Sunday, July 27, 2014

More Intralesional therapies for melanoma....abstracts from ASCO 2014

Wrote this post up in June, but with so much new info about anti-PD1 EAP's (from Merck and BMS) as well as the EAP for the ipi/nivo combo and all the other melanoma news...this got put on the back burner.  I still love the idea of intralesional therapy for folks with accessible tumors.  I don't think it will ever be a cure-all, but feel it holds real promise especially when combined with more systemic therapies.  This is what Weber and Ribas had to say about one in their chat:

Injectable therapies
Ribas:  ...a randomized trial of an injectable virus called T-VEC compared with granulocyte-macrophage colony stimulating factor (GM-CSF).

Weber:  ...the responses were 16% vs 2%.  Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero.  A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest....that is close to being able to show that there are benefits to giving this injectable therapy....Injectable therapies are making a comeback.....eons ago we were injecting BCG, interferon, and IL-2 into local-regional melanoma metastasis.....now there are some interesting drugs, and T-VEC is one of them.  I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipi, or a combination of those....that's where I see intralesional therapy going.

2 abstracts:

Tumor response and patient survival after intralesional therapy with low-dose GM-CSF and IL-2 in metastatic and primary cutaneous melanoma:  An exploratory study.
Abstract c20002, Elias and Sharma

Patients with dermal and subdermal mets, no matter the extent of their disease or previous therapy, were given intralesional GM-CSF once a week for 4-6 weeks. If no complete clinical response was noted at the injection sites, they were then given intralesional IL-2 for the same length of time. 
Results:  4 patients with more than 126 small in-transit mets, each lesion measured a few mm to up to 1 cm.  All had a complete response confirmed pathologically 6-8 weeks after cessation of therapy, with disease free survival of 37-54 months.  Another 3 patients with large sclerotic skin lesions failed to respond to either cytokine.  One of 2 patients with distant mets who also had palpable subdermal tumors had complete response of all mets. This patient is alive and disease free for over 48 months.  Conclusion:  [After examination of the tissues resected after treatment...] Intralesional therapy seemed to utilize the tumor site as a source for tumor-specific antigens giving rise to autoimmunization with strong antitumor response...

A phase I study with LTX-315, an immunogenic cell death inducer, in patients with transdermally accessible tumors.
Abstract 3067, Brunsvig, Aamdal, Kolstad, et al (London and Oslo)

LTX-315 is a chemically modified 9-mer peptide...and induces the release of potent danger signals and tumor-associated antigens.  Preclinical animal studies have demonstrated that treatment of a single tumor with LTX-315 generated systemic anti-tumor immune response that eradicated distant lesions and prevented recurrence following tumor rechallenge.  Patients received weekly ultrasound guided injections of LTX-315 into a single tumor for a max of 6 injections (dosage varied).  14 patients with lymphomas, malignant melanomas or breast cancer were enrolled.  Tumor necrosis was seen in 5 patients.  2 patients had a 50% reduction in tumor volume.   A new intratumoral study at 4 European sites is ongoing.  Clinical trial number - NCT01058616.

Don't forget good old Rose Bengal (PV-10) as well.  Sort of wish my buddy, J, could have had at least one of these injected into any residual tumors while surgeons were meddling around in there!!!  What the heck?  That's a thought for a trial!  When a melanoma patient has to undergo surgery....inject one of these bad boys into any accessible tumor that is not removed!  Why not?  Just a thought! - c

Thursday, July 24, 2014

Cytotoxic T cells and BRAFi work on melanoma brain mets! One more time....



...and this is OLD, y'all!

Melanoma brain metastasis:  overview of current management and emerging targeted therapies.
Expert Rev, Neurother. 2012.  Fonhem, Uhlmann, Floyd, et al.

