C'est moi!!! Results from the 33 ratties in my Nivolumb/Opdivo trial...published!

Wow!  When it rains it pours!!!  Nivoumab, now called Opdivo, was FDA approved today!  Unfortunately, with the same prerequisites (ipi/Yervoy and BRAFi, if BRAF positive, must be failed first) that Keytruda (Merck's Pembrolizumab/anti-PD1 product) has. Not what I was hoping for.  As far as the publication of my trial data.... No real surprises here....with the help of Ruthie and Bentie (for their good ears and memory during rapid fire, free floating discussions at my appointments and YEARS of tremendous support!!!) and all the other 32 ratties who signed up and put their lives on the line...I have been able to pretty accurately document our struggles and successes.  But...it is nice to see it in print somewhere other than my own ramblings.  Here is my synopsis of the article:

Safety, correlative markers and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.  Gibney, Kudchadkar, DeConti, Tetteh, Weber, et al.  clincancerres.aacrjournals.org December 20, 2014.

Nivo (at 1mg/kg in cohort 1, at 3mg/kg in cohort 2, or 10mg/kg in cohort 3...all IV) along with a multi-peptide vaccine was to be given every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses were given to 33 HLA-A *0201 positive melanoma patients {due to the vaccine} with completely surgically resected disease.  Two patients had stage IIIC disease and 31 had stage IV melanoma.  Prior systemic therapy (if given prior to surgery) and radiation were allowed except for anti-PD-1, anti-PD-L1/PD-L2, or anti-CTLA-4 agents.  Imaging studies (CT scan of the neck, chest, abd, and pelvis and MRI or CT of the brain) were performed at baseline and every 12 weeks during the trial, then every 6 months for 3 years.  Ten patients per cohort were selected based on sufficient samples for immune assessments.  Patients were replaced if not evaluable for safety and leukapheresis collection after the first induction phase. Patients were followed until relapse and/or death.  Correlative studies were performed on leukapheresis blood samples collected at baseline, week 12 and week 24.  Cells collected were assessed for...anti-CD3, CD8, CD25, CTLA-4 and PD-1 antibodies. Tregs and Myeloid-derived supproessor cells (MDSCs) were also assessed.  Tumors were tested for PD-L1 positivity.

Background:  Within the tumor microenvironment, the function of T-cells is thought to be impaired due in part to engagement of the programmed death 1 (PD-1) receptor found on T-cells with its ligand, programmed death receptor ligand (PD-L1), which is expressed by antigen presenting cells such as dendritic cells and macrophages as well as tumor and other cells.  Tumor cells can "hijack" this pathway by ectopically expressing PD-L1 on their surface, which often is associated with a poor outcome.  This interaction within the tumor microenvironment inhibits immune cell function leading to T-cell "exhaustion," thereby inhibiting T-cell function and promoting tumor growth.  A promising immunotherapy strategy being evaluated in multiple cancer centers is inhibition of this interaction between PD-1 and PD-L1 by the use of blocking antibodies, thereby overcoming a critical immune checkpoint to facilitate tumor cell destruction. 

Recent results from clinical trials of PD-1 and PD-L1 abrogating antibodies suggest that they can induce significant rates of tumor regression in melanoma, as well as renal cell, non-small cell lung and bladder cancer.  Objective response rated in ipi-naive and ipi-refractory metastatic melanoma patients treated with anti-PD-1 agents (nivo and pembro) range from 25-43%....

Adjuvant therapy for resected high-risk melanoma continues to be an area in need of more effective strategies.  Patients with resected stage IV melanoma have no FDA-approved adjuvant therapy option.  Median relapse free survival (RFS) has been reported to be as short as 5 months with overall survival (OS) ranging from 12 to 36 months.  Similarly, subset analysis of resected stage IV patients [in a] study comparing GM-CSF vs placebo demonstrated a median disease-free survival of 12 months and 6 months, respectively. ... Due to the high relapse rate (more than 80%), long-term survival of less than 30% and the need for evaluation of new adjuvant treatments for these resected melanoma populations we [engaged in this study].

Patients:  33 patients. 12 in cohort 1 {I was one of these}, 10 in cohort 2, and 11 in cohort 3.  Median age = 47.  2 patients had ocular melanoma and 2 had mucosal primaries.  10 had resected brain metastases. Radiation therapy was administered to 18 patients prior to or after surgery including 9 with resected brain mets.  16  received one or more systemic therapies prior to surgery and the study.  Chemo/biochem (6), adjuvant interferon (6), vaccine (3) and high-dose IL-2 (2).  All underwent surgery to be rendered free of disease (NED).

