Wednesday, July 1, 2015

BRAFi: What predicts resistance? Discontinuation after complete remission? Dabrafenib/trametinib combo and quality of life?


The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.  Massi, Brusa, Merelli, et al. Ann Oncol, June 2, 2015. 

BRAF inhibitors improve survival in metastatic melanoma patients but the duration of clinical benefit is limited by development of drug resistance.  Here, we investigated whether the expression of Programmed Death-Ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated melanoma patients. 
PD-L1 expression (cut-off - 5%) and TIMC were analyzed...from 80 consecutive melanoma patients treated with BRAFi at a single institution.  46 and 34 patients received vemurafenib and dabrafenib, respectively.  Membraneous expression of PD-L1 was detected in 35% of patients.  After analysis:  ABSENCE of tumoral PD-L1 staining and the presence of TIMC were associated with a better response to treatment.  Median PFS and OS were 10 and 15 months respectively.  Additionally, analysis demonstrated, PD-L1 expression and absence of TIMC correlated with SHORTER PFS.  Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 expression and density of immune cell infiltration of BRAF V600 mutated melanoma treated with BRAFi.

Thoughts:
1.  The study used a 5% cut-off for PD-L1 expression, while many studies use 1%, not sure that matters.
2. According to this study, patients treated with BRAF inhibitors did better if their tumors were negative for PD-L1 and loaded with TIMC.
3.  Now...these results can't (yet) be determined to mean that BRAFi was undermined by the presence of PD-L1 or facilitated by the presence of TIMC.  It is just one more study that demonstrates the presence of PD-L1 and absence of TIMC are bad prognostic indicators...unless...at least in the case of the PD-L1...you are taking anti-PD1 drugs.
4.  Notice...one more time...PD-L1 was present in 35% of patients.
5.  Clearly, we have lots to learn.

Complete remission of metastatic melanoma upon BRAF inhibitor treatment - what happens after discontinuation?  Tolk, Stzger, Mohr, et al.  Melanoma Res. June 8, 2015.

Treatments with BRAFi leads to complete remission in 3-6% of patients with BRAF mutant melanoma.  In cases of complete remission, it is unclear whether BRAFi therapy should be continued.  We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving CR.  In 12 patients, CR of melanoma was diagnosed after a median BRAFi treatment duration of 13 (0.3-32 months) months.  Reasons for d/c were side effects in 7 and patient demand in 5.  Six patients are still in CR after a median 17 months (2-26 months) after discontinuation of BRAF inhibition.  Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy.  Subsequently, these patients were again treated with a BRAFi, which resulted in 3 CR, one stable disease, and one progressive disease, and one patient who could not be assessed.  Melanoma patients achieving CR during BRAFi therapy represent a heterogenous group.  Discontinuation of BRAFi therapy after CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse.

Thoughts:
1.  While BRAFi provides a beneficial response in approximately 70-80% of BRAF positive patients, apparently only 3-6% of those gain complete remission.
2.  But, if you do....it seems that half of those will maintain remission (for at least 17 months...so far) after discontinuation of BRAFi.
3.  The half who do recur after stopping BRAFi, appear to have a 50% chance of regaining complete remission on retreatment. 
4.  These are very small numbers...but something to think about.

Health-related quality of life impact in a randomized phase III study of the combination of dabrafenib and trametinib vs dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.  Schadendorf, Amonkar, Stroyakovskiy, et al.  Eur J Cancer, March 17, 2015.

The COMBI-d trial that combined dabrafenib and trametinib vs dabrafenib monotherapy showed that patients taking the combo experienced significantly prolonged progression-free survival.  These same patients were evaluated regarding quality of life using an established questionnaire.  Questionnaire completion rates were more than 95% at baseline, less than 85% to week 40 and less than 70% at disease progression.  Baseline scores across both arms were comparable for all dimensions.  Global health dimension scores were significantly better at weeks 8, 16, and 24 for patients receiving the combo during treatment and at progression.  Pain scores were improved and meaningful in patients receiving the combo for all follow-up assessments vs those receiving monotherapy.  For other symptoms (nausea, vomiting, diarrhea, dyspnea, constipation) scores trended in favor of monotherapy.  This analysis demonstrates that the combo of dabrafenib and trametinib provides better preservation of quality of life measures and pain improvements vs dabrafenib monotherapy, while delaying progression.

Thoughts:
Given the better results and decreased side effects noted in the COMBI-d study when dabrafenib was combined with trametinib...improved quality of life is not really a surprise, but still nice to know.  For a refresher regarding BRAFi:  BRAFi for melanoma - dabrafenib, vemurafenib, and the dabrafenib/trametinib combo  For more info:  Data on BRAFi combo's

Wishing you all my best. - c




Monday, June 29, 2015

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

Sunday, June 28, 2015

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

Friday, June 26, 2015

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

Monday, June 22, 2015

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

Sunday, June 21, 2015

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

Thursday, June 18, 2015

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