Nothing mends the heart more...

....than a walk in the woods with friends.

Much love and thanks to you all, for sharing life and joy with me. - c

Lab values that may predict response to Ipi/Yervoy????

This article is not from ASCO, but I thought it was interesting after my last post on eosinophilia being associated with a response to anti-PD1...

Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients.  Br J Cancer, 2015, May 26.  Ferrucci, Gandini, Battaglia, et al.

Ipi improves survival of metastatic melanoma patients.  Despite documented, durable objective responses, a significant number of patients fail to benefit.  Patients treated at 3 Italian institutions - 187 dosed with 3 mg/kg ipi and 27 with 10mg/kg ipi - were evaluated.  Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy blood counts.  In the training cohort of 69 patients, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses.  Patients with baseline NLR less than 5, had a significantly improved progression free survival and overall survival compared to those with a NLR equal or greater than 5.  Associations of low NLR with improved survival were confirmed in three validation cohorts.

Background info:

Neutrophils are the most frequent kind of white blood cell (40-75%) we have.  They form from stem cells in the bone marrow.  They live only 5-90 hours.  They can undergo chemotaxis, which allows them to travel rapidly to the site of an infection or inflammation.  Once there, they release cytokines that increase the inflammatory process and attracts other cells to the area.  They can ingest microorganisms or particles, thereby helping fight off disease.  Low neutrophils = neutropenia, can happen in anemia, in some types of leukemia, or be caused by medicines like chemo....leaving the person at risk for infection.

Lymphocytes are any of 3 types of white blood cell:  natural killer cells, T cells or B cells, all of which play a role in immunity.  They are the main cell found in lymph, ergo the name.  They live for weeks to years to a lifetime (a good thing when thinking about immunity!!), much longer than other white cells.  NK cells generally kill viruses and tumor cells.  Helper T cells release cytokines and growth factors that regulate other immune cells.  Cytotoxic T cells also kill cells infected with viruses and tumor cells.  B cells work in the secretion of antibodies.  Increased levels of lymphocytes - lymphocytosis - is often a sign of a viral infection.  Increased lymphs in the presence of decreased numbers of neutrophils can be due to lymphoma. Decreased lymphocytes - lymphocytopenia - is usually due to infection (like HIV), surgery or trauma and leaves the person immunocompromised.

A simple test from a basic blood collection is a CBC, which is a complete blood count. It tells you the number of red blood cells, white blood cells, hemoglobin, hematocrit, sizes of various cells, and the number of platelets in your blood.  A differential is usually run with the CBC and it breaks down the number of all the white blood cells.  Normal counts of the various white blood cells are broken down in percentages: 

• Neutrophils: 40% to 60%
• Lymphocytes: 20% to 40%
• Monocytes: 2% to 8%
• Eosinophils: 1% to 4%
• Basophils: 0.5% to 1%
• Bands (young neutrophils): 0% to 3%

All this to say.... IF this report holds true, it would be pretty easy to test a person for their number of lymphocytes and neutrophils, compute the ratio, and determine whether they are likely to benefit from treatment with ipi.  If the answer is no....we could avoid wasting time, treasure, avoid an ineffective treatment with the potential for side effects, and move them forward to a treatment that WILL provide benefit!!! I guess time will tell! - c

ASCO 2015: Eosinophilia with Nivo and Pembro - A predictor of success?!!

Changes in blood eosinophilia during anti-PD1 threapy as a predictor of long term disease control in metastatic melanoma.  J Clin Oncol 33, 2015.  Gaba, Victoria, Pineda, et al.