Dosing:  12 of 33 have received all 20 treatments of nivo and vaccines (36%).  Two additional patients completed the full course but skipped 1-2 doses due to transient grade 2 toxicities.  Of 13 who prematurely discontinued therapy, 8 were due to relapse and 5 were due to toxicity and/or withdrawal.  Two patients relapsed after finishing all planned therapy.

Toxicities:  481 grade 1-5 adverse events were reported with 286 attributed to treatment.  AE distribution was similar across cohorts (#1 = 81, #2 = 104, and #3 = 101).  Most common AE's were vaccine injection site reaction (discomfort, granuloma, and/or reactive lymphadenopathy - 94% of patients), fatigue (82%), rash (55%), pruritis (42%), nausea (42%), arthralgias (42%), diarrhea (36%), headache (36%). 5 drug related grade 3-5 AE's were noted:  hypokalemia (1 in cohort 2), rash (1 in cohort 1), enteritis (1 in cohort 3), and colitis (2 in cohorts 2 and 3).  The colitis patients responded to high-dose steroids and supportive care. The patient with the grade 3 rash was re-challenged with the study drug after recovery; there was no recurrence of serious rash. Other immune-related events = grade 2 hypophysitis (2) leading to adrenal insufficiency in both patients, grade 2 thyroiditis (7) leading to primary hypothyroidism, and grade 1 pneumonitis (1) without clinical sequelae.  Adrenal insufficiency and hypothyroidism were successfully managed with hormone replacement.

Results:  Median f/u from enrollment = 32.1 months.  Of 33 patients, 10 (30%) have had a relapse event.  6 patients relapsed during weeks 1-12, 1 during weeks 12-24, 1 during weeks 24-120, and 2 after completing all treatment (more than 2.3 years).  All other patients remain disease free, and 14 (42%) have finished all treatment.  Estimated relapse free survival was 47.1 months. Median overall survival has not yet been reached.  The estimated 12 and 24 month survival rates are 87% and 82% respectively. Of the 10 relapsed patients, 5 died due to metastatic disease, 3 were rendered free of disease surgically and remain disease-free at 2, 27, and 54 weeks after relapse.  One patient had spontaneous regression of disease after a biopsy-proven relapse and has been free of disease for over 3 years.  One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib.

Brain metastasis subgroup:  10 patients with resected CNS disease were enrolled.  3 in cohort 1, 2 in cohort 2, and 6 in cohort 3.  Only 2 of these 10 patients have relapsed after median follow up time of 22.5 months, both were in cohort 1.  The first patient completed all doses of study drugs and developed a new solitary lung met that was resected after 47 months on protocol; she again has no clinical evidence of disease.  The second was diagnosed with recurrent CNS disease after her first treatment with study drugs and expired 3 weeks from start of protocol from CNS hemorrhage.

Post relapse spontaneous regression {THAT GUY!!!}:  Cases of regression of melanoma after RECIST progression have been well documented for ipi and anti-PD1 antibodies, and have led to new criteria for anti-tumor response called immune related response criteria.  This may complicate evaluation of patients on adjuvant trial[s]... Patient noted in 'results' = with resected chest wall and pulmonary disease initiated treatment in the 3mg/kg cohort.  At week 12, CT scans showed new chest wall disease and a splenic nodule of 2.7cm, biopsy proven with fine needle aspirate to be melanoma.  While waiting to initiate treatment for metastatic disease, a repeat CT scan 4 weeks later showed shrinkage of both lesions.  Over the  next 24 weeks, repeat CT scabs showed further regression and eventual disappearance of both lesions, he remains free of disease 38.8 months since relapse.

Correlative Studies:  The identification of potential biomarkers to predict relapse was explored.  There were (in all cohorts together) a trend towards lower baseline CD25+Treg/CD4+ T-cell and MDSC levels in non relapsing patients compared to relapsing patients. Baseline PD-L1 tumor expression was assessed on archived tumor specimens from 28 of the 33 enrolled patients.  Using a 1% PD-L1 cutoff, 18 samples were positive and 10 were negative.  Relapse occurred in 5/18 (28%) PD-L1 positive patients and 4/10 (40%) PD-L1 negative patients.  At a threshold of 5% PD-L1 staining, 12 samples were positive and 16 were negative.  Relapse occurred in 3/12 (25%) PD-L1 positive patients and 6/16 (38%) negative patients. ....there was no statistically significant association between PD-L1 tumor staining and relapse free survival in this population, although there is a non-statistically significant trend towards better relapse free survival in those whose tumors were PD-L1 positive using either threshold...

