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

ASCO 2015: Adverse effects from Nivo and how they are associated with survival

Nivolumab in resected and unresectable melanoma:  Immune-related adverse events and association with survival outcomes.  J Clin Oncol 33, 2015.  Freeman-Keller, Weber, et al.

Data was pooled and analyzed from 148 patients with resected (n=33) and unresectable (n=115) melanoma from Moffitt, given 1-, 3-, or 10mg/kg doses (with or without peptide vaccine) every 2 weeks for 12 wks, then every 12 weeks, up to 2 additional years if stable or better.  AE's of any level were found in 68% of patients.  Grade III/IV AE's were infrequent:  3 had a grade III rash, 2 had asymptomatic grade III amylase/lipase elevation, and 2 had grade III colitis.  Statistically significant progression free survival and overall survival differences were seen in patients who experienced any grade of AE.  Improved progression free survival was associated with rash and vitiligo.  Rash was associated with improved overall survival, with a non-significant association between vitiligo and overall survival.  No survival differences were seen with other AE's (endocrinopathies, diarrhea, or pneumonitis.)

Safety profile in nivolumab in patients with advanced melanoma:  A pooled analysis.  J Clin Oncol 33, 2015.  Weber, Antonia, Topalian, Schandendorf, Sznol, et al.

Retrospective safety review was conducted for 4 ongoing phase I-III trials in which melanoma patients were given nivo 3 mg/kg every 2 wks until disease progression or AE's.  576 patients were given nivo for median of 3.7 months.  312 had had prior ipi.  Most frequent AE's of any grade were:  fatigue (25%), itching (34%), GI problems (13%), endocrine (8%), and liver (4%).  Grade 3/4 AE's occurred in 4% of patients.  Median time of onset to AE's ranged from 5 wks for skin and 15 wks for renal.  Conclusion:  Drug related AE's to nivo were primarily low grade and the incidence of grade 3/4 drug related AE's was not affected by prior ipi.  Nearly all grade 3/4 AE's resolved with steroids which did NOT appear to impact on tumor response.

Wishing you much itching and a whiter shade of pale, my friends.  My goodness!  Itch away my fellow ratties, itch away!!  Still dealing with my 2 benadryl a day habit.  Guess that's a good thing. - c

ASCO 2015: Nivo plus ipi vs ipi alone. Results of the CheckMate 069 melanoma study.

Clinical response, progression-free survival, and safety in patients with advanced melanoma receiving nivolumab combined with ipilimumab vs ipi monotherapy in CheckMate 069 study.  ASCO J Clin Oncol 33, 2015.  Hodi, Postow, Chesney, Pavlick, Robert, Wolchok, et al.

Combined blockade of T cell checkpoints by Nivo and Ipi demonstrate a high objective response rate, promising overall survival, and manageable safety profile in a phase 1 study, based on which an appropriate dose was selected for registrational trials.  142 patients with metastatic and unresectable melanoma, including patients with poor prognostic factors were randomized 2:1 to receive IPI 3 mg/kg combined with either Nivo 1mg/kg or placebo every 3 weeks X 4, followed by Nivo 3mg/kg or placebo every 2 wks until disease progression or unacceptable toxicity.  Results:  In BRAF wild type (n=109) overall response rate was 60% (43/72) for Nivo plus ipi; 11% (4/37) for ipi alone. Complete responses were reported in 12 (17%) for the combo and 0 for ipi alone.  Higher overall response rate was observed for nivo plus ipi vs ipi in predefined subgroups such as:  elevated baseline LDH (53 vs 0%) M1c stage disease (62 vs 25%).  Similar results were found in 33 BRAF mutation positive patients.  Grade 3/4 AE's were reported in 51% of patients given the Nivo/ipi combo vs 20% for ipi alone and was similar across all groups.  Most resolved with immunosuppressive meds (more than 83%) with the exception of endocrinopathies.

Not really news at this point.  The ipi/nivo combo provides better results than ipi alone.  The combo causes more adverse reactions as well....  What'cha gonna do???  Hang in there, ratties!!! - c

ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Survival, biomarker, and toxicity analysis of Nivolumab (NIVO) in patients that progressed on ipi.  ASCO J Clin Oncol 33, 2015. Weber, Gibney, Yu, et al.