“While ipilimumab cannot cross the blood–brain barrier, activated T cells can migrate into the brain and exert an anti-tumor effect. However, data on its efficacy against melanoma brain metastases are limited.  Only one prior trial enrolled patients with known brain metastases and the inclusion criteria required them to be treated and to have achieved radiologic stability prior to enrollment. Nevertheless, anecdotal reports have indicated that ipilimumab may have efficacy against metastatic melanoma in the brain and the spinal cord. Hodi et al. reported a case of a woman with melanoma that had metastasized to the brain and spinal cord from an unknown primary. After initial treatment with neurosurgical resection of a symptomatic metastasis, adjuvant radiosurgery to other brain metastases, external beam irradiation to spinal metastases and adjuvant temozolomide, she received ipilimumab at the time of disease progression in the brain. Although a new brain metastasis was found during the maintenance phase of ipilimumab treatment, surgical removal of the metastasis demonstrated predominantly CD8+ cytotoxic T cells but few FoxP3+ Tregs, suggesting a fulminant immune response against this brain metastasis rather than tumor progression.”  

And there's this on the BRAFi:    


"The efficacy of vemurafenib against brain metastasis from melanoma is unknown. This is because past clinical trials excluded patients with active brain metastases. However, the physio-chemical property of vemurafenib suggests that it may have difficulty crossing the blood–brain barrier. This is because drug penetrance into the CNS depends on its size...and lipid solubility. Vemurafenib has a molecular weight of 489.9 and its large size makes it difficult to passively diffuse across the blood–brain barrier.

Despite these unfavorable chemical properties, there have been anecdotal reports of vemurafenib efficacy against melanoma brain metastases… A case report described the use of vemurafenib in a 16-year-old woman with rapidly progressive and hemorrhagic CNS metastases from BRAFV600E mutation-positive melanoma despite prior high-dose IL-2, ipilimumab and stereotactic radiosurgery. At baseline she was receiving dexamethasone as the largest of several lesions was 5cm with associated vasogenic edema. She had an excellent response while being dosed at 960mg twice daily, and after 6 months an MRI showed reduction in all brain metastases. 

Dabrafenib (GSK2118436) is another orally bioavailable and specific inhibitor of mutated BRAFV600E protein currently in development. It has the lowest IC against BRAFV600E among its competitors and may have a more favorable chemical profile for penetrating the CNS compared with vemurafenib. In a Phase I/II trial presented at the ESMO 2010 meeting in Milan (Italy), dabrafenib shrank the previously untreated brain metastases in seven out of ten patients. The overall reductions ranged from 20 to 100% of brain metastases that were 3mm or larger in diameter before treatment."
                                                                  


 The final note:

“Five years from now, there will most likely be additional targeted therapies and immunotherapies for metastatic melanoma. Because of the high rate of metastasis to the CNS, the treatment of brain, spinal cord and leptomeningeal metastases will become an even more pressing issue in the management of patients with advanced melanoma. The critical issues will include the design of small molecule inhibitors that have a high penetrance across the blood–brain barrier as well as immunotherapies that can drive more anti-melanoma cytotoxic T cells into the CNS.”

There is not much info included re: anti-PD1 as there was limited data available at the time of this publication.  Additionally, the caveat for most all recently developed drugs is that clinical trials denied access to patients with brain mets or any sort of CNS disease.  I can only hope that folks will start listening to the data and the researchers who have been pressing for a change in the way those issues are managed.  Don't forget this quote, also back in 2012...

Melanoma Brain Metastases: Is it time to reassess the bias? By: Flanigan, Sznol, et al. July 2012. These authors note that melanoma brain met patients are typically excluded from trials. They conducted a chart review of 251 metastatic melanoma patients diagnosed after 2005 to evaluate them in the context of eligibility for treatment with novel agents. And "found median survival of malignant effusion (mets in the pleural cavity) patients was significantly shorter than brain met patients (2 vs 8 months)." Therefore, "exclusion of melanoma brain met patients from clinical research programs is no longer justified and alternate investigational approaches, possibly combining local and systemic therapies, are greatly needed for these individuals."



