Straight Outta Boston!!! Latest melanoma research ~

From the recent Boston meeting of the Society for Melanoma Research:

 Preventing resistance by combining BRAF with hydroxychloroquine (HCQ). 

High response rates with combined BRAF and autophagy inhibition: results of 2 phase I trials  Gangadhar, et al.

Autophagy is a resistance mechanism to BRAF inhibitors that can be targeted with hydroxychloroquine (HCQ). We launched a Phase I trial of vemurafenib and HCQ in BRAFV600 melanoma patients. 7 patients in the 1st dose level (vemurafenib 960 po bid + HCQ 400 po bid) had 2 dose limiting toxicities ...  preventing further dose escalation. 6/6 patients evaluable for response had PR or CR. Prolonged PFS was seen in 1 CR (30+ mo) and 1 PR (20 mo).  Combined BRAF/MEK inhibition was adopted widely so this trial was closed, and a multi-institution phase I/II trial of dabrafenib (D), trametinib (T) and HCQ was opened. Phase I was completed with no DLT (n=7). Recommended phase II dose was HCQ 600 bid with D+T. Phase II enrollment continues. D+T+HCQ was well tolerated, with no evidence of visually significant ocular toxicity. Striking responses were observed: 6/7 patients responded and 5/6 patients had a CR. The only non-responder was found to have BRAFV600E amplification, and had pyrexia that required frequent dose interruptions. Only 1 of 6 responders has progressed (PFS for responders 7-19 months, ongoing, censored as of July 2016), with brain metastases harboring a BRAFV600E and PIK3CA mutation after 15 mo. A cell line created from this resected metastases showed continued sensitivity to D+T+HCQ in vitro. The patient developed progressive CNS disease despite brain radiation and restarted D+T+HCQ, benefiting from second response that continues to date. Patient derived xenografts were created from 4/4 pretreatment tumor biopsies from the 7 patients. A randomized PDX trial with all combinations of treatments is underway with PDX from responding and resistant patients to determine if the addition of HCQ to D+T is significantly contributing to the activity of this regimen. 

Stage IIIB/C treated with adjuvant BRAFi = 100% 6 month survival vs 28.6% with standard care!!!

Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma.  Amaria, et al.

The treatment of stage IV melanoma has been revolutionized by targeted therapy and immune checkpoint blockade, and there is a strong rationale to evaluate these agents in earlier stages of disease. The current SOC in patients (pts) with high-risk resectable melanoma (stage IIIB/IIIC) is upfront surgery +/- adjuvant therapy, but relapse rates are high. We hypothesized that treatment with neoadjuvant + adjuvant D+T in this population would result in lower relapse rates compared to SOC. Methods: We conducted a prospective randomized clinical trial (NCT02231775) in pts with resectable Stage IIIB/C or oligometastatic stage IV BRAF-mutant melanoma. Pts were randomized in a 1:2 fashion to SOC (Arm A) or neo + adjuvant D+T (Arm B, 8 wks neoadjuvant + 44 wks adjuvant). Planned enrollment was 84 pts. Primary endpoint was RFS. Results: Randomization was halted after 21 pts were enrolled (arm A=7, arm B=14). Arms were well matched for gender and stage of disease, though pts in arm A were younger. Perioperative complication rates were similar and toxicity in arm B was manageable. At week 8 the RECIST response rate with D+T was 77% and the pathologic complete response (pCR) rate was 58%. Early analysis revealed a significantly higher RFS in the D+T arm over SOC, with 6-month survival estimated at 100% in Arm B and 28.6% in Arm A, leading to trial closure. Conclusions: Treatment with neoadjuvant + adjuvant D+T is well tolerated, results in high clinical response and pCR rates, and markedly improves RFS in pts with high-risk resectable metastatic melanoma. Correlative analyses are underway to characterize mechanisms of response and resistance to neo + adjuvant D+T.   

T-VEC plus ipi = OOR of 50% vs 27.5% for ipi alone.

Interim analysis of a randomized, open-label phase 2 study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected, stage IIIB-IV melanoma.  Chesney, et al.  