PD-1 antibody, nivolumab was administered to 126 patients with unresectable melanoma that failed at least one regimen and were ipi naive (34) or progressed on ipi (92).  Patients refractory to ipi were given Nivo at 3 mg/kg. 2 cohorts were HLA 0201 positive: N = 10 had grade 2 or less ipi related AE's.  N = 21 had dose limiting grade 3/4 ipi related AE's.  A third cohort (N = 61) was not HLA restricted and had experienced grade 2 or less ipi related AE's.  RESULTS:  Median f/u for ipi refractory pts was 18.7 months. Response rate was 29%.  44% had clinical benefit with confirmed partial and complete response or stable disease at 24 weeks.  Median duration of response was 14.3 months.  Median progression free survival was 5.4 months and median overall survival was 20.1 months with 1 and 2 year OS of 69.2% and 39.1%.  Of 14 patients that have completed all therapy or stopped due to toxicity while stable or in response, all remain in remission. Of 21 patients with prior ipi induced grade 3/4 AE's, only 2 had subsequent dose limiting (and different) AE's with nivo, with 8 PR and 5 SD seen.  All 8 PR and 3 SD are without progression.  Biomarker studies showed that circulating MDSC (myeloid derived suppressor cells) were associated with progression and worse OS.  CONCLUSION:  Prior ipi related AE's were not replicated by NIVO.

Safety of pembrolizumab in patients who stopped ipilimumab due to immune-related adverse events.  ASCO J Clin Oncol 33, 2015.  Shoushtari, Postow, Horvat, Chapman, et al.

Pembro which blocks programmed death-1 was recently FDA approved (as was Nivo) for the treatment of patients with advanced melanoma after progression on ipi.  Ipi is associated with immune mediated adverse events which can lead to treatment cessation.  Researchers collected date on patients with melanoma who received pembro at Sloan Kettering and had received less that 4 doses of ipi due to AE's grade 2 or higher requiring steroids.  RESULTS:  N= 10.  12 AE's contributed to ipi cessation:  colitis, neuropathy, ALT elevation (increased liver enzymes), rash.  All were given steroids and 3 required infliximab.  Median pembro doses given = 5.  7/10 patients are still getting treatment.  2/10 had treatment with pembro interrupted due to AE's that required steroids.  Neither were the AE seen when on ipi.  CONCLUSION:  Patients who stop ipi due to AE's may have different AE's on pembro.  Severe AE's on ipi does not preclude a patient from taking pembro.


Efficacy and toxicity of treatment with the anti-CTLA4 antibody Ipilimumab in patients with metastatic melanoma who have progressed on anti-PD1 therapy.  ASCO J Clin Oncol 33, 2015.  Prithviraj, McArthur, Atkinson, et al.

Immunotherapy with anti-CTLA4 (ipi) and anti-PD1 antibodies has demonstrated overall survival benefits in patients with metastatic melanoma compared to standard therapy.  Early clinical trails suggests that combination therapy with ipi and anti-PD1 increases the response rate sompared to single agent treatment however is associated with increased toxicity.  Anti-PD1 therapy demonstrated equal efficacy and toxicity in patients that progressed on or were naive to treatment with the anti-CTLA-4 antibody Ipilimumab.  So far, only very limited evidence exists regarding efficacy and toxicity of ipi in pateints that have progressed on treatment with an anti-PD1 agent.  Study:  N= 10 patients who had received Nivo/Pembro in a clinical trial and were subsequently treated with ipi.  Ipi was given at 3mg/kg every 3 wks for 4 cycles and response was assesses by CT scan 4-6 wks after last dose.  Results:  Median time between last dose of anti-PD1 and ipi was 7 months.  4/10 patients had increased LDH on commencement of ipi therapy.  1/10 patients achieved a partial remission as their best response to anti-PD1 therapy with an additional 5/10 having stable disease. 4/10 were given all 4 doses of ipi.  F/U after last dose of ipi has been more than 3 months.  1/10 patients achieved a response to ipi with another 1/10 having prolonged stable disease.  3/10 experienced grade 3/4 immune related AE.  Conclusion: Ipi can induce responses in patients who have failed anti-PD1.  The response rate appears similar compared to patients who have not received prior anti-PD1 therapy.  AE's were observed.  Significance of these observation remains to be seen.