So...you melanoma movers and shakers....GET WITH THE PROGRAM!!!!  Are you listening over there on your forum???? And to all my little ratties....keep on pushing!  Much love - c

Monday, July 21, 2014

BRAF/MEK combo ~ vemurafenib with cobimetinib

Combination of vemurafenib and cobimetinib in patients with advanced BRAF (V600)-mutated melanoma: a phase 1b study.
Ribas, et al.  Lacet Oncol 2014, July 15 [epub ahead of print]

My synopsis:
The addition of a MEK inhibitor to a BRAF inhibitor has been found to enhance effects on tumors, delay resistance, and provide fewer side effects in patients. (As demonstrated in the CombiDT studies where the BRAFi dabrafinib was combined with the MEK inhibitor trametinib.)  Here researchers combined the BRAFi vemurafenib with the MEK inhibitor cobimetinib, the roche/genentech MEKi.

Patients had advanced melanoma, were positive for the BRAF (V600) mutation, and had either recently progressed on vermurafenib (n=66) or had never been given a BRAF inhibitor (n=63).  They were given vemurafenib 720mg or 960mg twice daily and cobimetinib 60, 80, or 100mg once a day for either 14 days on and 14 days off, 21 days on and 7 days off, or continuously.  Trial number:  NCT01271803.

129 patients were treated at ten dosing regimens. Dose limiting effects arose in 4 patients.  All were on a 960mg bid dose with differing cobimetinib doses. AEs = Grade 3 fatigue, Grade 3 prolonged QT (a heart problem), Grade 3 stomatitis, arthralgia and myalgia.  Maximum tolerated dose turned out to be:  vemurafenib 960mg twice a day with cobimetinib 60mg (21/7)  Across all doses side effects = diarrhea (64%), acne like rash (60%), liver enzyme abnormalities (50%), fatigue (48%), nausea (45%), photosensitivity (40%).  The most common Grade 3 reactions were:  squamous cell carcinoma (9%), increased alkaline phosphatase (9%), and anemia (7%).

Confirmed objective responses were recorded in 10 (15%) of 66 patients who had recently progressed on vemurafenib, with a median progression-free survival of 2.8 months.  Confirmed objective responses were recorded in 55 (87%) of 63 patients who had never received BRAFi, including 6 (10%) who had a complete response, median progression free survival was 13.7 months.

My thoughts:
  • The combination of vemurafenib with cobimetinib did better than results of prior studies in which vemurafenib was given alone.
  • Patients who were naive to vemurafenib responded better than those who had failed on it.
  • Both of these facts are being demonstrated with other meds (like the immunmodulators) in other studies.
  • Meaning, studies are showing that treatment naive patients respond better than patients who have already taken the drug...though some patients can still get a response.   And, when meds are combined (like in the ipi/nivo trials) there is a greater response, but also greater side effects.
  • It seems to me the researcher in my LAG3 post is really onto something when he talks about the issues surrounding getting the immune system to "RE-fire" once it has already mounted a response.
  • Also...though this may be premature....according to this data, the vemurafenib/cobimetinib combo did better, with a median progression free survival of 13.7 months, when compared to the dabrafenib/trametinib combo, with a progression free survival of only 9.3 months.  Perhaps they did not have as many BRAF naive patients, I'm not sure.  See slide and prior posts below:


Jan 2014 dabrafenib/trametinib combo FDA approved

Feb 2014 BRAF info and results from CombiDT

June 2014 BRAF studies from ASCO

Good luck to all my ratties!!! - c


Saturday, July 19, 2014

Word Crimes!

My children and some friends know what a weirdo I am about grammar, punctuation, contractions and being a Babylonian (a person who babbles on and on and on)!!! Your (as in something that belongs to you) in place of you're (as in something you ARE going to do) is like nails on a chalk board.  Peeps who protest "I could care less!" drive me nuts!!  Because, if you COULD care less, well, that says it all doesn't it?  You COULD care less, so that is not impressive!!  However, if you COULDN'T care less, that means you are maxed out and there is nothing more you could give.  Folks who pontificate on 'Brent and I' versus 'Brent and me', then use the wrong form anyway...give me chills.  By the way, easy rule!  When deciding whether to use one or the other:  Drop the other guy and see if you should be saying 'I' or 'me'.
"I went to the movies," or "Me went to the movies"?
It's easy.  "Brent and I went to the movies."
Would you say, "He went to the movies," or "Him went to the movies"?
Exactly! So, if you both go, you will say, "He and I went to the movies."  Arrangement makes no difference.  "I and he went to the movies" is correct, even though it sounds weird.
Another example:  This basket is for she and I, or she and me, or her and I?
Same thing.  Focus on one person.  "The basket is for me."  If you share it, it is for....?  Yep!  Her!
So, "This basket is for her and me."

