ASCO 2015: IL2 followed by anti-PD1 = GOOD!!!!

Overall survival of metastatic melanoma treated with high dose IL-2 followed by ipi.  J CLin Oncol 33, 2015.  Wong, Morse, McDermott, Kaufman, et al.

PROCLAIM is an IL-2 observational registry with over 40 participating sites consisting of a retrospective (n=70, locked) and prospective cohort (n greater than 343, ongoing). Previously, we reported a median overall survival of 20 months with a median f/u of 37 months in melanoma patients treated with HD IL-2 between 2007 and 2012 from a retrospective cohort (ASCO 2014).  We report this time,  analysis of 240 prospective patients. Patients must have received at least one dose of HD IL-2 prior to 2014.  Survival is current to Jan 2015.

For the 240 prospective patients, the median overall survival is 17.9 months and overall response rate is 15.2% at a median f/u of 20.1 months.  The 1 year survival rate of patients receiving anti-PD1 or ipi after HD IL-2 is 100% and 68% respectively, compared to 58% in IL-2 only group.  The median overall survival for these patients is 25.1 (n=20), 18.4 (n=75), and 14 months (n=112), and the median f/u is 24.2, 20.6, and 17.4 months respectively.  Of the 20 anti-PD1 patients, 12 received ipi first, 4 anti-PD1 first, and 4 anti-PD1 only.  The median time between the last IL-2 dose and start of ipi/anti-PD1 is 3.8 months.  There were no differences in IL-2 treatment intensity between these 3 groups.  Ten of 73 ipi patients suffered treatment-related autoimmune disease in post treatment f/u compared to 0 in the 20 anti-PD1patients.  There were no treatment-related deaths in the combined retrospective and prospective cohorts (n=578).

Conclusion:  The median overall survival for melanoma patients receiving anti-PD1 after HD IL-2 is significantly prolonged over either treatment with IL-2 only, or ipi therapy following IL-2.  The small 'n' for anti-PD1 group and intrinsic shortcomings of registries limits a definitive conclusion about the optimal sequencing of immunotherapies.  Checkpoint therapy after IL-2 appears to be well tolerated, does not impact therapeutic activity and provides a path forward for trials designed to enhance durable, unmaintained IL-2 responses.

Thoughts:
1.  Most researchers feel that combination therapy will hold the key to improved response rates for melanoma patients in the future.  Clearly the Ipi/Nivo combo is demonstrating that, albeit with increased rates of side effects.
2.  Here too, when IL-2 is followed by either ipi or anti-PD1, 1 year survival hits 68% after ipi and 100% after anti-PD1 vs 58% in patients given IL-2 alone. 
3.  Ipi remains the tricky component regarding side effects here...much as it is in the ipi/nivo combo.
4.  That 100% 1 year survival stat in patients having had IL-2 followed by anti-PD1 is AMAZING!!! 
5.  But....so far, that is in small numbers.
6.  And...patients selected for IL2 tend to be in pretty good health in order to be allowed to take the harsh regimen that it is.
7.  Will these numbers for the IL2/anti-PD1 combo end up beating the results for the ipi/nivo combo?
8.  Given the side effect profile and requirement for hospitalization with IL-2 administration...will the results be sufficient to make it worth the difficulty as a first line therapy?
9.  Will these results hold true for patients given anti-PD1 first....and IL-2 later?

Very interesting.  Keep up the good work, ratties.  Best - c

Opdivo/Nivo approved as firstline treatment in EU!

http://m.news.bms.com/press-release/european-commission-approves-bristol-myers-squibbs-opdivo-nivolumab-first-and-only-pd-

How wonderful is that??!! According to the article Opdivo has been given a rapid approval for use in previously treated melanoma patients AND as a first line therapy! The article goes on to describe various studies demonstrating the benefits and side effects of anti-PD1(Opdivo in particular). Stuff we already know as many of us were ratties in the fun and games. I can only assume that given this status, Opdivo is being covered by European payor sources. NOW! What the heck is going on here in the US? Hopefully, the tide will turn here very soon as well and we will all see anti-PD1 as a covered first-line treatment option!

Fingers crossed! -c

Major props to SCOTUS!!!! PEOPLE over politics!!!

