Monday, December 22, 2014

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. 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. 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, 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

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