Thursday, March 31, 2016

More serious side effects with Anti-PD1!


Just as we learned with ipi, as more folks take anti-PD1 products, we are learning how serious some of the immune related side effects can be.  First there was this:  Fasciitis and encephalopathy after Keytruda.  And more recently, this:  Immune reactions with anti-pd1 can be serious! 
Now these reports have been published:

Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy.  Goldinger, Stieger, Meier, et al.  Clin Cancer Res. 2016 Mar 8. 

Immunotherapy experienced impressive progresses in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes and vitiligo are reported. Although frequent, they are have not been further characterized yet. In this analysis we aimed to systematically assess and characterize the adverse cutaneous reactions observed in melanoma patients treated with anti-PD-1 antibodies.

Melanoma patients were treated with anti-PD-1 antibodies within clinical trials and early access program. Adverse cutaneous eruptions emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison to maculopapular drug rash, cutaneous graft versus host disease and the severe drug eruption toxic epidermal necrolysis.

Between Feb 2013 and Sept 2015, 68 stage IV melanoma patients were treated at the University Hospital Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes without signs of epidermal involvement to severe maculopapular rashes including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as toxic epidermal necrolysis-like reactions.

As predicted by the PD-1 knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases to a toxic epidermal necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions.

Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study.  Koelzer, Rothschild, Zihler, et al. Immunother Cancer. 2016 Mar 15.

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal.

This autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune-related end-organ damage due to lymphocytic myocarditis was found.

Autopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity.


Anti-PD1-induced collagenous colitis in a melanoma patient.  Baroudjian, Lourenco, Pagès, et al.  Melanoma Res. 2016 Mar 17. 

Targeted immunotherapy has markedly improved the survival of melanoma patients. We report the case of a melanoma patient who developed a collagenous colitis under an anti-PD1 regimen. A 68-year-old woman was treated for a stage IV melanoma. An anti-PD1, pembrolizumab, was introduced after the failure of a first-line therapy with an anti-CTLA4. At cycle 14, pembrolizumab was interrupted because of grade 3 diarrhea. Histologic analysis of colon mucosa showed a thickened apical subepithelial collagen layer with irregular collagen deposition of more than 25 µm thickness. Budesonide 9 mg/day and cholestyramin 8 g/day were then introduced, leading to a decrease in the number of stools to grade 2. Because of the prognosis of the disease, the efficacy of pembrolizumab in this patient and the lack of other efficient treatments, pembrolizumab was restarted, with no worsening of the diarrhea after a follow-up of 8 weeks. In the era of immunotherapy, a new type of drug-induced colitis has emerged because of monoclonal antibodies targeting immune checkpoints such as CTLA-4 and PD1. Gastrointestinal tract immune-mediated adverse effects are now well described with ipilimumab. To the best of our knowledge, this is the first report of a collagenous colitis in a patient treated with pembrolizumab, thus suggesting a new mechanism of toxicity. Classically, collagenous colitis first-line treatment is based on discontinuation of the suspected treatment. However, there may be a strong benefit to maintaining an anti-PD1 regimen in our patients. In this case, symptomatic management associated with budesonide and cholestyramin enabled continuation of pembrolizumab.


New-onset toxicity with programmed death-1 inhibitor rechallenge.  Ludlow, Andrews, Pasikhova, Hill.  Melanoma Res. 2016 Mar 15. 

Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor.


Nivolumab-induced thyroid dysfunction.  Tanaka, Fujisaw, Maruyama, et al.  Jpn J Clin Oncol. 2016 Mar 23.

Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

Limbic encephalitis following immunotherapy against metastatic malignant melanoma.  Salam, Lavin, Turan.  BMJ Case Rep. 2016 Mar 23.

Novel immunotherapies are increasingly being used to treat malignant melanoma. The use of such agents has been associated with triggering autoimmunity. However, there has been a paucity in reports of limbic encephalitis associated with these immunotherapies. Pembrolizumab, a monoclonal antibody against programmed cell death antigen (PD-1), is currently being trialled in the UK to treat malignant melanoma. We report a unique case of antibody-negative limbic encephalitis presenting 1 year after starting pembrolizumab, in the context of malignant melanoma. The patient presented with progressive cognitive decline. MRI of the brain revealed signal change within the limbic structures. Cerebrospinal fluid studies confirmed evidence of inflammation with raised white cell count and protein. We were able to prevent further progression of symptoms by stopping pembrolizumab and treating the patient instead with steroids. We advocate considering autoimmune neuroinflammation as a differential for neurological disorders presenting in patients receiving PD-1 antagonist treatment and immunotherapy in general.