    On Thursday, the Supreme Court ruled 6-3 that subsidies for the poor who qualify for them under the Affordable Care Act, to help pay for their insurance, is legal nationwide...even in the 34 states that failed to establish their own exchanges.  In writing for the majority, Chief Justice John Roberts noted, "Congress passed the Affordable Care Act to improve health insurance markets, not to destroy them." The majority opinion cited the law's "more than a few examples of inartful drafting," but added, "the context and structure of the Act compel us to depart from what would otherwise be the most natural reading of the pertinent statutory phrase."  Roberts was joined by the court's liberal justices, Ruth Bader Ginsburg, Stephen Breyer, Sonia Sotomayor and Elena Kagan, as well as by Anthony Kennedy. In his dissent, Justice Antonin Scalia said: "We should start calling this law SCOTUScare," and in a major sour grapes moment added that the court was playing favorites with laws.

    Go ahead, Scalia Scallywag!!!  That name works for me.  Thank goodness the high court of this country was willing to protect the ability of more than 6 million Americans to attain health insurance. And for those of you who think the subsidies are a gross expenditure of tax payer money.... Who do you think paid the bill for those same patients when they were without insurance and showed up in the ER, in horrible shape, since they had gone without care for far too long?  You did!!!  And at that point, the bill to taxpayers was even higher, not to mention the inhumanity we allowed fellow Americans to endure.  And...if you think... Who cares?  I've always paid for my own insurance!  You and me both, buddy.  Since I was 18 years old.  But, once diagnosed with melanoma, I happened to be on my husband's family insurance plan for which we paid extra.  That diagnosis, gave me a huge "pre-existing condition" and the insurance companies the right to refuse me the ability to purchase my own insurance should my husband quit, get fired, retire, or die.  Basically if he lost his job and the family insurance plan in any way...I would have been left with no insurance and no way to get it.  With SCOTUScare...those of us with melanoma and a bazillion other horrible diagnoses cannot be discriminated against in that way by the insurance companies!  Thanks, Antonin!  You're a doll.  NPR report 

    But, wait...before you raise your glass and start cheering the court.....they've made another good, reasonable and humane ruling!!! TODAY, in a 5-4 vote, SCOTUS ruled that the Constitution guarantees the right to gay marriage. Justice Anthony M. Kennedy, writing for the majority in the historic decision, said gay and lesbian couples had a fundamental right to marry.  “No union is more profound than marriage, for it embodies the highest ideals of love, fidelity, devotion, sacrifice and family,” he wrote. “In forming a marital union, two people become something greater than once they were.”  The decision made same-sex marriage a reality in the 13 (Arkansas, Georgia, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Nebraska, North and South Dakota, Ohio, Tennessee, and Texas) states that had continued to ban it.  

    So...even if you are not gay, don't understand it, think that all homosexuals are going straight to the devil...how does their being allowed to marry hurt anyone else?  Glad the court grew a pair, along with a conscience, and ruled that who you choose to love and marry is a legal right, not a blessing to be given or withheld by others.  Would love to visit, but glad I don't have to move to Ireland!  NY Times report

People over politics.  It's about time!  Cheers! - c

ASCO 2015: MEDI0680 - a new anti-PD1!??

A little background:  There are two FDA approved anti-PD1 products on the market:  Nivolumab/Opdivo and Pembrolizumab/Keytruda (albeit only after you have failed ipi and, if BRAF positive, BRAFi as well!).  They have similar side effect profiles and equivalent response rates in melanoma, about 30-40%.  Response rates are probably much higher if your tumor is PD-L1 positive, but the jury is still out due to some conflicting data....probably the result of the (in)accuracy of the test(s) used in testing the tumor.  Cure Tech launched Pidilizumab/CT-011 , another anti-PD1 product, at about the same time that nivo went into trials, to dismal results - a 5.9% response rate - and I personally feel that was inflated.  Additionally, the poor ratties who joined that trial rather than the ones ongoing with nivo and, just a bit later, pembro, quickly realized it was not working...but were then banned from the other anti-PD1 trials because "they had already taken anti-PD1"!!!!!  They were not allowed effective anti-PD1 products until Merck and BMS opened their expanded access programs.  We have heard nothing more from CT-011...thank goodness.  Meanwhile AstraZeneca is working on MEDI-4736, an antiPD-L1 product, in non-small cell lung cancer.  They are combining it with Incyte's INCB24360 (an oral IDO inhibitor) in Phase 1/2 studies.  They are also utilizing MEDI-4736 with an investigational anti-CTLA4 monoclonal antibody tremelizmumab (the same category drug as ipi) as well as with dabrafenib and trametinib.  And finally, AstraZeneca is also evaluating MEDI-0680 (previously AMP-514) an anti-PD1 monoclonal antibody.  So.....