The anti-PD1 antibody Nivolumab and Pebrolizumab have demonstrated improvement in overall survival of melanoma patients.  To date, no lab test has been identified to predict clinical benefit to anti-PD1.  This retrospective observational study looked at patients who received anti-PD1 treatment in a single institution.  The objective was to see if an increase of at least 100/mm3 at 3 wks over the baseline or an increase more than 400/mm3 at 12 wks in the absolute eosinophil counts could predict a clinical benefit.  Results:  From March 2013 - December 2014, 29 patients were treated with anti-PD1 (3 with Nivo, 26 with Pembro).  10.3% were stage M1a, 24.1% were M1b, and 65.5% were stage M1c.  51.7% had elevated LDH.  Patients who experienced an increase in absolute eosinophil counts over the baseline more than 100/mm3 at 3 wks had better response rates (55% vs 9%), progression free survival (9.9 vs 2.6 months), and overall survival (18.8 vs 6.9 months) than those who did not.  Moreover, patients with an absolute eosinophil count more than 400/mm3 at 12 wks responded to treatment (100% vs 18.2%) and showed more benefit regarding progression free survival (18.6 vs 3.6 months), and overall survival (not reached vs 11.4 months) compared to those who did not.  Conclusion:  An increase in AEC of 11/mm3 over baseline at week 3 and an AEC greater than 400/mm3 at week 12 during anti-PD1 treatment might identify patient with melanoma most likely to experience long term disease control with anti-PD1.

A little background:   Eosinophils are white blood cells and one of the immune system components that helps fight off parasites and other infections.  They are also associated with asthma and allergy.  They usually make up 1-6% of a person's total white blood cells.  They are found in tissue around the thymus, the lower GI tract, ovary, uterus, spleen and lymph nodes but NOT in the lung, skin or esophagus.  They can live 8-12 hours in circulation but as long as 8-12 days in tissue.  They develop in the bone marrow and differentiate from other cells in response to cytokines (IL-3, IL-5, and GMCSF.....sound familiar???).  They affect the production of proteins, lipid mediators, enzymes, growth factors and cytokines...all of which play a role in fighting viral infections, mediate allergic response and asthma flares, fight parasites, play a role in mammary gland development, graft rejection, and neoplasia.  Recently it has been discovered that they play a role in antigen presentation to T cells.  Increased levels of eosinophils - eosinophilia - greater than 500 eosinophils/microlitre of blood - is seen in people with intestinal parasites, rheumatoid arthritis, Hodgkins disease, skin disorders, Addisons Disease, esophagitis, and in response to certain drugs like penicillins. The most common cause of eosinophilia is an allergic condition like asthma.

The graph above is from online access to my labs at Moffitt and plot the eosinophil counts from my start in December of 2010.  It is a little hard to match up with the time data points from the article...but it is clear that by Feb of 2011, 12 weeks after my start on Nivo, I had an increase in my absolute eosinophil count from about 140 to 500.  In March of 2011 my eosinophil count per the lab print out was 460.  Clearly, I have spent the past 5 years over my baseline.  Interestingly, B mentioned this phenom at my last visit.  I hadn't noticed this trend!!!  Additionally, Weber had previously told us, at various points, that his patients on anti-PD1 had been found to have eosinophils in their biopsies in everything from skin papules to lung nodules that had looked worryingly like tumor growth.  None were filled with melanoma...just eosinophils.  So.....what does all this mean????  Don't really know.  When you figure in my asthma it just gets more confusing....but there you go!!! - c

Ipi/Nivo combo... Immunotherapy hitting the big time!

article and video on CNN

Med Page Today...reporting on ASCO statements

All of us hanging around in melanoma world have known this jazz for a while!!! 

Ipi plus nivo vs ipi alone

Ipi/nivo combo in new trial for melanoma brain mets

Info on ipi/nivo combo from ASCO 2014

Weber's 2014 presentation on the combo

Still...glad word is getting out to more of the general universe.  Perhaps such exposure will make those in need more aware of the combination as a treatment option.  Hopefully, public recognition with greater use and demand will facilitate a more rapid FDA approval, increase use of the combo at more facilities, and expedite recognition and treatment of any side effects created.  Hang in there my rattie friends!!!  You give ALL of us soooooo much!!! - c

ASCO 2015: Pembrolizumab (Keytruda) - characteristics predictive of response, atypical responses, and effect on brain mets so far....study still enrolling!

Clinical characteristics predictive of response to pembrolizumab in advanced melanoma.  J Clin Oncol 33, 2015.  Tsai, Loo, Khurar, Daud, et al.

Advanced melanoma patients (110) from 12/2011 - 10/2013, were given Pembro in 1 of 3 dosing patterns:  2mg/kgq3wk, 10q3wk, or 10q2wks.  In this set, overall response rate was 40%.  Factors that correlated with significantly higher overall response were:  LDH at or below normal (ORR = 52%), no previous ipi (48%), lung mets (52.8%).  Patient with liver mets had a worse response (ORR = 18%) as did those with liver and lung mets (31%).  Conclusion:  Normal LDH, no prior ipi, and lung mets correlated with better response to pembro.  Correlations were observed regardless of BRAF status, presence of brain mets, or site of primary (cutaneous vs uveal).