The first two reports are not really news.  Patients who had to stop taking ipi due to side effects can take anti-PD1 (Nivo OR Pembro) without being cursed with their prior side effects from ipi and gain a response.  Additionally, and this is newer as fewer patients have reached this position, you can get a response from ipi after having taken anti-PD1. And ~ myeloid derived suppressor cells need to get out of our way!!! Hang in there ratties.  Sometimes it's a long ride! - c

Merde....again...

Alisa Linton - RIP

Bleeding hearts

There are no words.  C

ASCO 2015 - intralesional therapy for melanoma

I've been reviewing articles that have come out of ASCO the past couple of weeks.  Here is my round up of those related to intralesional therapy.

A multicenter, open-label trial of talimogene laherparepvec (T-VEC) plus pembrolizumab vs pembrolizumab monotherapy in previously untreated, unresected, stage IIIB-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Ribas, Puzanov, Gajewski, et al.

T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to preferentially replicate tumors, produce GM-CSF and stimulate an anti-tumor immune response.  {Remember this definition from a prior post:  GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.}  OPTiM, a phase III trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma (n=436), ....had improved durable response rate in the T-VEC arm (16 vs 2%).  Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody [anti-PD1 product, Keytruda] FDA approved in US for patients with unresectable or metastatic melanoma [after failing ipi and if BRAF V600 positive, BRAF inhibitors as well].  
     In this study, started Dec 2014, T-VEC is injected into cutaneous, subcutaneous or nodal lesions at up to 4 ml on day 1, then up to 4 ml on day 22 and every 2 weeks  (phases 1B and 2).  Pembro is given at 200 mg IV every 2 weeks from day 36 in phase 1B (n=20) and day 1 in phase 2 (n=90).  Treatment with both therapies will be given (whichever comes first) until: complete response or progression of disease, intolerance, for up to 2 years.  T-VEC injections stop when there are no longer injectable lesions. Patients in Phase 2 will be randomized 1:1 to T-VEC and pembro vs pembro alone.

Tumor size and clinical outcomes in melanoma patients treated with T-VEC. ASCO - J Clin Oncol 33. Kaufman, Amatruda, Nemunaitis, et al.

436 patients.  Previously treated and untreated.  Stage IIIB-IV mel in OPTiM, randomized 2:1 phase 3 trial of IT T-VEC vs subq GM-CSF.  288 T-VEC and 126 GM-CSF patients.  Median calculation for size of tumor at baseline was 14.8cm squared for T-VEC and 14.1 for GM-CSF.  Median size was higher with advanced stage.  Results for this study:  T-VEC patients, patients with lower than median sized tumors and lower stage were associated with better overall survival.

Survival, safety, and response patterns in a phase 1b multicenter trial of talimogene laherparepvec (T-VEC) and ipi in previously untreated, unresected stage IIIB-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Puzanoz, Milhem, Hamid, Kaufman, et al.

History on T-VEC as noted above.  Requirements:  Stage IIIB-IV melanoma patients with no prior systemic treatment, measurable disease and at least 1 injectable cutaneous, sub q, or nodal lesion.  T-VEC was given IT at week 1, week 4, and every 2 weeks until injectable tumor was gone or disease progression.  Ipi was given at 3mg/kg every 3 wks for 4 infusions starting week 6.  RESULTS:  At cutoff, all patients were 17 months from start of treatment.  18 patients were treated.  Grade 3/4 AE's occurred in 32% and grade 3/4 immune related AE's occurred in 2 patients with no treatment-related deaths.  Overall response rate was 56% (33% complete response) and DRR was 44%.  Median time to response was 5.3 months.  Median progression free survival was 10.6 months.  Median overall survival was not reached.  12 month and 18 month survival were 72% and 67%.  On a lesion level, 24 and 11 of 35 indexed lesions and 8 and 5 of 16 uninjected lesions regressed at least 50%  and 100%, respectively.  Conclusion:  At more than 17 months out, T-VEC + ipi continued to demonstrate durable response with 2/3 patients alive at 18 months and no new safety signals.
 

A phase 1 study of intratumoral injection of ipilimumab and interleukin-2 in patients with unresectable stage III-IV melanoma.  ASCO - J Clin Oncol 33, 2015.  Bowen, Meek, Williams, Grossman, et al.