I don't want to frighten anyone with all the crazy events documented here.  Overall, anti-PD1 products have minimal side effects compared to many other cancer treatments.  However, I published these so that should any "strange" things start happening to you after, or during, anti-PD1 therapy, you can speak with your doctor and get them checked out as quickly as possible.  After all, as Dr. Weber mused YEARS ago, 'This stuff is weird!" - c

Tuesday, March 29, 2016

Melanoma abbreviations ~ and random thoughts on posting melanoma crap-ola....


Here is a list (not at all comprehensive!) of abbreviations frequently used in melanoma discussions per the request of a melanoma patient on the MRF forum having trouble getting through the acronyms. It was fairly well received (though I'm not sure everyone read the ENTIRE list!!!) so I thought I would share it here:



NED - no evidence of disease
NEAD - no evidence of active disease (a rather new acronym in melanoma world)
Mets - metastatic disease
SLN - sentinel lymph node (the node most proximal to the lesion)
WLE - wide local excision (the area of tissue to remove around  a lesion to provide standardized accepted clear margins)
CLND - complete lymph node dissection (removal of all nodes in local area)
SRS - stereotactic radio surgery (radiation beamed in to one area from a variety of vantage points so surrounding tissue has minimal damage)
WBR - whole brain radiation
Immunotherapy - treatment that stimulates the immune system to attack tumors (types below)
Ipi - ipilimumab/yervoy - anti-CTLA 4 immunotherapy
Anti-PD-1 - nivo = nivolumab/opdivo or pembro = pembrolizumab/keytruda
ifn - interferon
Targeted therapy - therapy aimed at  a specific variation in a tumor 
BRAF or NRAS or CKIT ....some labels for different variations in tumors
BRAFi - BRAF inhibitors - meds for folks with those mutations
MEK - another place to block tumor metabolism.  MEKi (MEK inhibitors) have been found to make BRAFi work better, last longer, with fewer side effects and so are most often prescribed with BRAF inhibitors.
PR - partial response
CR - complete response
SD - stable disease
ORR - overall response rate
DFS - disease free survival
PFS - progression free survival
OS - overall survival
DLT - dose limiting toxicity
AE - adverse event
Ir AE - immune related adverse event
WTF - whiskey tango foxtrot - you gotta have a sense of humor!
(Folks.....if you like this...please refer folks back to this cause...IDHTS (I don't have the strength!) To type this again!
Hope this helps. Wishing you all my best. Celeste

I crack myself up!!!  Hee hee!!!  Later I shared it with a friend; watching her face as she read it through.  Her eyes widened and she looked up at me!!  "You really are you!!!  All the time!"  Yep!  That's all I got, so I guess I'll stick with it.  And...while I don't for one moment believe that positivity will cure cancer, a sense of humor will sure make it a little less painful.

Obviously, I still blog (and occasionally share on the melanoma forums) the latest data in melanoma research.  It takes a great deal of time and effort.  At times I long to stop.  Still, I know I have access to information that others do not.  And...perhaps...the ability to share it in ways that makes it a bit more comprehensible to others.  I receive frequent emails from folks looking for additional information.  Those are a mixed bag.  Some incredibly demanding and critical.  Not long ago a writer really said...."I guess I could actually read your blog and find the answers to my questions, but, are you the one who had melanoma or what?"  (Wow!!!  The answer to that one seems pretty clear at the very top of the page! Not that she stopped there!!!) Others are clearly desperate or utterly confused.  Some intelligent, thoughtful and appreciative.  Still others never bother with a thank you or kiss my foot (including the one mentioned above!!!). But, many have become dear friends.  A mixed bag indeed!!  And, yes.  Against the advice of some who care about me....I answer them all.  Melanoma doesn't make you nice or smart....folks are....or aren't.  But, it can make you out of your mind with worry and fear...so I try to give folks a chance.  And before you start feeling sorry for me....or get the impression that I am feeling sorry for myself....the support of many...especially 'MY boys!!!' - Josh, Ed, Mat, Jonathan, Paul, Steven, John, Eric, and Brian helps keep me going and can make me laugh out loud.  Many others will live in my heart forever.  In total...a much greater gift to me, than any I have given.