Atypical patterns of response in patients with metastatic melanoma treated with pembrolizumab.  J Clin Oncol 33, 2015.  Wolchok, Hamid, Ribas, Robert, Weber, Hodi, et al.

Immune-related response criteria were developed to better characterize the atypical response patterns observed with ipi.  Previously we showed that 7.2% of melanoma patients treated with the anti-PD1 monoclonal antibody pembro also demonstrate atypical response patterns and that immune-related response criteria (irRC) may better represent the clinical benefit of pembro than conventional RECIST.  Patients were given pembro at 2mg/kg q 3 wks, 10mg/kg q 3 wks, or 10mg/kg q 2 wks with imaging done q 12wks.  Early pseudoprogression was defined as more than 25% increase in tumor burden at first assessment that was not confirmed as progressive disease at the next assessment performed about 4 wks later.  Delayed pseudoprogression was defined as more than 25% increase in tumor burden at any point after the first assessment, followed by non-progressive disease at the next assessment.  Results:  655 patients.  327 had more than 28 wk f/u by imaging at the time of analysis and were assessed for atypical responses.  Overall, 29 (8.9%) patients experienced atypical response.  Early pseudoprogression was observed in 15 (4%) Late pseudoprogression was observed in 14 patients.  In the 592 patients who survived more than 12 wks, 331 (56%) had best overall response of non-progressive disease per RECIST and irRC.  177 (30%) had progressive disease per both criteria.  84 (14%) was progressive disease per RECIST by non-progressive disease per irRC. CONCLUSION:  Results of this expanded analysis are consistent with previous reports suggesting that pembro may result in atypical response patterns and that conventional response criteria may underestimate the therapeutic benefit. 

Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases.
J Clin Oncol 33, 2015.  Kluger, Goldberg, Sznol, Chiang, et al.

Brain mets develop in 40% of metastatic melanoma patients.  Untreated brain mets are excluded from most clinical trials. Prior trials of metastatic melanoma show treatment with pembro produced a response rate of more than 30%.  A phase II study was started in patients with previously untreated or progressing melanoma brain mets (recruitment is ongoing).  Patients with brain mets from melanoma or non-small cell lung cancer are accepted if they have at least 1 asymptomatic 5-20mm brain met not requiring immediate local therapy or systemic steriods, and at least 1 brain met amenable to biopsy or resection.  Prior PD-1/PD-L1 are excluded.  Pembro is given 10mg/kg q 2 wks. Brain MRI is done q 4 wks and restaging is done q 8 wks.  RESULTS thus far:  Between April and December of 2014, 17 patients were accrued.  6 had BRAF mutations.  10 had previously received ipi.  5 were unevaluable for brain met response due to: rapid progression of disease in the body (3) and intralesional hemorrhage (1) and 1 patient was too early in treatment.  Of 12 evaluable patients:  brain met partial responses were observed in 3 patients (1 with prior ipi), stable disease was found in 2, progressive disease in 7 (2 with a mixed response and 1 with progressive disease by imaging but with pseudoprogression on histology). Brain met responses are ongoing at 7+, 6+, and 3+ months.  One complete response and 3 partial responses were observed in extra-cerebral metastatic disease, 3 of these 4 with concordant brain met response.  The only grade 3 adverse event from pembro was liver function abnormalities.  2 patients had seizures, 1 from perilesional edema, 1 from tumor growth.  They were treated with anti-convulsants and transient use of steroids.  

Here is the link to the study...as noted accrual is ongoing:  Pembro for brain mets

No corticosteroid treatment for symptomatic disease allowed, though low dose replacement therapy is.  No leptomeningeal or autoimmune disease allowed.  No other concurrent treatments.  No radiotherapy for 14 days prior.  Yale is only recruiting site listed.

For what it's worth! Wishing you all my best. - c  

ASCO 2015: New BRAF inhibitor combo's for melanoma

Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.  J Clin Oncol 33, 2015.  Ribas, Butler, Lawrence, Robert, et al.