Discussion:  Nivo and vaccine were well tolerated with only 4 of 33 patients discontinuing due to drug toxicities, and only 2 dose limiting toxicities (colitis) observed.  Grade 3 events occurred in 4 of 33 patients (12%) and were manageable.  Adverse events with adjuvant high-dose or pegylated interferon [show] 40-60% of patients experienced grade 3 events, 5-10% experience a grade 4 event, and as many as 31%...discontinued therapy due to toxicities.  Rate of grade 3 events for ipi at 10mg/kg for resected stage III melanoma patients [was reported as] 36.5% and 5.5% of patients experienced grade 4 AE's.
                    High dose and pegylated interferon have both been approved by the FDA as adjuvant therapy for resected stage III melanoma patients....but studies have failed to show a statistically significant improvement in overall survival [with these treatments].  Studies looking at bevacizumab (AVAST-M) and GM-CSF have each demonstrated improvement in disease free survival over placebo, but no statistical improvements in overall survival were seen.  Adjuvant ipi for resected melanoma is currently under investigation in two large randomized phase III trials.  Recent preliminary data presented in resected stage III patients demonstrated a median relapse free survival of 26.1 months with ipi compared to 17.1 months in the placebo group.
                    Our data suggest that nivo is clinically active in resected stage IIIC/IV melanoma, based on low rate of relapse (10 of 33), impressive relapse-free survival - estimated RFS of 47.1 months, and median overall survival not yet reached with over 32 months of follow up.  Median RFS for Canvaxin-IV trials was 7.2 months with median OS of 32 months.  Median OS for patients with metastasectomy {surgical removal of mets alone} has been found to be 12 months.  Overall, ...data suggests that a median RFS over 12 months would be a reasonable benchmark by which to judge the potential of an adjuvant treatment for stage IIIC/IV high risk resected melanoma.  By that criterion, our data with adjuvant anti-PD1 therapy surpasses RFS expectations and longer follow up will clarify whether superior median OS can be achieved.  Furthermore, the low event rate in resected brain metastases patients suggests a potential benefit in this very high risk population.
                    Enthusiasm for the use of PD-L1 as a predictive biomarker has diminished as other studies have shown that patients with PD-L1 negative melanomas can still respond to anti-PD-1, albeit at lower rates.  In our study, there were slightly fewer relapses in patients with PD-L1 positive tumors, but this was not statistically significant.  Other correlative studies showed that non-relapsing patients tended to have lower baseline levels of CD25+Treg/CD4+ and MDSC populations. This is supported by other data indicating the suppressive role of these immune cell populations, which may mitigate the effect of cytotoxic T-cells (and other immune cells) expected with anti-PD-1/PL-L1 therapy, resulting in dampened anti-tumor activity.

Wow. Very weird to read a scientific journal article that is talking about ME and my fellow ratties.... Lots to think about.  My thoughts will follow.  best - c

Survival graphs for my adjuvant resected Nivo trial

Pretty interesting, huh?  I think the line dropping down in the relapse graph on top is just a ditzle on the copy from printing, but not absolutely sure.  Hang on to your hats, ratties!! - c

SRS combined with anti-PD1 makes things better in ratties....this one's for you Artie!!!!

Stereotactic Radiation Therapy Augments Antigen-Specific PD-1 Mediated anti-Tumor 
Immune Responses via Cross-Presentation of Tumor Antigen.  Cancer Immunol Res.  Sharabi, Mirschl, Kochel, et al.  2014 Dec19.

"The immune modulating effects of radiation therapy have recently gained considerable interest and there have been multiple reports of synergy between radiation and immunotherapy. ....we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy.  [In] small animal radiation research...image guided sterotactic radiotherapy to...melanoma or...breast [cancer] tumors resulted in development of antigen-specific T-cell and B-cell mediated immune responses.  These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 or regulatory T cell (Treg) depletion, resulting in improved local tumor control.  ...radiotherapy increased the percentage of antigen-experienced T-cells and effector memory T-cells.  ...radiotherapy up-regulates tumor associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors.  These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic."