Intratumoral IL-2 is highly effective and well tolerated, but does not generate systemic immunity or response in untreated lesions.  IV ipi lowers the threshold for T cell activation leading to a durable clinical response in a minority of melanoma patients, but is associated with potentially severe toxicities.  Since IV ipi doesn't have tissue distribution, circulating anti-tumor T cells activated by the drug may differ greatly from tumor infiltrating lymphocytes activated by INTRATUMORAL ipi in terms of quantity and quality.  Therefore, we hypothesized that a combination of IT IL-2 and IT ipi would effectively hyperactivate and expand TILs to engender systemic immunity with minimal toxicity.   This phase 1 dose escalation trial for ipi and fixed dose IL-2 involved patients with unresectable stage III/IV melanoma and at least one injectable lesions.  A single lesion in each patient was treated with IL-2 IT TIW for 2 wks, then BIW for 6 wks, with escalating doses of ipi IT weekly for 8 weeks.  RESULTS:  12 patients were treated with 3 ipi dose levels.  Treatments were well tolerated.  The only grade 3 toxicity was injection site/tumor necrosis, not dose limiting.  Other toxicities were grade 1.  An abscopal effect (response in a least 1 NON-injected lesion) was seen in 9/12 patients (75%).  10 patients were evaluable for immune response:  4 with partial regression (40%) and 6 had progressive disease, though later one PD was later found to be a complete response by resection.  The 2 nonevaluable patients had regression of multiple skin lesions.  An increase in the frequency of IFN producing CD8+ T cell was detected in 6/8 abscopal responders.  Tbet+ and granzyme B+ CD8+ T cells were observed in 4/5 and 3/5 responders tested, respectively.  Researchers plan to conduct a phase II trial using IT Ipi/IL-2 in conjunction with systemic immunotherapy.

Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma.  ASCO - J Clin Oncol 33, 2015.  Andtbacka, Curti, Kaufman, Daniels, et al.

CVA21 is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21.  Intratumal injection initiates preferential tumor cell infection, cell lysis [death] and enhancement of a systemic anti-tumor immune response.  The CALM study looked at 57 patients with treated or untreated, unresectable Stage IIIC-IV melanoma.  Patients were given injections on study days 1, 3, 5, 8, and 22, then every 3 weeks for a further 6 injections.  Patients showing immune-related progression-free survival or better at 6 months were eligible for 9 additional injections.  RESULTS:  21 of 57 (38%) patients displayed progression free survival at 6 months with median PFS of 4.2 months.  Overall response rate was 28% (16 of 57) with a more than 6 month durable response rate of 19% (11 of 57).  Median time to response was 2.8 months, 1 year survival rate was 75% (43 of 57 patients).  At more than 16 months, median duration of response in responders and median overall survival for all patients was not yet reached.  Most common side effects = Grade 1 fatigue, chills, local injection site reaction, and fever.  No grade 3 or 4 reactions.  Further studies with CVA21 in combination with other immunotherapies are in process.

Another recent intralesional therapy report, but NOT from ASCO:

Intralesional administration of L19-IL2/L19-TNF in stage III or stage IV  melanoma patients:  results of a phase II study.  Cancer Immu Imm. 2015 May 14. Danielli, Patuzzo, Di Giaomo, et al.

IT injection of IL2 has shown promise for cutaneous melanoma patients.  We recently reported that the IT injection of L19-IL2, an immunocytokine combining IL2 and the human monoclonal antibody fragment L19, resulted in efficient regional control of disease progression, increased time to distant metastasis and evidence of effect on circulating immune cell populations.  Results of phase II clinical trial with intralesional administration of L19-IL2 and L19-TNF in patients with stage IIIC and IVM1 metastatic melanoma, who were not surgical candidates.  In 20 patients, 32 melanoma lesions exhibited complete responses after IT administration of the two products.  Side effects were mainly injection site reactions.  We observed complete responses in 7/13 (53%) NONINJECTED lesions (4 cutaneous and 3 lymph nodes), indicating a systemic activity of the IT therapy.  This therapy represents a simple and effective method for the local control of inoperable melanoma lesions, with a potential to eradicate them or make them suitable for a facile surgical removal of the residual mass.

Obviously, there are no results from the first study report as yet.  Logically, smaller tumors seem to respond better.  But, I find these intralesional therapies promising. With the possibility of eradication of the injected tumor, potential for abscopal responses, and if only for the reduction of tumor size so that it can then be resected surgically with a very benign side effect profile...it sounds good to me.  The combination of IT injections with systemic immune therapies just makes sense to me.  Of course, time will tell.  But, I think I'd certainly try it if I had the need.  Wishing all my fellow ratties well. - c

New Immunotherapy Trial with NBS20 for Stage III recurrent/IV metastatic melanoma

Not much coming out of ASCO yet....but will keep looking.  However, my resident researcher did come across this:  (Click on link for entire article, pertinent excerpts below!)