T is a herpes simplex virus 1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses. I (anti-CTLA-4 Ab) blocks inhibition of antitumor T-cells. Both T and I monotherapy are approved in the US and EU for the treatment of advanced melanoma. The primary endpoint for the phase 2 part was ORR by immune-related response criteria. Key secondary endpoints are safety, progression-free survival, time to response, duration of response, and survival. Key entry criteria are unresectable stage IIIB-IV melanoma, with 2 or fewer prior tx, measurable/injectable tumor(s), and no symptomatic autoimmunity or clinically significant immunosuppression. T was given on d1 w1; w4, then q2w in arm 1 until no injectable tumors, disease progression, or intolerance. I started with the 3rd dose of T in arm 1 or alone in arm 2 at 3 mg/kg IV q3w x 4. An interim analysis (IA) for efficacy was performed when 82 patients (pts) had ≥48 w of follow up. 173 pts were randomized: 88 T+I; 85 I. Characteristics for all pts were similar: 54% stage IIIB-IVM1a, 45% IVM1b/c. Median follow up time for 82 pts in the efficacy set was 61.2 w. Confirmed ORR was 35.7% (T+I) and 17.5% (I); unconfirmed ORR was 50% (T+I) and 27.5% (I). Of 165 pts in the safety set (85 T+I, 80 I), most common adverse events (AEs) for T+I, I (%) were fatigue (52, 39), chills (51, 3), diarrhea (39, 34), pyrexia (39, 8), rash (39, 31) and pruritus (38, 35). 20% T+I and 18% I pts had grade 3/4 tx-related AE. A grade 5 autoimmune hepatitis occurred in the T+I arm (investigator attributed to I). ORR was higher for T+I vs I alone at this IA. AEs were comparable between arms except for increased fatigue, chills, and pyrexia in the T+I arm. 

Intra tumoral HF10 plus ipi = good! 

A Phase 2 multicenter trial to evaluate efficacy and safety of HF10, oncolytic virus immunotherapy and ipilimumab in patients with unresectable or metastatic melanoma. Andtbacka, Ross, ...Agarwala,... Daud, et al. 

HF10 (intratumoral injection) shows activity in injected lesions and non-injected metastatic lesions presumably via an antitumor immune response elicited by viral destruction of injected lesions. An ongoing Phase 2 study of HF10 combined with ipilimumab (ipi) in melanoma pts is assessing whether the antitumor effect of HF10 is enhanced by concurrent ipi treatment. Efficacy and safety of HF10+ipi treatment are reported herein. An immunologic correlative data analysis is currently ongoing. Ipi naïve adults with stage IIIB, IIIC or IV unresectable melanoma with measurable non-visceral lesion(s) received HF10 injections into single or multiple tumors; 4 injections qwk; then up to 15 injections q3wk. Ipi (4X at 3 mg/kg, IV) was administered per SOC. Tumor responses were assessed at 12, 18, 24wks, and 36, 48wks for pts continuing HF10 monotherapy. Best Overall Response Rate (BORR) was determined at 24wks. Of 46 pts treated, 20% were stage IIIB, 43% stage IIIC, and 37% stage IV. Most HF10-related AEs were ≤G2, similar to HF10 monotherapy. No DLTs were reported; 3 G4 AEs reported, all not treatment related. 30.4% had G3 AEs. HF10-related G3 AEs (n=3) were left groin pain, thromboembolic event, lymphedema, hypoglycemia, and diarrhea. Of 43 efficacy evaluable pts, preliminary BORR at 24 wks per irRC was 41.8% (11.6% CR, 30.2% PR), disease stability rate 67.4% (25.6% SD). 8 responders (53%) were stage IV. Overall study BORR, including those after 24 weeks, by irRC was 48.8% (18.6% CR, 30.2% PR), disease stability was 67.4% (18.6% SD). In summary, HF10+ipi treatment does not appear to exacerbate ipi toxicity, is safe and well tolerated, has both local and systemic antitumor activity, with promising response rates when combined with ipi.

Ipi/Nivo for Stage 3 mel.

(Neo-)adjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage 3 melanoma – the OpACIN trial.  Blank, et al. 

 IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore depends on the amount of antigen present, arguing for that adjuvant immunotherapy willwork most efficiently, when initiated prior to surgery. Two-arm Phase 1b feasibility trial consisting of 20 high risk AJCC stage 3B/C melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split neo-adjuvant and adjuvant. To date, 17 patients are evaluable (9 neoadjuvant; updated data and first analyses of melanoma specific T cell responses will be presented.). Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 15/17 patients (88%) had to stop earlier due to grade 3/4 toxicities. ORR in the neo-adjuvant IPI+NIVO arm was 78% (3 pCR, 3 near pCRs [minimal remaining micrometastasis], 1 pPR [remaining metastasis of 0.5mm], 1 SD and 1 PD). So far, post-surgery, none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for 1 neoadjuvant SD patient and for 3 patients within the adjuvant arm. The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage 3 melanoma patients is feasible. However, severe grade 3/4 toxicity was more frequent than expected from stage 4 melanoma patient study data. In parallel, response rate and depth of response also may be higher than in stage 4 melanoma patients. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage 3 melanoma, which will be tested in adjusted schemes in the upcoming phase 2 OpACIN-neo trial, with the aim of preserving efficacy, but reducing toxicity. 

Brain mets post SRS/crani: nivo vs pembro.

Control of brain metastases with anti-PD-1 therapy in patients with melanoma post-SRS/craniotomy.  Ozgun, et al. 

While anti-PD-1 antibodies have shown significant clinical benefit in patients (pts) with advanced melanoma, a majority of these pts develop brain metastases for which standard treatments remain radiation therapy and/or surgery. We examined outcomes in pts who were diagnosed with melanoma brain metastases (MBM) and received upfront locoregional therapy, to determine how well their subsequent anti-PD-1 therapy could control their MBM. We retrospectively reviewed 146 pts with advanced melanoma who were treated with anti-PD-1 therapy, to identify 23 pts who had received prior stereotactic radioasurgery (SRS) or craniotomy for MBM. There were 13 men and 10 women, with median age 56 (27-85). Most common site of metastases was in the frontal lobe (n=13, 57%). Primary treatment for the MBM was SRS in 17 (74%), and craniotomy in 6 (26%) pts. Median follow-up was 2 years post-locoregional therapy. Eleven pts subsequently received pembrolizumab and 12 pts received nivolumab; median duration of therapy was 5 months. Eight pts received these drugs as their first-line systemic therapy post-SRS/craniotomy, 13 as second line therapy, and 2 as third-line; other first-line therapies included ipilimumab, chemotherapy or BRAF-targeted therapies. While receiving their anti-PD-1 therapy, five (22%) pts had no recurrence of any brain metastases (n=2 with pembro, n=3 with nivo) and eight (35%) pts had stable MRI brain imaging with no new or growing lesions. However, ten pts (44%) had progession of their brain metastases while on anti-PD-1 therapy (n=3 with nivo, n=7 with pembro). Median overall survival from time of SRS or craniotomy was 24 months (5.6-32) for pts treated with pembro and 36 months (1.7-84) with nivo. While there may be a suggestion of improved outcome with nivolumab in MBM after locoregional therapy, larger analyses are needed for definitive conclusions.  

Aspirin helps NRAS affected mice!

Acetylsalicylic acid governs the effect of Sorafenib in mutant NRAS melanoma. Hammerlindl, et al. 

