'

Now...this is only in a petri dish, not demonstrated in humans...and therefore is a long way from use in peeps...but it certainly sounds promising to me!!!  Way to go, smart researcher people!! - c

SUMMER READING, Part 1

I love so many things...reading, cooking, working, running, my garden, sewing, music, writing, time with family and friends, my efforts to spread hope and knowledge for those with melanoma. There hardly seems time to do it all.  However, I have enjoyed some of my reading so much this summer, that I thought I would share a bit of it with you.

I Am Malala  By:  Malala Yousafzai
     Malala began writing about life under the Taliban, in Swat Valley, Pakistan for the BBC when only 11.  In 2012 she was targeted and shot in the head by the Taliban in retribution for speaking out for the education of girls and continuing to attend school herself.  Her willingness to stand up for what is right, while still indulging in the desires of a young girl for pretty hair and fair skin, is shared in high relief.  The book provides a clear picture of Pakistan, it's beauty, history - Hinduism in India, the departure of Muslims from India to Pakistan, Hindus returning to India.  Ahmadi Muslims who are not recognized as such by the Pakistani government.  The Muslim split between the Sunnis and Shias, the Taliban, ISI.  Veils and punishment in the street.  An unthinkable situation, yet the only life that exists for so many...today.  All told by an amazing young woman.

Other related incredible reads:
Three Cups of Tea:  One Man's Mission to Promote Peace...One School at a Time
By:  Greg Mortenson and David Oliver Relin  Though some controversy bubbled up about the organization, expenditure of funds collected, and accuracy of some bits of his story...it is still a good read and vivid portrayal of life in remote regions of Pakistan and Afghanistan.
Desert Queen, The Extraordinary Life of Gertrude Bell
By:  Janet Wallach  The story of Gertrude Bell (1868-1926) who explored, mapped, and excavated Arabia while other women never ventured beyond their doorsteps alone; playing a major role in the British Empire, as they drew lines in the sand to create the modern Middle East.

Cloud Atlas  By: David Mitchell
     An amazing compilation, six incredible stories with unique characters, really.  Yet, all strangely connected, as we all are, if we just pause to see it.  A treatise on race, equality, consumerism ~ hidden in beautiful prose.  So many unforgettable lines. One, you've already heard me use:
"Do whatever you can't NOT do."

"Truth is singular.  Its 'versions' are mistruths."

"...it is attitude, not years, that condemns one to the ranks of the Undead, or else proffers salvation.  In the domain of the young there dwells many an Undead soul."

     And while I most often hold more with the phrase above, I have seen life become such that the following becomes plausible.... 

"People are obscenities. Would rather be music than be a mass of tubes squeezing semisolids around itself for a few decades before becoming so dribblesome it'll no longer function."

"List'n, savages an' Civ'lizeds ain't divvied by tribes or b'liefs or mountain ranges, nay, ev'ry human is both, yay."

"I got to live with not knowin'....I ain't the fist un who lived so, an' I ain't the last neither."

"...social strata was demarked, based on dollars and, curiously, the quantity of melanin in one's skin."

"Because you cannot discern our differences, you believe we have none."

"What precipitates outcomes?  Vicious acts and virtuous acts.  What precipitates acts?  Belief.  '...only as you gasp your dying breath shall you understand, your life amounted to no more than one drop in a limitless ocean!'  Yet what is any ocean but a multitude of drops?"

Beautiful and true.  No? - c

Robin Williams...we never really knew you...enough...

Such passing is so hard for me to understand.  Robin Williams, a man I've never met, was such a part of our lives.  My kids really feel the loss.  Mrs. Doubtfire.  Aladdin.  Dead Poets Society.  Good Will Hunting.  Good Morning Vietnam. Awakenings.  And two of my very favorite movies EVER....The Fisher King and What Dreams May Come.  How we've cried through both of those!!!  And how we've laughed....James Lipton's interview from Inside the Actor's Studio, will bring you to tears due to laughing so hard.

On a lighter note...for Fred and Ruthie...from the man himself:
"Okra is the closest things to nylon I've ever eaten.  It's like they bred cotton with a green bean. Okra, tastes like snot.  The more you cook it, the more it turns to string."

And so that we can go on:
"No matter what people tell you, words and ideas can change the world."

And so you did, Mr. Williams.  May you now have peace.  -c

Review of interleukin-2 as intra-lesional melanoma treatment

Treatment of in-transit melanoma with intra-lesional interleukin-2: A systematic review.  Byers, et al. J Surg Oncol. 2014. July.

Authors searched databases to find studies evaluating the clinical response to IL-2 for in-transit melanoma done from 1980-2012.  Data was then pooled and analyzed to determine lesion and patient responses.  49 studies found.  43 didn't meet criteria.  Of 6 observational trials - dose, treatment interval, and response rate were variable.  Overall, 2,182 lesions and 140 patients were treated in these studies.  Pooling the lesions, complete response was seen in 78%.  Pooling subjects, 50% achieved a complete response.  Treatment was generally well tolerated. Side effects were:  localized pain and swelling, mild flu-like symptoms.  Only 3 grade 3 adverse events were noted: including rigors, headache, and fever with arthralgia.  Conclusion:  Intra-lesional IL-2 safely and effectively provides locoregional control of in-transit melanoma.

While the specifics and exact "how to's" are a little vague here, the response sounds pretty good.  Y'all know I'm a fan of looking deeper into intralesional therapy!!!!  Best - c

How many pickled, roasted, teaching peppers???

More bounty from summer and B, the pepper master!!!

So pretty!!

Pickled jalapenos and two jars of "mixed" pepper surprise!!

Ready for roasting...

Once they are desiccated enough...

He grinds them up and we have a variety of pepper flakes!

The Pepper Professor!

First day of school...for the Peppiest Math Teacher!!!

Yep!  LOTS of peppers!!!  Hope your day was filled with hot, happy peppers, too!!! - c

Abscopal Effects of radiotherapy on melanoma...more info...

Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy.  Grimaldi, et al.  Oncoimmunology.  2014, May.  Synopsis:

...'the "abscopal effect" is the regression of non-irradiated metastatic lesions distant from the primary tumor site directly subjected to radiation.  This response is rare, but is thought to be an immune-mediated phenomenon, suggesting that if RT and immunotherapy were combined the effect could be enhanced.  In this study, patients were treated with ipi followed by radiation in an expanded access program in Italy.  Those who progressed on ipi (21) qualified. 13 patients received RT for brain mets, 8 were given RT at extracranial sites.  An abscopal response was observed in 11 patients (52%).  Median time from RT to abscopal response was one month.  Median overall survival for all 21 patients was 13 months (range 6-26).  Median OS for patients with abscopal response was 22.4 months (range 2.5-50.3) vs 8.3 months without the response.  A local response to RT was detected in 13 patients, and of those, 11 patients (85%) had an abscopal response and abscopal effects were noted ONLY in patients exhibiting local response.'

The authors recommend additional trials with greater numbers to validate these results...and I say, "Go for it!!!"  Not just in studies, but here in the US these are treatment measures that oncs can already provide!!!  Best - c