Inhibition of the MAPK pathway with dabrafenib (D) and trametinib (T) is efficacious in BRAF-mutant melanoma.  MEK inhibitors have also shown activity in BRAF WT melanoma, particularly in NRAS-mutant tumors.  However, most patients develop resistance.  MEDI4736 (M), is a human IgG1 mAB that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown clinical activity with durable responses and an acceptable safety profile in multiple tumor types.  Combine therapy with these agents may lead to enhanced durable tumor responses.  Phase 1 study:  MEDI4736 was given at 3 or 10 mg/kg IV q2w in combination with dabrafenib 150mg twice daily and trametinib 2 mg daily, OR trametinib alone in patients with stage IIIc/IV melanoma.  Patients were divided into various cohorts based on BRAF status and dosing combo.  Prior BRAF/MEK inhibitor use was prohibited.  Prior immmunotherapy (including anti-PD1 and anti-PD-L1) was allowed.  RESULTS:  As of 12/5/2014, 50 patients were treated.  After review, MEDI 4736 at 10mg/kg q 2 wks was chosen for expansion.  Most frequent AE's were fever (63%) and fatigue (54%), along with diarrhea and rash in cohort B, and vomiting in cohort C.  2 patients stopped treatment due to toxicity - 1 with Grade 3 thrombocytopenia, and 1 with reversible choroidal effusion.  
Cohort A1 - (3mg/kg M + D + T):
n = 6, Any AE = 100%, Grade 3 AE = 17%, Complete response = 6.
Cohort A2 - (10mg/kg M + D + T):
n = 18, Any AE = 94%, Grade 3 AE = 39%, Complete response = 10.  Partial response = 15
Cohort B - (10mg/kg M + T)
n = 20, Any AE = 90%, Grade 3 AE = 40%, Complete response = 3. Partial response = 14.
Cohort C - (sequential T + 10mg/kg M)
n = 6, Any AE = 100%, Grade 3 AE = 17%, Complete response = 3. Partial response = 6.

Phase 1 trial of the CDK 4/6 inhibitor, P1446A-05 (voruciclib) in combination with the BRAF inhibitor vermurafenib in advanced, BRAF-mutant melanoma.  J Clin Ocol 33, 2015.  Diab, Martin, Simpson, Daud, et al.

P1446A-05 is a potent, selective CDK 4/6 inhibitor with activity in multiple BRAF-mutant and wild type cell lines.  BRAF inhibitors have been transformative in the therapy of BRAF-mutant melanoma.  However, resistance does develop frequently, often in only a few months.  The addition of a CDK 4/6 inhibitor to BRAFi is supported by extensive preclinical data.  Phase 1 trial.  4 cohorts.  Plan = Vermurafenib from 720mg po bid to 960mg po bid and P1446A-05 from 150mg up to 350mg po q d.  Each cohort to have 3-6 patients.  Eligible patients could be BRAFi naive or resistant.  RESULTS:  9 patients so far. (3 BRAFi naive and 6 refractory).  AE's = fatigue, headache, and constipation.  No DLTs.  Responses were seen in 3/3 BRAFi naive patients - 1 complete and 2 partial.  Combination recommended for further testing = Vermurafenib 960mg po bid with P1446A-05 150mg po qd.

A phase Ib/II study of BRAF inhibitor encorafenib (ENCO) plus MEK inhibitor binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment.  J Clin Ocol 33, 2015.  Sullivan, Weber, Patel, et al.

MEKi addition to BRAFi therapy has been reported to increased response rate and duration of response.  ENCO and BINI have each shown promising single-agent activity in BRAFV600 mutant melanoma.  BRAF positive, BRAFi naive patients were enrolled. 9 patients were given ENCO at 400 or 450 mg daily.  39 patients were given ENCO at 600mg daily.  All were given BINI.  At ENCO 600 AE's = nausea (54%), diarrhea (44%), fatigue and arthralgia (both at 33%), vomiting, fever, and increased AST (31% each).  At 400/450 ENCO dose, AE's = nausea/fatigue (44% each), diarrhea, vomiting, and increased AST (33% each), arthralgia and fever (11% each).  Grade 3/4 AE's in 600 group were 64%, most often = increased ALT, lipase, AST, and creatine phosphokinase.  At 400/450 dose, grade 3/4 AE's occurred in 67% of patients and was increased lipase most often.  Photosensitivity and fever were rare.  Response rate for patients treated at ENCO 400/450 was 78% (1 complete and 6 partial).  At ENCO 600 response rate was 72% (3 complete and 25 partial).  