To date no therapies directly targeting mutant NRAS melanoma have been approved, leaving chemotherapy with very low response rates or immunotherapy for the treatment of mutant NRAS melanoma patients. Here we report a novel strategy to target mutant NRAS melanoma by combining the multi kinase inhibitor Sorafenib and the nonsteroidal anti-inflammatory drug acetylsalicylic acid (Aspirin), both of which are clinically tested and approved. The addition of Aspirin, but not isobutylphenylpropanoic acid (Ibruprofen) or Celecoxib significantly increased the invitro cytotoxicity of Sorafenib resulting in a fivefold reduced effective Sorafenib dose in WM1366, WM832, and WM1361 mutant NRAS melanoma cells. Mechanistically, combined exposure resulted in the simultaneous hyperactivation of AMPK and ERK pathways. Combining Sorafenib with other AMPK activators like Metformin or A769662 was not sufficient to induce cell death due to sole activation of the AMPK pathway. Accordingly, cytotoxicity of Sorafenib and Aspirin was blocked by concurrent inhibition of AMPK or ERK pathways using pharmacological inhibitors of RAF (LY3009120), MEK (Trametinib) and AMPK (Compound C) or shRNA targeting BRAF or AMPKα1/2. The combination was found to be specific for mutant NRAS and had no significant effect in wild type RAS keratinocytes or melanoma cells. In-vivo the treatment of SCID mouse xenografts with Sorafenib and Aspirin significantly reduced tumour volume compared to single treatment alone. Combined Sorafenib and Aspirin selectively target mutant NRAS melanoma cells by simultaneously affecting two independent pathways. The combination represents a novel treatment strategy for mutant NRAS melanoma by repurposing clinically approved drugs with the potential to reduce Sorafenib induced adverse effects while maintaining clinical efficiency. 

Ok.  I'm tired now.  But...some pretty interesting stuff. For what it's worth - c

May we all rise...

Like Colbert in his monologue below, my first realizations of politics were Watergate as well as President Jimmy Carter's peace talks with Anwar Sadat and Menachem Begin - examples of American leaders at their worst and best.

So what are we, the polarized folks...living through this round of American politics to do?  I offer these words from these bright and very different minds - Stephen Colbert, Dan Rather, Maya Angelou, and Ellen DeGeneres.

As Colbert expertly sums things up:  "We all now feel the way Rudi Giuliani looks!"  As he notes, "Politics is everywhere and that takes up precious brain space needed to remember all the things we actually have in common."  But, in a lighter vein, he points out that "you cannot laugh and be afraid at the same time."  Take a look and a listen:  Stephen Colbert....signing off on this election

A thought from Dan Rather and strength, beauty and wisdom from Maya Angelou: 

In times like these, when waves of emotion threaten to overwhelm me and a fogged brain struggles with contemplation, I often seek space and solace in the world of poetry. Tonight I have found myself returning to a spirit of uplift courtesy of Maya Angelou's Still I Rise. I thought it was worth a share here. 


STILL I RISE
You may write me down in history With your bitter, twisted lies, You may tread me in the very dirt But still, like dust, I'll rise.
Does my sassiness upset you?
Why are you beset with gloom?
'Cause I walk like I've got oil wells
Pumping in my living room.
Just like moons and like suns,
With the certainty of tides,
Just like hopes springing high,
Still I'll rise.
Did you want to see me broken?
Bowed head and lowered eyes?
Shoulders falling down like teardrops.
Weakened by my soulful cries.
Does my haughtiness offend you?
Don't you take it awful hard
'Cause I laugh like I've got gold mines
Diggin' in my own back yard.
You may shoot me with your words,
You may cut me with your eyes,
You may kill me with your hatefulness,
But still, like air, I'll rise.
Does my sexiness upset you?
Does it come as a surprise
That I dance like I've got diamonds
At the meeting of my thighs?
Out of the huts of history's shame
I rise
Up from a past that's rooted in pain
I rise
I'm a black ocean, leaping and wide,
Welling and swelling I bear in the tide.
Leaving behind nights of terror and fear
I rise
Into a daybreak that's wondrously clear
I rise
Bringing the gifts that my ancestors gave,
I am the dream and the hope of the slave.
I rise
I rise
I rise.                           ~ Maya Angelou

And - just so you know, Ellen shows us there is:  Hope for your little iguana

And from me ~ Each of us are beauty full.  Love stops hate.  Beauty and a generous spirit stops negativity.  And, yes - laughter stops fear.  ~  May we all rise.  c

Anti-TYRP1 monclonal antibody - The next good thing for melanoma?????

I don't often publish the newest, latest and greatest.  We melanoma ratties have too often been used and abused by such things....not to mention sorely disappointed.  But....there's this...  (Check out the list of Melanoma Big Dogs as authors!)