A phase 1, multicenter, open-label, first-in-human study to evaluate MEDI0680, an anti-programmed cell death-1 antibody, in patients with advanced malignancies.  Infante, Goel, Tavakkoli, et al.  J Clin Oncol 33, 2015.

PD-1 is an inhibitory regulator or checkpoint of T-cell activation.  MEDI0680 is a humanized immunoglobulin ...that blocks PD-L1 and PD-L2.  Blocking both PD-L1 and PD-L2 may provide more efficient pathway inhibition and may be more specific for different tumor groups in comparison to blocking either one alone.  This is an ongoing, phase 1, multicenter, open-label, first-in-human, dose-escalation study NCT02013804.  Recruitment is ongoing.

Thoughts:  
1. Blocking both the PD-L1 and PD-L2 pathways sounds cool and sure (????) to be effective.
2.  Hmmmm.....
3.  First-in-human....
4.  Recruitment is ongoing....sites include: NY, CT, Oregon.
5.  No prior BRAFi or immunotherapy (ipi, anti-PD1, or anti-PD-L1) allowed.
6.  Could be the next best thing.
7.  While I am certain combination therapies are what will win the war...I would make sure before signing on...that this treatment would not preclude my ability to take ipi or the current anti-PD1 products should I need them.

Ratties are the best.  Much love and best wishes. - c

Happy father's day!

Bentie, you have been there...on hikes, at soccer games, through moves, dance recitals, scraped knees, temper tantrums, sadness, track meets, training wheels, laughter, transitions, celebrations, hamburger helper, puppet shows, family dinners, sleepless babies, hair 'dudes', science projects, tiropita schmopita, crazy discussions, and even on an elephant.  No daddy has ever done it better!!! We love you. - c

B has decided!

B is ok with his race and gender...but...he is trans-height. Hence forth, he identifies as TALL!  I, on the other hand, have always been an elf.  Yep. It's true. Be yourself! (AMAZING 11.5 mile hike to Gregory Bald today. Story and pics coming soon!) -c

ASCO 2015: Stage IIIA melanoma, deciding treatment by testing sentinel node?

PD-L1 expression, immune cell correlates, and PD-1 + lymphocytes in sentinel lymph node positive melanoma patients:  Implications for adjuvant PD-1 clinical trials.  Kakavand, Vilain, Wilmott, et al.  J Clin Oncol 33, 2015.

Patients with positive sentinel lymph node biopsies that undergo a completion lymphadenectomy have variable five-year survival rates ranging from 39-70%.  PD-1 and PD-L1 inhibitors have significantly improved recurrence free survival (RFS) and overall survival (OS) in stage IIIC/IV melanoma patients.  The aims of this study were to characterize populations of lymphocytes that interact with metastatic melanoma cell in sentinel lymph node biopsy, to determine tumoral PD-L1 expression and to identify whether the PD-1/PD-L1 pathway contributes to immune escape in these patients to provide a rationale for the use of anti-PD-1 inhibitors in the adjuvant setting and aid in the selection of patients for this treatment modality.

The metastatic melanoma containing sentinel nodes from 60 treatment naive patients were analyzed for CD3, CD4, CD8, FOXP3, PD-1 and PD-L1 and correlated clinico-pathologic features and outcomes.  Tumoral PD-L1 expression (greater/= to 1%) was present in 43.3% (n=26) cases.  Cox analysis showed a positive correlation between intratumoral CD3+ lymphocytes and RFS/OS, a positive correlation between intratumoral CD4+ lymphocytes and RFS/OS, and a positive correlation between intratumoral CD8+ lymphocytes and RFS/OS.  There was a negative correlation between peritumoral PD-1+ lymphocytes and RFS/OS.  

CONCLUSION:  Expression of PD-L1 in metastatic melanoma-positive sentinel node biopsy provides a rationale for trials of anti-PD1 therapy in stage IIIA melanoma patients, particularly those with peritumoral PD-1+ lymphocytes.  The expression of immune markers may also be useful to predict the outcome of patients following a positive sentinel lymph node biopsy.