Prior post with two articles noting synergistic benefit when radiation was combined with ipi: http://chaoticallypreciselifeloveandmelanoma.blogspot.com/2014/01/ipi-and-radiationa-good-combo-for.html

Individual patients, like dear Artie, seem to be experiencing this sort of effect when given radiation for pain control and other reasons, when already on or in rapid succession with immune therapy.  Way to go, ratties....the big and little ones!  Best wishes, Artie!  You rock!   - c

With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade.  Lipson, Velculescu, Pritchard, et al.  J Immunotherapy Cancer. 2014 December 16.

Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation.  We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents.

Tumors from 12 patients with metastatic melanoma undergoing treatments with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT.  Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes.  In 5 of 10 patients studied, mutations were detected in BRAF (1), NRAS (2), TERT (1) and ALK (1).  Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens.  Plasma ctDNA levels ranged from undetectable to 5.5% of total circulating cell-free DNA.  In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography.  In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit.  In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement.

Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression.  Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs.

How cool would this be if it works?!!!  Patients and their docs would be able to accurately assess tumor response earlier, allowing patients to proceed to a different therapy sooner rather than later when needed, thus saving time and money....and ultimately, lives!!!

Fingers crossed! - c

Songs that make movies worth watching...and romantic!!!

I've always loved and easily remembered tunes and lyrics. Once when I was a little girl I cried because I couldn't remember the multiplication tables.  However, I insisted that if only they were a song I would have no problem!!! Yes, I hear the Muzak...in the elevator, the grocery store.  But when I comment on the song, folks I'm with often say, "What song?"  Yep, that's me...the sound man's girl.  Whenever and wherever I hear these songs, I can see the scene in the movie...NOT necessarily the scenes shown in the videos below.  Check out all the songs...and maybe some of the movies.  You'll hear how perfectly placed within the story they are. Some of my fav's....

The reason to watch GI Jane

The reason to watch Playing by Heart

Step Mom

Good Morning Vietnam

A Man and A Woman

Love Story

Last of the Mohicans

Pretty Woman

Mrs. Doubtfire

Phenomenon

One more....from Phenomenon

Mr. and Mrs. Smith

Knotting Hill

Bridget Jones's Diary

And if the sound man's smart, here's what she'll be using next......

Joan Osborne....what if God was one of us?

Joan Osborn...Work on Me

Norah Jones...Turn Me On

Norah Jones...I've got to see you again


Sing out loud, sing out long!!!! - c

Vitamin D and Melanoma

Vitamin D level at diagnosis and its variation during follow up as prognostic factor of cutaneous melanoma.  Saiag, Aegerter, Vitous, et al.  June 2014 ASCO.

Low 25-hydroxyvitamin D3 serum concentration at diagnosis of melanoma might be associated with worse survival.   Patients were collected from Paris hospitals from 2003 -2008 as they were diagnosed with Stage I-IV melanoma and were followed until June 2011.  1,171 patients were included, with 411 relapses during f/u, and 303 deaths.  Median serum Vit D levels at inclusion were inversely correlated with prognostic factors such as AJCC stage, Breslow's thickness and ulceration, but were not associated with disease free survival.  Changes in Vit D levels during follow-up were significantly associated with worse disease free survival.  We show that Vit D variation during follow-up is an independent melanoma prognostic marker, but not its level at diagnosis.  Previously reported association between low Vit D level at diagnosis and poor prognosis were probably due to insufficient adjustment for prognostic factors.

I'm not sure what these peeps are saying in their last sentence.  That seems an odd conclusion for them to draw.  By their own admission, folks with lower levels of Vit D had increased Breslow thickness and ulceration.  So...we can't KNOW that the decreased Vit D levels CAUSED that...but....  And, we can't KNOW whether low Vit D or those known risk factors for worse prognosis (increased thickness and ulceration) did in fact, create the poor prognosis that did materialize....but....???

Low Serum 25-Hydroxyvitamin D Concentrations are Associated with Increased Risk for Melanoma and unfavorable Prognosis.  Bade, Zdebik, Wagenpfeil, et al.  PLoS One.  Dec 2014.

