Tuesday, June 19, 2018

TIL outcomes with and without melanoma brain mets

So....there is this:

Outcomes of Adoptive Cell Transfer With Tumor-infiltrating Lymphocytes for Metastatic Melanoma Patients With and Without Brain Metastases. Mehta, Malekzadeh, Shelton, et al. J Immunother. 2018 Apr 18.

Brain metastases cause significant morbidity and mortality in patients with metastatic melanoma. Although adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) can achieve complete and durable remission of advanced cutaneous melanoma, the efficacy of this therapy for brain metastases is unclear. Records of patients with M1c melanoma treated with ACT using TIL, including patients with treated and untreated brain metastases, were analyzed. Treatment consisted of preparative chemotherapy, autologous TIL infusion, and high-dose interleukin-2. Treatment outcomes, sites of initial tumor progression, and overall survival were analyzed. Among 144 total patients, 15 patients with treated and 18 patients with untreated brain metastases were identified. Intracranial objective responses (OR) occurred in 28% patients with untreated brain metastases. The systemic OR rates for patients with M1c disease without identified brain disease, treated brain disease, and untreated brain disease, and were 49%, 33% and 33%, respectively, of which 59%, 20% and 16% were durable at last follow-up. The site of untreated brain disease was the most likely site of initial tumor progression (61%) in patients with untreated brain metastases. Overall, we found that ACT with TIL can eliminate small melanoma brain metastases. However, following TIL therapy these patients frequently progress in the brain at a site of untreated brain disease. Patients with treated or untreated brain disease are less likely to achieve durable systemic ORs following TIL therapy compared with M1c disease and no history of brain disease. Melanoma brain metastases likely require local therapy despite the systemic effect of ACT.

So...this is not really news.  Folks with brain mets didn't do as well as those without.  But, still good to know!!  Sounds like for brain mets, you need SRS (or gamma knife radiation) no matter what other therapy you do!!  For what it's worth - c

Saturday, June 16, 2018

Sew Chaotically! - Another By Hand London, Polly Top

As a last 'remnant' (Ha! Ha! Sewing humor!!!) of Rosie's closet clean-out, she gave me a cotton gauze scarf she never wore, to use in some capacity as I desired.  When questioned, she said, "I don't know how.  But, I'm sure you can come up with something to do with it!!!"  

Well, it sat for a minute and I remembered this:  Sew Chaotically! - Tale of 2 tops - Polly and Sally???? 

The Polly top is great.  The curved front is a miracle of fitting without darts.  Not sure how it would do for those more fully endowed, but for those belonging to the Itty Bitty Titty Committee, it is lovely!!!  Oh!!!  Did I mention that the lovelies at By Hand London give it away for FREE??!!!
Check this out:  Please welcome the Polly Top sewing pattern! (Oh yes, and she's free).

So with the aforementioned scarf and a bit of gauze fabric left over from a top I made for Ruthie last year ~ I made this!!!

I fully lined the front with the yellow gauze....

....while leaving the back un-lined and employed bias binding for all finishes.

Isn't she the cutest????

I think Polly and Roo are a great combo!!!

And a lily, cause...well...pretty and matching!!!  Enjoy your Saturday and...Sew Chaotically! - les

Thursday, June 14, 2018

Trial option for folks with uveal melanoma with IMCgp100

For a very long time folks with brain tumors, LMD, mucosal and uveal melanoma have been left out most trials that brought current melanoma therapies FDA approval.  Things have improved a bit for brain met folks - but new approaches and entry into trials to try them remain hard to find for those other melanoma peeps.  This data and the trial options listed at the bottom of the report offer some hope and options for uveal folks.

Here's the link and the report from OncLive, May 2018:

Novel Immunotherapy Shows Early Efficacy in Uveal Melanoma

IMCgp100, a novel immune-based treatment, demonstrated a 1-year survival rate of 73% (46%-88%) for patients with heavily pretreated, advanced uveal melanoma, which is nearly double the historical expectations for patients with the disease, according to lead investigator Richard D. Carvajal, MD.