So....it seems that these results indicate that if you have a sentinel node that is positive for melanoma, you should have it tested for the presence of immune cells.  (How readily available this testing is...I'm not sure.)  Then...if your tumor contains intratumoral CD3+, CD4+, CD8+ lymphocytes...you have a better chance of recurrence free survival/overall survival.  If your tumor contains PD-1+ lymphocytes you may do less well, but may respond better to anti-PD1 therapy.  It is not likely a coincidence that in this study, 43% of the tumors present were positive for PD-L1...as that is the rough number of treatment naive patients who attain a response to anti-PD1 therapy.

By the way....none of this was remotely on the horizon much less available as a test when I had a positive sentinel node in 2003, so I have no idea what immune cells were present in my tumor. Additionally, though my melanoma tumor samples have since been tested in the course of my clinical trial, I still don't know if PD-1 or PD-L1 positive lymphocytes were present.

For what it's worth. - c

"Alternative" treatment for melanoma

I started this blog in 2010 (or rather, Rosie did!!) as a way to communicate my personal story to family and friends.  Around the end of 2011, it began to change.  As I was contacted by melanoma patients and their families, I began researching better answers to their questions. Suddenly I realized, if there was one who found me seeking information...there must be many more who also needed to know.  This blog has become my message board to all those families.  Those who read this strange conglomeration will still find my general random craziness, a glimpse into my passions (reading, cooking, sewing, family, running, music), the best research I can find regarding melanoma, and...extreme honesty!  While I put out the latest and greatest about every single development in melanoma, I work hard to include context about what is actually known, what we can hope the treatment will provide, and when I can find the info....how it all turns out. I admit complete hatred of insurance companies...every single one of them!!!  There is so much that needs to be repaired in the way medicine, Big Pharma, clinical trials and the FDA work that I could dedicate every post to those topics alone.  I have absolutely no tolerance for medical providers who treat patients badly, quacks who are no more than elaborate con artists taking advantage of fear and desperation, or legitimate researchers who continue to use FDA approved medications instead of  better, more effective ones.  So, lets start there!

Folks can be very protective of the medicine "they" took.  They seem to take it as a personal insult when treatments they utilized turn out to be lacking.  Interferon is a classic example.  It has little to no effect on melanoma, has been clearly proven to have absolutely NO positive influence on survival, yet docs still use it both as treatment and as a comparative arm in trials, and some of those who took it go into attack mode when it is criticized.  When the good news about ipi was just coming out in 2011, I noted this:  Is interferon still an appropriate treatment?  Though dacarbazine offers at least a bit more help for those who are running out of better options, many of the same criticisms can be applied to its use.  Ribas and Robert had this discussion in 2013:  No more dacarbazine!  I took peptide vaccines as part of my nivo trial.  Since then we have learned - Peptide vaccines do NOT trigger an effective immune response!  Thankfully, they are no longer used in my trial!  (Although one of my fellow ratties bemoaned the fact that patients in the trial currently don't "go through what I went through" as though it was unfair!  OMG!!!  Learning from mistakes made on fellow ratties is the ONLY thing that IS fair in a clinical trial!!!!)  ADC's (antibody drug conjugates) sound great, but so far leak too much nasty chemo into the patient's body (rather than just in the tumor). Hopefully, they will get better.  The Cure Tech anti-PD1 product was a dismal failure and despite the suffering of the ratties (Love you, J!!!) who participated in that trial, it was ended and hopefully will never be heard from again.

All this to say, that melanoma patients can only do the best we can.  We can research things to the best of our ability, find the best care we can afford to get to, and choose!  Sometimes it feels no better than throwing a dart at a board....with your eyes closed!  Educated guesses and desperate decisions.  I am certain I owe my existence to the clinical trial I was lucky enough to be in.  However, there were many ways in the course of that experience in which I was used and treated unfairly.  I think many people fear speaking out....lest they not be allowed to continue or be punished in some other way.  Not me:  Patient rights in a clinical trial. An oxymoron???  I also have no timidity whatsoever when it comes to medical providers who do not serve their patients as they should:  The Jerk!  I did end up getting an apology, as my letter was forwarded to the Jerk in question, perhaps he learned something...we can only hope.  I have even less tolerance for folks who pose as reputable medical providers, when in reality they are nothing more than con artists taking money from desperate, suffering, and frightened patients.  Even when their "treatments" do no harm (though many actually do) they all waste time and treasure as the patient adopts ineffective care, often until it is too late.  My heart will never forget Mike Brockey and the time he lost on Gerson.  Even when you are minding your own business, the Snake Oil Salesmen will even try to attack via blogs!!!  Fredda Branyon, posing as a doctor offering stem cell therapy, was already CONVICTED and facing jail time when she (or her minions) began commenting on every blog they could find with the word 'cancer' in the title:  Dr. Fredda Branyon is a CRIMINAL!  Yes, the conversations I had with many other bloggers were very interesting!