 While all that is dull and boring...this is funny!!!  And...true!!  And...awesome!!!

Word Crimes and Weird Al

Are you listening, Miley?  This opens me up to all sorts of grammatical criticism!  So, bring it on!!  It'll be fun. Love, c

Thursday, July 17, 2014

Beware of sharks!!!!!

OK!  Between posts about T cells, the effects of anti-PD1 on them, subsequent effects in the brain, LAG3, and all the recent updates regarding Pembro, Nivo (Opdivo for heaven's sake!!), and the ipi/nivo combo....my brain is tired!!!  So....I just couldn't resist!  Check it out...






Not only do they bite....they might have melanoma!!!

Melanoma in the skin of a nurse shark.  Waldoch, Burke, et al.  Indianapolis Zoo

A female nurse shark, aged 27 years, had a 5.5 year history of a 6 cm black, raised, nodular skin lesion on the right side of her tail. The lesion was biopsied and diagnosed as a slow-growing melanoma.  The shark was euthanized due to systemic illness 4.5 months after the diagnosis.  No evidence of metastasis was found on evaluation.

Hmmm....I'm thinking sun exposure was not involved.  Who knew?  Be careful with fun in the sun...for LOTS of reasons!   - c

Monday, July 14, 2014

There's no place like home!!!!!

Isn't that right, J????  I'm gonna hook you up!  That way you can just click your heels, should there ever be a need!

           "There's no place like home! There's no place like home!"

Much love and hugs my friend!!!!  - c

Sunday, July 13, 2014

Nivo/ipi combo, Nivo vs Pembro, PD-L1: SugarCone and 2014 ASCO data


B found two posts from SugarCone Biotech Blog, June 12, 2014. The author was apparently at ASCO scoping things out; taking screen shots from the presentations.  Good stuff.  My synopsis:

...PD-1 appears to be a central control point for curtailing T cell responses...similar to the role CTLA4 plays in regulating initial T cell activation...Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed that the PD-1 pathway was used by tumor cells as a shield against immune system attack.  It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers.  Less clear is...why certain patients respond or don't, what biomarkers might predict response, how to increase response..., how to..measure response, and how to safely combine anti-PD-1 with other therapies.

This table lists PD-1 therapies in development, for various tumor types [side highlight...not mine]:

 This table defines response parameters and their abbreviations:


Background note:  The very first trials of [anti] PD-1 began with...Nivolumab in metastatic melanoma.  [For comparison] ipilimumab (Yervoy) an anti-CTLA1 antibody...is approved for treatment of metastatic melanoma....In a Phase 3 trial....of Stage IV melanoma patients who had failed prior therapy (chemo), the trial compared ipi to a tumor vaccine targeting the melanoma antigen gp100.  Ipi treatment = OS of 10 months vs 6 months with vaccine.  1 year survival = 45%.  ORR was only 10%.  AEs (adverse events) were autoimmune issues (colitis, pituitary inflammation) and 2% of patients had treatment related deaths.  In separate study of treatment naive Stage IV mel patients:  Ipi = OS of 11.2 months, 1 year survival = 47%, falling to 21% by year 3.  Patients were given ipi or placebo plus dacarbazine, then moved to ipi or placebo alone if there was a response measured or if the initial therapy caused toxicity.  AEs went up, with 38% of patients experiencing Grade 3/4 SAEs (severe AEs).

Nivolumab (Anti-PD1 by BMS)...provides median OS of 17 months, 1 and 2 year survival rates of 62% and 43%.  ORR = 33%.  AEs less significant than ipi.  Immune-related events occurred in 54% of patients (skin, GI, endocrine problems), but only 5% of patients had Grade 3/4 events and there were no drug related deaths.