At a median follow-up of 12.8 months, the median overall survival had not yet been reached in the phase I study. The objective response rate with IMCgp100 was 11% among (2%-30%), with 5 additional patients (26%) showing signs of stable disease with minor responses (greater than/= to10% reduction in target lesions). The median progression- free survival (PFS) with the treatment was 24.3 weeks, and 62% of patients remained alive and progression free at 1 year.  (See table)

“Advanced uveal melanoma has a 1-year overall survival rate of approximately 40%, and no cytotoxic, targeted, or immunological therapy has been previously identified to meaningfully improve outcomes,” Carvajal said at the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting, where he presented the data. Carvajal is director of Experimental Therapeutics and the Melanoma Service at Columbia University Medical Center in New York, New York.

“The 73% 1-year overall survival we observed in the heavily pretreated patients with metastatic uveal melanoma treated with IMCgp100 is quite notable,” he said. “We are excited about the continued development of IMCgp100 for patients with this disease.” IMCgp100 is the leading candidate in a new class of investigational therapies targeting the T-cell receptor (TCR) called immune-mobilizing monoclonal T-cell receptors. It contains 2 functional ends, 1 that targets the soluble affinity–enhanced TCR and the other an anti-CD3 single-chain variable fragment. The TCR end binds to the melanoma-associated antigen gp100, and the effector end activates an antitumor CD3-positive T-cell response.

 IMCGP100 Clinical Efficacy Findings

Dose Escalation Strategy

The dose escalation study included 19 patients across 4 dose levels ranging from 54 μg to 73 μg. The study utilized an intrapatient escalation strategy: on day 1 of the first cycle, patients received IMCgp100 at 20 μg, which was escalated to 30 mcg on day 2 of cycle 2. This was followed by enrollment to 1 of 4 cohorts testing a range of doses (54 μg, 64 μg, 73 μg, and 68 μg).

Dose-limiting toxicity in the form of abnormal liver function tests was observed in 3 patients. Two of these events were seen in the 4 patients who received the highest dose, which was subsequently reduced to 68 μg. This dose was identified as the maximum tolerated dose of IMCgp100 and will be further explored in phase II trials.

The median age of patients was 55 years, and the ECOG performance scores were 0 (74%) and 1 (26%). Participants had undergone a median number of 4 prior therapies (range, 0-8), which included chemotherapy for 95% of patients and prior immunotherapy for 68%. Prior immune therapy included ipilimumab (47%), pembrolizumab (32%), and nivolumab (16%). All patients had liver metastases, and lactate dehydrogenase levels were greater than the upper limit of normal for 73% of patients.

In terms of responses, the median time to objective response was 27.8 weeks and the median duration was 24.1 weeks. The disease control rate (responses plus stable disease) was 53% at week 16 and 32% at week 24. There were no complete responses, and 26% of patients developed progressive disease as their best response, which occurred mostly in doses below 68 μg.

A pharmacokinetic (PK) analysis of the study showed consistent dose-dependent activity. The half-life for the drug was determined to be 6 to 8 hours across all doses above 20 μg.

Evidence of T-cell infiltration was seen using immunofluorescence in pharmacodynamic assessments. Immune activation was seen in the tumor after 3 weekly doses of IMCgp100, which was consistent with T cell redirection, the researchers noted.

Following treatment, there was a temporary reversible decrease in peripheral lymphocyte counts, which is indicative of lymphocyte trafficking. Immunofluorescence analysis of biopsy samples after 3 doses of IMCgp100 showed high levels of lymphocyte trafficking into the tumor, with persistent lymphocyte infiltration. At progression, there were high levels of PD-L1 expression, gp100 antigen expression, and CD8 T cells present in the tumor.

All patients in the study experienced treatment- emergent adverse events (TEAEs), with 79% having a grade 3/4 event. The most common all-grade TEAEs were pruritus (90%), pyrexia (84%), fatigue (84%), hypotension (74%), chills (63%), nausea (68%), dry skin (63%), and peripheral edema (63%). The most frequent grade 3/4 TEAEs were fatigue (16%), hypotension (16%), erythema (16%), and macular rash (11%).

The skin toxicity observed in approximately two-thirds of patients persisted during the first 4 weeks of treatment and then began to taper off. There were no grade 3/4 skin toxicity events beyond 4 weeks, and by week 7, skin toxicity events reached a plateau, with approximately 26% of patients having a rash beyond 100 days of treatment.

“While research is still ongoing, I am encouraged by the results from this phase I study in ocular melanoma. We are committed to progress research to benefit patients,” Carvajal said.