An Open-Label, Dose-Escalation Phase I Study of Anti-TYRP1 Monoclonal Antibody IMC-20D7S for Patients with Relapsed or Refractory Melanoma.  Khalil, Postow, Ibrahim, Ludwig, Cosaert, Kambhampati, Tang, Grebennik, Kauh, Lenz, Flaherty, Hodi, Lawrence, Wolchok.  Clin Cancer Res. 2016 Oct 19. 

Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S.

The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose-escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks.

Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed.

IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted.

No dose limiting toxicities?  Only constipation and fatigue?  41% disease control?  In patients with progression after at least one line of treatment????  One complete response????  

OK...so it is only in 27 patients.  It is preliminary data.  But, it has some big names behind it.  It might even work better as first line...maybe?  As we learned about anti-PD1, BEFORE ipi?  Or with other immunotherapy, as we learned with nivo AND ipi?  

Lots of questions.  Small numbers.  But, certainly something I'd be asking about if I were in need.  Hang in there ratties!!! - c 

Sew Chaotically! - Happy Birthday, Carla!!! - with another Vogue 1440....

I had a lot of fun making and wearing this:  Vogue 1440 - such a cute top!!

So, when Carla complimented a picture of it...I thought, "Hmmmmm....maybe she could use one for her birthday!!!"  And here it is:

I had just enough of my indigo dyed fabric from Maiwa to use as the trim!  Hope she likes it!  Happy Birthday, Kik!!! love, c

A beautiful fall hike....

As much as I love to travel and see new places and faces ~ I try to make sure I never take the beauty and love around me for granted....

Thanks for another beautiful hike on our special trail, B!!!  Happy Birthday, Baby!!!   love, c

Side effects to immunotherapy...Part 6!

Those of you who have been following the blog for a bit know that I have been regularly updating the running saga of side effects caused by immunotherapy, which includes treatments with ipi, both the anti-PD1 products, Keytruda and Opdivo, as well as anti-PD-L1!!!  Always remember that most of these are pretty rare.  But, the ratties have suffered so that you and your doc can figure out things with YOU quicker and more effectively!!!  Here's a link (with others within) to what was posted in the past: Side effects to immunotherapy....Part 5

Here are recently published reports, the first two addressing cardiac issues associated with immunotherapy....something we already knew happened in mice, back in 2010 before I joined my nivo trial....

Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy.  Heinzerling, Ott, Hodi, et al.  J Immunother Cancer. 2016 Aug 16. 

Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall survival has been demonstrated with anti-CTLA-4 and PD-1 inhibition. However, a plethora of immune-mediated adverse events has been reported with these agents. Immune-mediated cardiotoxicity induced by checkpoint inhibitors has been reported in single cases with variable presentation, including myocarditis and pericarditis. Among six clinical cancer centers with substantial experience in the administration of immune-checkpoint blocking antibodies, eight cases of immune-related cardiotoxicity after ipilimumab and/or nivolumab/pembrolizumab were identified. Diagnostic findings, treatment and follow-up are reported. A large variety of cardiotoxic events with manifestations such as heart failure, cardiomyopathy, heart block, myocardial fibrosis and myocarditis was documented. This is the largest case series to date describing cardiotoxicity of immune-checkpoint blocking antibodies. Awareness, monitoring of patients with pre-existing cardiac disorders and prompt evaluation by the treatment team is essential. Treatment including application of steroids is critical for patient safety.

Fulminant Myocarditis with Combination Immune Checkpoint Blockade.  Johnson, Balko, Compton, Chalkias, ... Sosman, Moslehi, et al.  N Engl J Med. 2016 Nov 3.  

Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction.

 

Incidence of Thyroid-Related Adverse Events in Melanoma Patients Treated with Pembrolizumab.  de Filette, Jansen, Schreuer, et al.  J Clin Endocrinol Metab. 2016 Aug 29.

Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 receptor (PD-1) monoclonal antibody (mAb), remains to be fully characterized.  Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a referral oncology center. ¹⁸Fluorodeoxyglucose uptake on positron emission tomography/computed tomography (¹⁸FDG-PET/CT) was reviewed in cases compatible with inflammatory thyroiditis.  99 patients with advanced melanoma (aged 26.3-93.6 years; 63.6% females) who received at least 1 administration of pembrolizumab.  18 adverse events of thyroid dysfunction were observed in 17 patients. Thyrotoxicosis occurred in 12 patients of which 9 evolved to hypothyroidism. Isolated hypothyroidism was present in 6 patients. Levothyroxine therapy was required in 10 of 15 hypothyroid patients. Thyroid autoantibodies were elevated during thyroid dysfunction in 4 of 10 cases. Diffuse increased ¹⁸FDG uptake by the thyroid gland was observed in all 7 thyrotoxic patients who progressed to hypothyroidism.  Thyroid dysfunction is common in melanoma patients treated with pembrolizumab. Hypothyroidism and thyrotoxicosis related to inflammatory thyroiditis are the most frequent presentations. Serial measurements of thyroid function tests are indicated during anti-PD-1 mAb therapy. Thyrotoxicosis compatible with inflammatory thyroiditis was associated with diffuse increased ¹⁸FDG uptake by the thyroid gland. The prospective role of thyroid autoantibodies should be further investigated together with the histopathological correlates.

Acute visual loss after ipilimumab treatment for metastatic melanoma.  Wilson, Guld, Galetta, et al.  J Immunother Cancer. 2016 Oct 18.

Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).  Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.  This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.

(No....you weren't losing your vision there...just dealing with the vagaries of copy and paste on blogger!!!)

Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy.  Naidoo, Wang, Woo, et al.  J Clin Oncol. 2016 Sep 19. 

Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described.  Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes.Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152  combination, 11 of 115 v four of 57). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse.

Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.  

Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients.  Nguyen, Kuo, Budiman, Christie, Ali. Melanoma Res. 2016 Oct 21.  

Immune checkpoint inhibitors have changed the landscape of the treatment of multiple solid malignancies, and have been used increasingly in the recent years. Although usually well tolerated, given the relative inexperience of using immune checkpoint inhibitors, we are still learning of new side effects from the treatment. We report on two cases of ocular myasthenia gravis that occurred after treatment with pembrolizumab, an antiprogrammed-death (anti-PD1) monoclonal antibody for advanced melanoma in responding patients. One case is in an 81-year-old man and the second case in an 86-year-old woman, both with BRAF-negative metastatic melanoma receiving pembrolizumab. These two cases of ocular only associated myasthenic syndrome appeared 7 and 11 weeks after the initiation of pembrolizumab. We conclude that the condition is most likely associated with pembrolizumab as symptoms started after treatment with pembrolizumab, neither patient had other evidence of neurological cause for presentation, and symptoms also improved rapidly with administration of steroids. Both patients showed good oncological response to anti-PD1 treatment and one patient successfully continued to receive ongoing treatment with no further complications.

Don't be afraid.  But....Be wise!  Consult your doc with any new or strange symptoms.  Hang tough!!! - c

Chaotic cookery! - From Someone Else's Table: Butternut squash, brussies, and chick peas!

Long promised, never fulfilled...'til now!!!  I am going to try to routinely create posts of one of my favorite things:  cooking (or is it eating?  or sharing?)  When I think about it, they end up being the same thing!!  And I love them all!  I wrote up a little cookbook some years ago, titled The Black Magic Cookbook, by my kiddo's.  Just recipes that were my fav's and things my family enjoys, with little anecdotes about how the dishes came to be, along with family stories.  It was well received....by most who were gifted a copy...and that is more than enough encouragement for me!!!

From Someone Else's Table.  A title I settled on after some struggle when "writing my cookbook", because, who really created the first rendition of THAT dish? Who made the first mac 'n cheese?  Who deserves credit for cioppino?  Fried chicken?  Pumpkin pie?  Julia Child did not invent Boeuf Bourguignon, though much to the chagrin of many a Frenchman I would imagine, her name is synonymous with it....at least here in the states.  Add to that, the fact that very often after our travels, or a yummy meal at at a restaurant, I come home and attempt to re-create a dish that I enjoyed...my way.  So...whose dish is it?  I work very hard to give credit where it is due in literature, melanoma research, sewing patterns...everything I do, really.  Folks deserve credit for their hard work!!  But sometimes....things just are what they are.  No matter how many folks re-do them.  Bottom line, I figure all MY dishes really came From Someone Else's Table!  I will do my best to acknowledge the source as best I can!  So, here we go....