New Immunotherapy Phase 3 trial for melanoma

'New York, April 29, 2015 — NeoStem, Inc. (Nasdaq:NBS), a biopharmaceutical company developing novel cell-based individualized medicine therapies, announced today the randomization of the first patient in the Intus Phase 3 clinical trial investigating the efficacy of the Company’s patient-specific targeted cancer immunotherapy candidate NBS20 (USAN = eltrapuldencel-T) in patients with stage III recurrent or stage IV metastatic melanoma. 

The Intus trial is based on consistent, compelling results from two Phase 2 trials in identical patient populations evaluating the therapeutic vaccine that has become NBS20. The more recent of the two trials was a randomized trial comparing NBS20 to injections of autologous irradiated (inactivated) tumor cells in 42 patients. At two years, survival was 72% compared to 31% for control patients (p=0.007), which was consistent with the previous Phase 2 trial’s findings in which NBS20 demonstrated 73% two-year survival in 54 patients, with a median survival of five years. Toxicity was minimal and consisted of mild to moderate local injection site reactions of the type normally associated with injections of GM-CSF (a protein secreted by immune cells that helps stimulate other immune cells to promote immune defenses against disease).

“The randomization of the first patient in the pivotal Phase 3 trial for NBS20 represents the achievement of a significant milestone for NeoStem, marking our transformation into a Phase 3 immuno-oncology company. We are now part of a select group of immunotherapy companies at such an advanced clinical development stage,” said Dr. David J. Mazzo, Chief Executive Officer of NeoStem.

The Intus study is a multi-national, randomized, double-blind, placebo-controlled Phase 3 clinical trial in which stage III recurrent or stage IV metastatic melanoma patients will be randomized in a 2:1 ratio to receive either NBS20 (autologous dendritic cells loaded with antigen from self-renewing, proliferating autologous tumor cells in GM-CSF) or a control treatment (peripheral blood mononuclear cells obtained from apheresis product in GM-CSF). The study is expected to randomize 250 eligible patients across approximately 50 sites internationally (US, Canada, Australia, New Zealand and, potentially, select countries of the EU); each patient will receive subcutaneous injections once weekly for three consecutive weeks, and then once monthly for five months.

In addition to metastatic melanoma, the platform technology on which NBS20 is based is potentially applicable across multiple solid tumor types, including advanced lung, colon, kidney, ovarian and hepatocellular carcinomas, and glioblastoma multiforme—indications that collectively lead to more than 200,000 deaths in the United States each year.'

I have some reticence about things announced by the pharmaceutical company itself....but looks like this might be worth investigation for some, especially for patients who have tried multiple therapies and are still in need of additional treatment options.
Here's the link on clinicaltrials.gov - Autologous dendritic cell-tumor cell immunotherapy for metastatic melanoma
It is currently recruiting.  Sites:  CA, Indiana, Kentucky, Louisiana, Maryland, Ohio, New Jersey, PA, Texas, TN.  Patients must have measurable disease and at least one tumor that can be resected. The "cell line can be initiated with either a specimen of fresh tumor or tumor that has been previously cryopreserved."  Patient must have already been treated with IL2, Ipi, vemurafenib (if BRAF+) OR dacarbazine.  These may have been given in combination or individually.  Must be 4 weeks post systemic therapy and more than 3 weeks post radiation.

NOTE:  The inclusion/exclusion section doesn't seem to address the status of patients who have had anti-PD1.  So I'm not sure about that.  As for all trials, if you are interested....CALL!  Ask any questions of the trial coordinator and make the best decision you can for YOU!!!

Wishing you my best - c

Melanoma kills...

...the best people.  Not my usual upbeat bullshit is it?  I believe in hope.  I believe in new treatments that have extended, saved and maybe...just maybe...cured some from the scourge that is melanoma.  But, I also KNOW that if you turn your back on melanoma, if you decide you are immune and don't have to trouble yourself with being vigilant, under the care of a melanoma specialist, NO MATTER what stage of melanoma you find yourself diagnosed at...you are going to be in world of hurt my friend.  Hell, you can end up in a world of hurt no matter what you do.  If you care about somebody with melanoma, you might want to see some of these posts, from some of the most generous folks....so you know what you could be in for, how quickly your world can change, how fleeting life can be.  Really....if you care about ANYBODY....   You might want to make sure they know that.  We don't get a re-do, no matter how much we might like one.