A pivotal phase II trial is enrolling participants with uveal melanoma to further test IMCgp100 compared with investigator’s choice of systemic therapy, which could include the CTLA-4 inhibitor ipilimumab or the anti–PD-1 agent pembrolizumab. The open-label phase II study plans to enroll 327 participants, with an estimated primary completion date of July 2020 (NCT03070392).

In addition, a phase II portion of the study reported at ARVO is now open for additional participants. This expansion cohort of the study hopes to enroll 150 patients. The estimated completion date for this expansion trial is December 2018 (NCT02570308).

For what it's worth.  Fingers crossed! - c

Wednesday, June 13, 2018

Sew Chaotically! - Another little casual/exercise top!

I have had such fun making these little exercise tops for Roo!!!  The first couple were made from scraps, while the last two were made with a little more thought, specific material selection, and care!!  But, they have all been a party in the back!!!

This burned out knit from MOOD turned out even better than expected!! I picked it and the purple up during a knit sale they were having.  Like the purple, per Roo's request, it was lengthened about 2 inches.  Given a curved hem, and per one top I have and others I've seen in photos, I created a pattern piece for this back!!!  Yes.  It hurt my small brain, which is completely devoid of spatial relation aptitude, but I really like how it turned out!!!
Such a cutie!!  Then we were off to class, where the 8 1/2 month pregnant instructor ~
Sew (and exercise!!) chaotically!!! - les

Sunday, June 10, 2018

ASCO 2018 - Optimal sequencing of anti-PD-1 and BRAFi in Stage III patients

Okay.  One of the many zillion dollar questions in melanoma (for those who are BRAF positive) is:  "What treatment should I do first ~ BRAFi or immunotherapy?"  Right now [SPOILER ALERT!!!] we don't know, though the report below is trying to figure that out (at least for Stage III patients). And before I get to the report/ad for the study now enrolling:  Neoadjuvant Dabrafenib, Trametinib and/or Pembrolizumab in BRAF Mutant Resectable Stage III Melanoma (NeoTrio)  ...here's a little review on adjuvant vs NEOadjuvant treatment.

In adjuvant trials or treatments, like the one I participated in, the melanoma patient must have all of their "measureable" melanoma removed.  (Would that we really could have ALL of our melanoma removed!!!) In real terms this means that all positive nodes or lesions that are visible on scans are surgically removed.  Additionally, though it depends on the study, if one has brain tumors, patients can have them zapped and if, over a certain period of time (this varies study to study) they do not recur, and the area fails to light up on subsequent scans, the patient may join the adjuvant trial/treatment, at which time they are given the treatment du jour.

In NEOadjuvant treatments/studies, patients keep the lesions they have and start the treatment du jour.  Sometimes after a certain amount of therapy the lesions are then removed, if they have not evaporated with the treatment, sometimes not.

Here is a March 2018 report I put up:  BRAF/MEK before surgery as well as after is MUCH better, than just AFTER surgery for melanoma!! Plus trial still recruiting resectable stage III/IV melanoma peeps.  Clearly you can read the entire report and abstract for yourself, but this was my take:

In this study of only 21 stage III/IV patients who had never taken BRAF/MEK, whose tumors were BRAF positive, and could be removed surgically, were divided in 2 groups. Folks with "metastases to bone, brain, or other sites where complete surgical excision was in doubt" were excluded.  7 got standard of care:  complete excision of their tumor and "consideration" of adjuvant therapy.  21 got the BRAF/MEK combo (dabrafenib and trametinib) BEFORE surgical removal of their lesion as well as AFTER!  Ten of the 14 treated with BRAF/MEK before and after excision were alive without disease progression "vs none of seven in the standard of care group".  These results were deemed so good that this phase of the trial was stopped and only the neoadjuvant/adjuvant arm is continuing, and in fact, recruiting.