So....when you combine ipi and Nivo:  At ASCO last year....trial data reported 4 cohorts of patients given different doses of nivo and ipi in combination.  ORR across cohorts = 40% and 1 year survival was 82%.  Median OS had not been reached.  SAE across cohorts = 53%.  Slide describing cohorts:


In trial update by Sznol this year (Table below)...at optimal dose rates of 1+3 and 3+1. ORR = 43-53%.  "Aggregate Clinical Activity Rate" = 81-83% in cohorts 3 and 4. (Note that Cohort 4 was the maximum tolerated dose due to SAEs and will no longer be used.) The percent of patients whose tumor burden was reduced by more than or equal to 80% at 36 weeks was 42% across the cohorts.  In patients who responded the median DOR in cohorts 1-3 and cohort 8 has not yet been reached.  In cohorts 2-3 the 1 year OS = 94%, 2 year OS = 88%.  Median OS in cohorts 1-3 = 40 months.


These data are best-in-class for treating advanced melanoma....one outstanding issue remains that of toxicity...23% of patients had to discontinue therapy due to toxicity, and one died of complications of treatment....Sznol...pointed out that...toxicities are controlled by standard intervention...but that includes cessation of therapy.  We have already learned from ipi...that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1-2 doses....time may not be kind.

....The activity of pembrolizumab, formerly MK-3475 (Merck's anti-PD1) in melanoma is very similar to that of nivo...and closely resembles nivo except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating.  Slide comparing pembro and nivo:


...the pembro data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma...Merck...made a strategic decision to stratify patients by prior exposure to ipi...This gave [Merck] a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients.  Due...to the toxicity profile of ipi, there are a lot of these patients....  If we focus on the ipi-naive ORR and 1 year survival data...we have to conclude that these drugs are pretty comparable...To differentiate these...data will have to come from longer duration...ongoing trials....In the nivo trial...half of the responding patients stopped therapy for reasons other than disease progression, most likely...due to AEs.  [Though] 3/4 of nivo patients stopping therapy maintained a response, some for extended periods.  In pembro...the SAE rate was 12% but only 4% of patients discontinued therapy.  The catch is that in order to move ORR higher than 40%, combination therapy may be needed.  But..the ipi/nivo combo comes with much higher toxicity and drop-out rates.

Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway...PD-L1 is also important in...predicting response to therapy...the utility of this marker...was subject of considerable discussion.  When ORR is 40% it is helpful to select patients prospectively.  In a study of responsiveness to pembro, Kefford, used an analysis of PD-L1 expression to demonstrate a remarkable difference in...response between patients with greater or = 1% PD-L1 expression vs patients who were PD-L1 negative.  Biopsy 2 months before pembro determined PD-L1 expression.  Patients were given Pembro at either 10mg/kg q2wk, 10mg/kg q3wk, or 2mg/kg q 3 wk with median treatment of 23 weeks and 13 month follow-up.  ORR = 41%.  Median PFS = 31 weeks and median OS was not reached.  1 year survival = 81%.  So this was a terrific cohort within the larger pembro study, likely due to the higher dose used.  PD-L1 expression was associated with improved ORR by 51% vs 6%, PFS = median 12 vs 3 months, and 1 year survival = 84% vs 69%.  No treatment related deaths, 14% experienced SAEs, again reflecting the aggressive dosing schedule.

In the larger trial of ipi naive patients treated with Nivo, PD-L1 tumor staining was associated with ORR, but only weakly with PFS and OS.  Why the data are less robust than the Kefford study is unclear.  What is abundantly clear however is that there were profound responses in patients scored as PD-P1 negative, as shown in the screen grab from Dr. Weber's review:


Not exactly new information from posts I made in June 2013 or within more recent ones...but some interesting view points and nice access to slides.  You can check out the posts themselves via the link below.  Best - c

PS...I couldn't get the address to work as a link...but if you copy/paste the address below and then search....the information will come up.  C