Alisa, loving wife and mother of 4 boys

A small peek of Alisa's life, loves, and one of many treatments

An amazing couple get the news....Jeanne and 9TS

9TS - as should be

Amen

Patti - pehaps the most amazing woman I will never meet

Patricia Garcia-Prieto, her leap

Hard Talks - Meagan and her Cabana Boy

Nurses teach the Cabana Boy

Meagan - her words

Beautiful Kathy - her light and loves

Eric and Jill - The hard reality  They caught a lot of flack for this graphic video of Eric's tumors.  Don't look if you are not up to it.  However, I think they were the bravest couple.  He was perhaps the world's sweetest man.  graphic video of melanoma tumors

Eric's beautiful life....

For all of you, past and present....  For those of you who have loved well and work to carry on....

"I hope the days come easy and the moments pass slow,
And each road leads you where you wanna go,
And if you're faced with a choice, and you have to choose,
I hope you choose the one that means the most to you.
And if one door opens to another door closed,
I hope you keep on walkin' till you find the window,
If it's cold outside, show the world the warmth of your smile.

I hope you never look back, but you never forget,
All the ones who love you, in the place you live,
I hope you always forgive, and you never regret,
And you help somebody every chance you get,
Oh, you find God's grace, in every mistake,
And always give more than you take.

But more than anything, yeah, more than anything

My wish, for you, is that this life becomes all that you want it to,
Your dreams stay big, your worries stay small,
You never need to carry more than you can hold,
And while you're out there getting where you're getting to,
I hope you know somebody loves you, and wants the same things too,
Yeah, this, is my wish."

                          ~ STEELE/ROBSON and Rascal Flatts

...I hope to live as bravely, as fully, and with as much grace...  
"When you live in the hearts of those you love, remember then - you never die."  ~ Meagan McPhee
I will hold you all in my heart, forever. - c

Happy Mother's Day!!!! From another kind of mother!

Being a mother...hmmm....  Not sure of all the things that motherhood means, or should mean, or most often does....  Not sure how good this movie will be.  But, it seems to hit some serious high notes:

Trailer for Ricki and The Flash with Meryl Streep

This certainly sums up my view on motherhood...  "It really doesn't matter if the kids love you or not.  It's not their job to love you.  It's YOUR job to love THEM!"

As for my kids...they would probably tell you this is similar to the typical words of wisdom they have been given from THEIR mother...  "Lots of things are going to change in your life.  One day you're going to wake up and find a grey hair....  And I don't mean on your head!!!"

Sorry punkins!  Lots of mistakes have been made.  You have had to endure all kinds of crazy.  But... I KNOW, YOU KNOW.....I love you. - mommy

No. Concealed. Ugliness. Redux!

no concealed ugliness per Oona!

The link above certainly explains my attachment to the phrase and the mission.  It is not always easy to be open and honest and proud of what's on the inside.  It takes a lot of work to keep things pretty, neat, and clean in places that are fairly easily hidden - under appliances, inside closets, clothing innards, and our hearts.  However, when we go to the trouble - there are fewer bad smells, less time wasted searching for what we need, and clothing as well as life...just hangs better.  You can walk around with much fewer worries about all your underpinnings. 

 

For years I have challenged myself to purge the anger, share the love, and go to the trouble to clean up messy layers - inside and out.  Every new experience and garment certainly comes with a learning curve.  I have never attained 100% success.  The inside of these dresses took more work than the outside!!! Yet, I am happy with my attempts, what I've learned, and what I am able to share with those who want to share with me.  Sadly, there is always ugliness - disease, war, disasters (natural and man-made), and plain old, mean, ornery folks to deal with.  I will still work to keep my side of any relationship open and honest.  What others choose to do will either foster their own lives and feelings of self worth as well as their relationships....or not!  And while the beautiful forsythia was indeed planted to block the view of a power pole and its supporting wires, I know what's real, what's underneath, and what I can do (if I choose) to make the world a better place....with no. concealed. ugliness.

Working to make the world beauty full! - c
PS  Happy day, Roo!!!