This is great news.  However, I do see several flies in this report.
1.  You researchers left out some folks in serious need of care...folks with brain, bone and other mets that you didn't see as a winning ticket.  I've been one of those peeps and was given adjuvant care.  Those folks need neo-adjuvant/adjuvant care as much (or more!!!!) than anybody!!  Here's a small tirade on their being left out of clinical trials:  A really good review of treatment data for Melanoma Brain Mets!!! (And this is from 2015!!!!!!!!)
2.  These are really small numbers...in both arms.
3.  The fact that the 7 in the standard care arm were eligible for "consideration" of adjuvant care is pretty lame.  That language tells me that some chose to forego adjuvant care!!!  So OF COURSE!!! ~ those who had no additional care did less well!!!!  To provide greater clarity and benefit, the authors should have clearly defined the standard of care group in regard to whether they actually utilized BRAF/MEK after resection or not.
4.  Finally, I really don't care for the major drama, yet lack of real information, posed in this categorization of the 7 peeps in the standard of care group:  "more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group".  At first blush it seems that all of the 7 are dead, along with the 4 out of the 14 in the neo/adjuvant group!!  Come on, Amaria!  You have better writing skills than this!  Some of these peeps may well have passed, but it is also possible that ALL these folks are alive, albeit with disease progression.  Clarification of that could easily have been included in this abstract and is hopefully made more clear in the actual published article.


One more pertinent side note - Researchers have been working on seeing how things go for melanoma patients who are treated with immnotherapy (like anti-PD-1) COMBINED with targeted therapy (BRAF/MEK) for a while now.  Here are some reports:  ASCO 2017 (with links to the "whole she-bang") BRAFi and anti-PD1/PD-L1

Now, there's this:

Determining optimal sequencing of anti-PD-1 and BRAF-targeted therapy: A phase II randomised study of neoadjuvant pembrolizumab with/without dabrafenib and trametinib (D+T) in BRAF V600 mutant resectable stage IIIb/c/d melanoma (NeoTrio trial). Gonzalez, Menzies, Saw, ... Georgina V. Long. ASCO 2018. 

Background:  BRAF targeted and CTLA-4/PD-1 immunotherapies have high response rates and improve survival for patients (pts) with metastatic melanoma, however, most still die of this disease. It is hypothesised the activated cytotoxic T cell infiltrate that occurs early during treatment with BRAF/MEK inhibitors is potentiated by adding checkpoint inhibitors, resulting in improved response and survival. While trials combining BRAF/MEK inhibitors and anti-PD-1/L1 antibodies are underway in the metastatic setting, the neo-adjuvant (neo-adj) setting provides an opportunity to test different treatment schedules in small cohorts of pts. Tissue and blood biomarkers can be drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response, biomarkers of efficacy, and to select the best schedules to take forward to larger-scale trials.

Methods: Eligible pts with BRAF V600 mut, stage IIIB/C/D, resectable and measurable melanoma are evenly assigned to 3 cohorts (n = 60). All pts undergo complete macroscopic resection (RES) at wk 12 and receive neo-adj therapy for 12 wks preceding RES, followed by 40 wks of adjuvant (adj) therapy. Cohort 1 receive sequential therapy with D+T for 2 wks, then 4 pembrolizumab (pembro) doses until wk 12, and 3 wkly pembro after RES. Cohort 2 receive concurrent D+T and 3 wkly pembro before and after RES. Cohort 3 receive 3 wkly pembro for the entire treatment course. Pembro is given at a flat dose of 200mg. Ultrasound of known disease areas is undertaken during the neo-adj period. CT and FDG PET/CT are used to measure response and exclude progression in theneo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, wk 1, 4 and 12. The primary endpoint is the complete pathological response rate at RES following 12 wks of therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analysis. First patient enrolled 29Nov2017. Clinical trial information: NCT02858921

Best as I can tell they are going to take 60 Stage III patients with measureable disease, and put 20 into each of 3 groups.  The groups are treated as noted below, per ClinicalTrials.gov
Group 1 = 
  Sequential D + T, THEN Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day for 2 weeks, then followed by treatment with Pembrolizumab 2mg/kg delivered intravenously at weeks 2, 4, 6, and 9, then once every 3 weeks from week 12 for 50 weeks
Group 2 = 
 Concurrent D + T AND Pembrolizumab
Dabrafenib 150mg orally twice a day + Trametinib 2mg orally once a day + Pembrolizumab 200mg intravenously once every 3 weeks for 52 weeks
Group 3 = 
Pembrolizumab 200mg intravenously once every 3 weeks alone for 52 weeks.

It seems to me that they should have offered immunotherapy followed by BRAF/MEK in a Group 4, so there could be a complete answer, but I guess that's just me.  CT's and PET/CT's along with blood and tumor sample testing will be used to follow patients and determine results.