These comments by Ed and Paul still make me smile:  Abbreviation post!

Whiskey Tango Foxtrot!!!! - c 

Saturday, March 26, 2016

Biomarkers - blood components, circulating tumor cells AND of the tumor itself

Biomarkers.  Sounds important.  What are they?  What can they really tell us? 

Researchers have been seeking to find a connection between nonspecific biomarkers (things we ALL have circulating in our blood) like LDH, various white blood cells (neutrophils and monocytes - whether as an absolute count or as a neutrophil to lymphocyte ratio), myeloid-derived suppressor cells (MDSCs) and T-regs (See post with links about all that here:   Blood markers associated with clinical outcomes).  And while many meaningful correlations have been drawn between these components and response to treatment (or lack thereof); the fact that they are all affected by numerous circumstances other than melanoma and its treatment, create limitations in the clarity with which they can be used to PREDICT responses.

With recent scientific advances, PCR testing (Polymerase chain reaction) has become more efficient and cost-effective, allowing labs to copy or "amplify" small segments of DNA or RNA though screening blood or other biological specimens.  This ability allows the cellular identification of whatever may be floating in that blood sample....whether it is a virus or fungus, or actual bits and pieces of tumor cells themselves, to allow a determination of  disease burden, prognosis, and response to treatment.  Here is an earlier post:  Circulating tumor cells: how they may eventually impact melanoma diagnosis and evaluation of response

Now there are these reports:

Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients.  Haung and Hoon.  Mol Oncol. 2015 Dec 17.


Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective.

Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis.  Hida, Yoneta, Wakamatsu, et al.  Australas J Dermatol. 2016 Mar 1.

TNM staging is mainly used to evaluate the prognosis of melanoma patients. Serum biomarkers such as 5-S-cysteinyldopa (5-S-CD) have occasionally been used but most do not respond until the tumour burden becomes high. Recently, circulating melanoma cells (CMC) have been reported as a possible new biomarker to detect metastasis, monitor treatment response and predict prognosis. The object of this exploratory study was to evaluate the efficacy of CMC to detect metastasis and predict prognosis by cross-sectional and prospective observational analyses, respectively. Altogether 15 patients with stages II-IV melanoma were enrolled and CMC were enumerated by CellSearch system with cut-off values of two cells/7.5 mL. Serum 5-S-CD and lactate dehydrogenase (LDH) were also measured. The sensitivity of CMC and 5-S-CD for the detection of metastasis was 33 and 50%, respectively. The combination of CMC and 5-S-CD showed a sensitivity of 67%, the best performance among CMC, 5-S-CD, LDH and any combination of two of the markers. Additionally, a 30-month prospective observation showed that CMC could segregate patients with poorer prognosis. The median survival time for the patients with less than 2 CMC and those with greater than or equal to 2 CMC was 19.5 and 4.5 months, respectively. The limitation of this study is the small sample size. These preliminary results indicate CMC may complement the efficacy of 5-S-CD to detect metastasis and can be a prognostic marker. Although there is still room for improvement to maximize the sensitivity, the CellSearch system is reproducible, standardized and suitable for multi-center studies.

Then, there's the examination of the properties of the tumor sample itself.  This article talks about looking at the tumor in regard to how well it is being recognized by the immune system....specifically t-cells:
 
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.  Johnson, Estrada, Salgado, Sosman, et al.  Nat Commun.  2016 Jan 29.

Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.

Here...the tumor is being characterized by surface molecules that are correlated with prognosis:

Molecular markers to complement sentinel node status in predicting survival in patients with high risk locally invasive melanoma.  Rowe, Tang, Hughes, et al.  Int J Cancer. 2016 Mar 14. 

Sentinel lymph node status is a major prognostic marker in locally invasive cutaneous melanoma. However this procedure is not always feasible, requires advanced logistics, and carries rare but significant morbidity. Previous studies have linked markers of tumour biology to patient survival. In this study we aimed to combine the predictive value of established biomarkers in addition to clinical parameters as indicators of survival in addition to or instead of sentinel node biopsy in a cohort of high risk melanoma patients. Patients with locally invasive melanomas undergoing sentinel lymph node biopsy were ascertained and prospectively followed. Information on mortality was validated through the National Death Index. Immunohistochemistry was used to analyse proteins previously reported to be associated with melanoma survival, namely Ki67, p16, and CD163. Evaluation and multivariate analyses according to REMARK criteria were used to generate models to predict disease-free and melanoma-specific survival. 189 patients with available archival material of their primary tumour were analysed. Our study sample was representative of the entire cohort (N=559). Average Breslow thickness was 2.5 mm. 32 (17%) patients in the study sample died from melanoma during the follow-up period. A prognostic score was developed and was strongly predictive of survival, independent of sentinel node status. The score allowed classification of risk of melanoma death in sentinel node negative patients. Combining clinicopathological factors and established biomarkers allows prediction of outcome in locally invasive melanoma and might be implemented in addition to or in cases when sentinel node biopsy cannot be performed.