And....this trial is starting:

Neoadjuvant BRAF (dabrafenib) and MEK (trametinib) inhibition for high-risk stage III and IV melanoma.  J Clin Oncol 33, 2015.  Wargo, Amaria, Ross, et al.

2 currently recruiting phase II trials - at MD Anderson and Melanoma Institute Australia - of neoadjuvant combined BRAFi (dabrafenib, 150mg po bid) and MEKi (trametinib 2mg po q day) for high risk resectable metastatic melanoma.  Both trials incorporate serial biopsies during the course of treatment for research on biomarkers.  At MD Anderson patients are randomized in a 2:1 fashion to neoadjuvant BRAF/MEK X 8 wks with adjuvant BRAF/MEK X 44 wks vs surgery alone with standard of care for disease per study doc.  (target accrual = 48 patients). 

Here's the MD Anderson trial link  Here's the Clinicaltrials.gov description of the groups:

Experimental Group A: Surgery + Standard of Care.  Surgery alone within 4 weeks after enrolling in study. Participant then treated with standard care for the disease after surgery per study doctor.

Experimental Group B: Dabrafenib + Trametinib + Surgery. Starting Dose of Dabrafenib: 150 mg by mouth twice a day. Starting Dose of Trametinib: 2 mg by mouth once daily. At Week 8 after starting Dabrafenib and Trametinib, participant has MRI and/or CT scans of brain to check status of disease. Participant also has CT scans of the chest, abdomen, and pelvis. If scans show disease has not spread or grown, surgery is scheduled. Participant continues taking study drugs until day of surgery. Study drugs continued after surgical recovery for up to an additional 44 weeks.

Don't forget this BRAFi info from earlier this year:  BRAFi, better when combined with or after immunotherapy or surgery!

Lots of new drugs and new combo's.  Time will tell.  Sosman has been doing good things for a while with the CD4/6 inhibitor LEE011 combined with a MEK inhibitor.  Hopefully, that will hold up.  BRAFi with surgery was shown promise as well.  You gotta love Phase 2 trials...where somebody ends up with little or nothing!  I can only hope that some of these drugs or combo's will quickly prove worth it, so that "something" can be available and effective for everybody!! - c

ASCO 2015: New trial for melanoma brain mets!!! Ipi and Nivo, followed by Nivo alone (CheckMate 204)

A multi-center phase II open-label study (CheckMate 204) to evaluate safety and efficacy of Nivolumab (NIVO) in combination with ipilimumab (IPI) followed by NIVO monotherapy in patients with metastatic melanoma to the brain. J Clin Oncol 33, 2015. Margolin, Tawbi, Hodi, et al.

Brain mets develop in approx 50% of patients with metastatic melanoma.  (Median overall survival after diagnosis = 4 months.)  Nivo (a fully human IgG4 PD-1 checkpoint inhibitor antibody) and ipi (a fully human IgG1 CTLA-4 immune checkpoint inhibitor antibody) are each approved as monotherapy for advanced melanoma. In an already completed Phase II study, ipi showed some activity in patients with melanoma brain mets.  This study builds on that. It is anticipated that 50% of enrolled patients will have had stereotactic radiotherapy. Patients with measurable melanoma in extracranial sites and with asymptomatic brain mets will be included.  Patients with leptomemingeal disease, history of whole brain radiation, autoimmune disease, or steroids ongoing will be excluded.  Patients will be given Nivo 1mg/kg with ipi at 3mg/kg every three weeks for 4 doses, followed by nivo along at 3mg/kg every 2 weeks until progression or toxicity.  SRT for progression of a single brain met will be permitted.  

Here's the link to the study on clinicaltrials.gov

This trial is actively recruiting.  Sites so far in California and Pennsylvania.

This post includes links to prior studies where ipi and nivo demonstrated effect in the treatment of melanoma brain mets:  Ipi, nivo, the combo and radiation for melanoma brain mets

Given what we already know, this seems hopeful to me! - c