Important stuff.  Good luck, ratties.  And...thanks. - c

Saturday, June 9, 2018

Sew Chaotically! - A small ASCO break and an easy purple, almost maxi - McCall's 7242

This little red dress (below) was probably one of the first "harder" things I made.  The material was pretty cheap and has not held up as well as it might have, but the look is easy and it has gotten a lot of wear.  On examining it for this make, I found sooooo many mistakes - some known and some a surprise!  Live and learn, right???

My "flimpy" version of this dress got a full report here:  Cute little summer dress ~ McCall's 7242
But, with that history and this inspo, I wanted to make another!
With that, I opted for a longer, sleeveless version.  My only real complaint with the first dress was that the "waist" was a bit high for me - something I've learned to deal with ahead of time since.  So, I lowered that by an inch.  Additionally, as many other sewists had noted - given the way the pattern has you insert elastic to the waist, stopping about an inch to either side of the button band - the dress tends to gap open in that area.  I had to add snaps there to fix the problem in my red version.  For this one, rather than use elastic, I simply made two button holes, one on either side of the button band, and inserted a tie all the way round through the tunnel made for the elastic!  Problem solved.  My "tie" may, or may not, be a shoe lace!!!  Hey, use what you've got!

Pretty happy with my fun easy summer dress!!  I can see one in linen for next year.  Sew chaotically!!! - les

Friday, June 8, 2018

ASCO 2018 - Nivo vs ipi as adjuvant in resected melanoma

Not really news here.  Guess what drug does better and in whom???  Nivo or ipi????  (But, spoiler alert!!!!  As I've been saying, even patients with minimal PD-L1 expression can still gain a response!!!) 

Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). Weber, Mandalà, Del Vecchio, ... Ascierto. ASCO 2018.

In the initial report of data from CheckMate 238, at a minimum follow-up of 18 mo, NIVO demonstrated significantly longer recurrence-free survival (RFS) vs IPI in patients (pts) with resected stage III or IV melanoma. Here, we report updated efficacy results from this phase III study with an additional 6 mo of follow-up.
Methods: Eligible pts included those greater than/= to15 yrs of age who underwent complete resection of stage IIIB/C or IV melanoma. 906 pts were randomized 1:1 (stratified by disease stage and PD-L1 status at a 5% cutoff) to receive NIVO 3 mg/kg Q2W (N=453) or IPI 10 mg/kg Q3W for 4 doses, then Q12W (from week 24) (N=453) for up to 1 yr, or until disease recurrence or unacceptable toxicity. The primary endpoint was RFS; distant metastasis-free survival (DMFS) in pts with stage III disease was an exploratory endpoint.
Results:   At a minimum follow-up of 24 mo, RFS continued to be significantly longer for NIVO vs IPI, with 171/453 and 221/453 events, respectively. The 24-mo RFS rates were higher for NIVO vs IPI in subgroups defined by disease stage, PD-L1 expression, and BRAF mutation status (Table). DMFS also continued to be significantly longer for NIVO vs IPI, with 24-mo rates of 70.5% and 63.7%, respectively. Subsequent therapies were received by 31.1% of pts in the NIVO group and 41.1% in the IPI group. Per protocol, there was no additional safety assessment for the current analysis given that all pts had been off study treatment for 100 days at the time of the previous data cutoff.
Conclusions: With extended follow-up, NIVO demonstrated a sustained efficacy benefit vs IPI in pts with resected stage III/IV melanoma at high risk of recurrence, regardless of disease stage, PD-L1 expression, or BRAF mutation status. Clinical trial information: NCT02388906

Sorry about the sad pic.  Best I could do.  ASCO doesn't make this easy.
In this study Stage III and IV melanoma patients had their disease completely removed.  906 of these peeps were randomly assigned to the ipi group (n- 453) or the nivo group (n- 453) (dosage and administration noted above).  Consistently, across all groups, Nivo did better to lengthen recurrence free survival. Not surprisingly the people with a lower stage did better on both drugs.  Meaning folks who were only Stage IIIb progressed less than those who were Stage IV.  BRAF status made basically NO DIFFERENCE with both drugs.  AND....while those with a higher level of PD-L1 expression did a bit better...folks with minimal PD-L1 expression STILL RESPONDED!!!!!!
Okay.  There you go.  Happy Friday!!! - c