I've often mentioned all the veggies consumed at the Morris Table when folks are extolling me and others to cure our melanoma and other ills in that manner.  That technique hasn't worked for me, yet...but I do love my veggies.  Here are three of my favorite veggie dishes that just happened to make up dinner recently...

Roasted Butternut Squash Salad with Warm Cider Vinaigrette

     This salad has been a hit with everyone I've ever shared it with.  It comes from Barefoot Contessa Back to Basics, by Ina Garten.

1 butternut squash, peeled, and diced into bite size pieces             olive oil
1 T maple syrup              salt/pepper            3 T dried cranberries (though I really like to use dried cherries and did so here!)
         
Dressing:  3/4 c apple cider, apple juice, or white wine   2 T cider vinegar     2 T minced shallots          2 t Dijon mustard            salad greens     {walnuts per her...NOT per me since I am allergic....but I'm sure they'd be good!}   grated Parm to top if you like (sometimes I have it, sometimes I don't....today was 'don't!)

Preheat oven to 400.  Toss squash pieces in olive oil, syrup, salt and pepper.  Place on sheet pan and roast 15-20 minutes, turning once, until tender.  Add the dried fruit to pan for the last 5 minutes.

Dressing:  Combine vinegar, apple cider, and shallots in saucepan and bring to boil.  Cook 6-8 min, until reduced to about 1/4 c.  Off heat add mustard, 1/2 olive oil (I generally use less), salt/pepper.

Place greens on plate.  Top with roasted squash, dressing, and toppings if using.  Serve immediately as it can get soggy!!!

Cochon Brussies

     I looove New Orleans.  And of all the yummy choices, Cochon Butcher may be my favorite restaurant there.  (I know.... Where is THIS dish from THIS place going in a veggie meal, right???)  And, B looooves brussel sprouts...so on a visit there a couple of years ago....we shared this amazing dish.  After sneaky talks with the server and practice at home....here is my version:

Prep fresh brussel sprouts...frozen would be okay...but fresh will hold up better.  Half if large.  Blanch til barely tender in salted water.  Drain.  Saute 1/2 c diced red onion in bacon drippings if you want to be bad and delicious, but olive oil works just fine, in an oven proof pan.  Return drained brussies to pan.  Add splash of champagne vinegar, fresh chopped mint (about 1 T, dried is ok, just use less), red pepper flakes to taste (you can also add more after serving if tastes at your table vary), and crumbled bacon if desired. (I didn't for this meal.)  Roast at 375 or 400 for about 20-30 minutes until roasted and golden.  Enjoy!

Roasted Chick Peas 

     I am not one for a lot of heat in my food, though many of my favorite eaters love it.  But we all love flavor.  Here are some awesome flavors of the world that are delicious. 

I also love garbanzo beans....in salads, pasta salads, soups, sauteed with spinach, onions and lots of paprika, a' la  Espinacas con Garbanzos, that I adored in Spain.  Here is a super quick and tasty snack, hors d'oeuvre, or as I used it here...a way to put a yummy veggie protein into a meal. (I think Ruthie shared this one!)

Obviously you can cook up your own garbanzo's from dried.  I just used a can here.  But...you can roast or pan saute them with any seasoning you like.  Serving Spaghetti?  Season with salt, pepper, basil and oregano.  Steak with a side salad?  How bout seasoning the beans with a steak seasoning blend, or  salt, pepper, paprika, garlic and parsley?  There are no limits to your options.  Here I drained the chickpeas, placed them in hot skillet with a drizzle of olive oil and a sprinkle of South African Peri Peri Blend shown above. Roasting in the oven works great, too.  So good!!!

So that's the first installment.  Hope it gave you some cookery ideas of your own - From Someone Else's Table!!! - c