Here the tumor is being analyzed for specific genetic variations:   

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.  Hugo, Zaretsky, Sun, et al.  Cell. 2016 Mar 15. 


PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.


While none of these (other than those that are simple measures of recognized blood components) are validated and ready for daily screening of cancer patients across this country....every step is important in helping docs...eventually....determine the best treatment options for the individual and monitor their response to that treatment in ways that are specific, easily measured, and less invasive and damaging to that patient.  What a beautiful day that will be!!!  Minimized only by the day we figure out how to avoid cancer entirely!  Hey....might as well live large and dream big!!! - c

Thursday, March 24, 2016

Sew Chaotically! - The beauty of a simple wrap skirt!



This pattern is ancient.  But, the darts to front and back make it fit much nicer than it appears it would.  The material is a cotton from Hancocks that I got last year that is soft but substantial, with a little slub and faint pin stripe.  I know, I know!  It's ANOTHER grey skirt!  But look what it can do!



My favorite blues...
Classic with a twist in the fabric of the blouse...
You know I LOVE me some stripes.  Especially with a fav scarf Roo got me on her visit to Kew Gardens, London.
Pink and ruffles....done right....are always good!!!
I had fun with this one.  Perhaps I missed my calling as a window dresser or stylist.  Or perhaps I like playing with a life size Dawn Doll!!!  Anyhow....I do like these outfits.  They meet my own challenge of choosing to make things that I really like to wear, rather than choosing items based on whether or not I think they would be easy to make.  Although this one WAS super easy....AND....I made NONE of these tops....AND....that is OK with me!!!! Have fun and sew chaotically!!! - c

Wednesday, March 23, 2016

More good news...local and systemic responses...to TVEC



With T-VEC's October FDA approval...I put together this post: Collection of reports on T-VEC Now there is this:
  
Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study.  Kaufman, Amatruda, Reid, et al.  J Immunother Cancer. 2016 Mar 15.

We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor-specific immunity, we sought to determine the independent response rate in virus-injected and non-injected lesions. Fifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions-non-visceral lesions and visceral lesions.

Eleven of 23 patients (47.8 %) had a more than/= 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a more than/= 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by more than/= 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by more than/= 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by more than/= 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non-visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec. These results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma.

Local AND systemic responses!!!!  AWESOME!!! - c

Monday, March 21, 2016

Melanoma big dogs review results of pts treated with Pembro = Don't stop too soon!!!


I've posted it a zillion times from all sorts of articles and webinars ~ when dealing with immunotherapy... 'Be patient with the patient!'...(from the webinar by Weber and Agarwala).  Repeatedly we've been warned that "progression" and "pseudoprogression" early on has to be evaluated with a grain of salt...rather than considering the measure ineffective and  yanking patients off their therapy as one fellow rattie was in my Nivo trial back in 2010 before we learned better.  (Though, if you've forgotten....while Weber was looking for another treatment for him...he started to improve!!!!  And continued to do so....with no further treatment.)  Folks treated with various immunotherapies, and combo's of same, have had side effects that rendered continuation of such treatment impossible.  Yet....they continued to respond.  Here a cadre of melanoma big dogs look at the results of 655 patients treated with pembro and tell us that as many as 15% of those treated could have had their treatment effect disregarded if old time evaluative criteria continue to be utilized.....


Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab.  Hodi, Weber, Daud, Hamid, Patnaik, Ribas, Wolchok, et al.  J Clin Oncol. 2016 Mar 7.

"We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study.

Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with greater than/= 28 weeks of imaging. Pseudoprogression was defined as greater than/= 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Of the 655 patients with melanoma enrolled, 327 had greater than/= 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived greater than/= 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177).

Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment."

Way to go, ratties.  Teaching the Big Dogs.  And dogs...thanks for listening! - c