Low vitamin D status (Serum 25(OH)D concentration is associated with increased incidence and unfavorable outcome of various types of cancer.  Serum Vit D concentrations were retrospectively analyzed in 324 melanoma patients and 141 healthy controls.  Vit D levels were significantly lower in melanoma patients (med = 13.6 ng/ml) vs controls (med = 15.6 ng/ml).  When looking at Vit D levels in the melanoma patients:  those with lower levels of Vit D had greater Breslow thickness and inferior survival (med = 80 months) vs the melanoma patients with higher levels (med = 195 months).  Our data support that concept that serum Vit D concentrations are associated with risk and prognosis of melanoma.  Whether normalizing serum Vit D in these patients improves outcomes will require testing in future clinical trials.

This report is at least consistent within its own data.  Clearly, there is much related to Vit D and its effects on cancer that we don't understand.

For what it's worth! - c

In-Transit Melanoma..a little info

In-transit mets for melanoma are a type of Stage III regional metastatic disease, occurring in about 10% of melanoma patients, that are within or just below the skin as nodules within the lymph system and not in nodal basins. Unfortunately these lesions are an independent adverse prognostic factor and are frequently associated with distant metastasis....which makes sense when you think about where they reside.  Isolated limb perfusion therapy has been utilized with some success.  Here are a few of the latest articles:

In-transit Melanoma Metastasis:  Incidence, Prognosis and the Role of Lymphadenectomy.
Read, Haydu, Saw, et al.  Ann Surg Oncol. 2014 Sep 26.

11,614 patients with single primary cutaneous tumors were treated at Melanoma Institute in Australia between Jan 1994 and Dec 2009.  Of these, 505 developed ITM.  Their clinical characteristics, sentinel node status, disease pattern and progression as well as outcomes were analyzed.

Of this 505:  Primary tumor thickness was 2.95mm.  39.4% were ulcerated.
ITM rates for patients with primary melanomas less than 1 mm = 0.4%, for those with primaries equal to or greater than 1 mm = 7.8%, and for those with  sentinel node biopsy = 7.2%.
ITM rates for SN positive = 21.6%.  For SN negative = 4.7%.  
Median time from primary diagnosis to development of ITM = 17.9 months.
After dx, median survival time = 19.9 months.  5 year survival = 32.8%.  10 year survival = 27.5%.
Primary tumor site (head/neck and trunk) and ulceration were predictors for poorer survival.
Five year survival from the time of ITM ranged from 47.9% for non-ulcerated limb primary lesions to only 13.6% for ulcerated trunk lesions.
Elective lymph node dissection in clinically node negative patients with ITM did not significantly alter overall survival.

CONCLUSION:  "This large study demonstrated that the diagnosis of melanoma ITM carries serious adverse prognostic implications and will assist in improving the accuracy of staging and prognostic estimates as well as treatment in these patients."

Burden of Disease Predicts Response to Isolated Limb Infusion with Melphalan and Actinomycin D in Melanoma.  Muilenburg, Beasley, Thompson, et al.  Ann Surg Oncol. 2014 Sep.

Isolated limb perfusion with melphalan is minimally invasive, effective treatment for in-transit melanoma.  Databases from two academic centers were analyzed. Burden of disease was characterized as high or low (with low being ten or fewer lesions with none greater than 2 cm). Responses were measures at 3 months post isolated limb perfusion.  60 patients had low and 100 patients had a high burden of disease (BOD).  Low BOD patients had an overall response rate of 73%  and complete response of 50%.  Patients with high BOD had only a 47% ORR and CR of 24%.  Patients with a CR at 3 months demonstrated improved progression free survival, but overall survival was similar.  Low BOD patients had an increased median PFS of 6.9 months vs 3.8 months and an increased median overall survival of 38.4 vs 30.9 months.

Pathologic Complete Response to Intralesional Interleukin-2 Therapy Associated with Improved Survival in Melanoma Patients with In-transit Disease.  Hassan, Petrella, Zhang, et al.  Ann Surg Oncol.  2014 November.

Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies.  Retrospective collection of data on 31 patients treated with intralesional IL-2 for in-transit melanoma:  Ten patients (32%) achieved complete response.  17 (55%) had a partial response.  4 (19%) had progressive disease.  Higher CD8+ T cell infiltrates were noted in patients having a complete response vs that which was present in other lesions and improved progression free survival.

So, much like treatment data for melanoma generally, patients with the lowest disease burden and the greatest infiltration of T cells did best.  No real surprises there.  When thinking about this aspect of melanoma, I realized...this is a hard row to hoe, in the already difficult melanoma field.  Wishing you all my best. - c