With some regularity, folks contact me here, or post on forums, asking what diet or 'alternative' treatment they could use to 'fight' their melanoma.  While I believe in a healthy diet and exercise, sadly, so far, no particular diet or food has been found to prevent or cure melanoma.  But, I cover them all:  Sugar free, Ketogenic, Gerson, Cellect  There's Strawberry Juice, Eggplant, potatoes, and tomatoes, Red wine, Coffee, doxycycline, curcumin, cimetidine, NSAID's and shitakes, Vitamin D, Snake venom, beta blockers and Vietnamese sophora root, exercise, Curry again!!!  and today there are these:

Anticancer effects of Sandalwood.  Santha and Dwivedi.  Anticancer Research, June 2015.
Effective management of tumorigenesis requires development of better anticancer agents with greater efficacy and fewer side effects.  Natural products are important sources for the development of chemotherapeutic agents and almost 60% of anticancer drugs are of natural origin.  Alpha-Santlol, isolated from Sandalwood, is known for a variety of therapeutic properties.  Our laboratory identified its anticancer effects in chemically-induced carcinogenesis in [special] mice and in vitro models of melanoma, non-melanoma, breast and prostate cancer.

Good to know.  However, that's a long way from peeps.  Not sure what "non-melanoma" is!  And, while I will be the first to laud the lowly periwinkle (the source of one of the best and most effective chemotherapy drugs, Vincristine) and work to protect the rain forest, nature also provides us with poison ivy, oleander, and hemlock!

Coffee drinking and cutaneous melanoma risk in the NIH-AARP diet and health study.  Loftfield, Freedman, Graubard, et al.  J Natl Cancer Inst.  Jan 2015.
Cutaneous melanoma is the fifth most common cancer in the US.  Modifiable risk factors, with the exception of exposure to ultraviolet radiation, are poorly understood.  Coffee contains numerous bioactive compounds and may be associated inversely with melanoma.  Coffee intake was assessed at baseline with a food frequency questionnaire in the NIH-AARP prospective cohort study.  Among 447,356 non-Hispanic whites who were cancer-free at baseline, 2,904 cases of malignant melanoma were id'd during a median 10.5 year follow-up.  After statistical analysis, the highest category of coffee intake (more than or equal to 4 cups a day) was inversely associated with malignant melanoma, but only if was caffeinated.

Though the authors admit they are not sure if the effect was from the coffee or the caffeine, guess I'll have another cup!!!

No matter how strange the findings, when it comes to melanoma, I will certainly put it all out there!!!  You never know!  But, if it walks like a duck, quacks like a duck, smells like a duck, seems just a little too easy, too crazy, or too good to be true....it probably is!!!!  Don't let desperation trick you into doing something that could prevent you from getting the best REAL help you can.  This oped/report on cancer therapy by QuackWatch 
provides good analysis of particular treatment scams as well as basic information about how treatments and programs are analyzed to determine their real value and how quacks twist the 'data' and prey on the fears of frightened folks.  This paragraph really hit home:
    "Quacks typically charge that the medical profession, drug companies, the food industry, government agencies, and/or other "vested interests" are conspiring against "natural" cancer cures. No such conspiracy has ever been exposed. Yet many patients—especially those whom standard medicine cannot cure—embrace the notion that a small but dedicated band of rebels is defying the medical establishment by making natural cures available. And desperate patients may find it more comfortable to believe that cures are being suppressed than to feel that their situation is hopeless."

Don't let jerks take advantage of you.  Melanoma is fight enough. There are more viable treatments (as lame as they are!!!) for melanoma than ever before.  It is not easy, but don't let fear and denial rule your decisions.  I hope this helps.  I wish you well. - c 

They're back....

....just in time to celebrate 25 special years!!!

But, they are not alone....

Even this little guy....

All sending special birthday wishes!!!  We love you Fred-o!!!!!  Happy, happy day!!! - mommy

Cades Cove...

 

I have been so fortunate to have experienced many lovely hikes and adventures in Cades Cove this season.  As spring gives way to summer...I look forward to the beauty that nature will bestow.  Enjoy.  - c