ASCO 2016 - Using amount of progression as marker of response and OS with anti-PD1

Immune-related tumor response dynamics as a marker for survival and treatment benefit during PD-1 inhibitor therapy.  ASCO 2016.  #9521.  J Clin Oncol 34, 2016.    Nishino, Giobbie-Hurder, Bailey, Hodi, et al.

PD-1 inhibitors are promising anti-cancer agents and are associated with unique immune-related response patterns. We characterized patterns of tumor response dynamics on CT scans during PD-1 inhibitor therapy and investigated the association with overall survival (OS) in advanced melanoma patients (pts). Methods: Forty-nine advanced melanoma pts (22 males; median age: 55) treated with single-agent pembrolizumab at DFCI were retrospectively studied. Baseline and all follow-up CT during therapy were reviewed to quantify tumor burden using irRECIST, which uses unidimensional measurements and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. Association between OS and tumor burden dynamics was studied. Results: Tumor burden change at best overall response ranged from -100% to 357% (median:-11%). Response rate was 41% . Spiderplot showed 3 distinct patterns of tumor response dynamics: A) tumor burden less than 20% increase from baseline throughout therapy (n = 27, 55%); B) tumor burden greater than/= to, 20% increase from baseline without subsequent response (n = 19, 39%); and C) pseudoprogression with initial tumor burden increase ( less than/= to, 20%) and subsequent response (n = 3, 6%). Pseudoprogressors were younger than others (median age: 40 vs. 56), and achieved response after irPD was confirmed on 2 consecutive scans. Using a 3-month landmark analysis, pts with less than 20% tumor burden increase from baseline at 3 months had longer OS than pts with greater than/=to 20% increase (12-month OS rate: 78 vs 51%). In extended Cox models, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death. Conclusions: Three distinct patterns of tumor response dynamics were noted during pembrolizumab therapy. Pseudoprogressors achieved response after experiencing confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluation. Tumor burden less than 20% increase from baseline on follow-up CT scans was associated with longer OS, proposing a practical marker for survival and treatment benefit of PD-1 inhibitor therapy.

My take:

So....there are three patterns of response.  

1.  Tumor burden never increased more than 20% during treatment.

2.  Tumor burden that did increase, but no more than 20%, with no further improvement.

3.  Tumor burden that did increase, but no more than 20%, with subsequent improvement. (pseudoprogression...about 6% of patients) 

Early in treatment, within 3 months, if your tumor is essentially stable, or better, your overall survival is better.  If your tumor burden increases more than 20%....chances of response are unlikely.  Though there is the 5-6% of folks who demonstrate 'pseudoprogression' and later DO respond...however, this study points out that the amount of growth remains at a 20%, or less, increase.  Note:  This portion of responders with pseudoprogression at 5-6% is consistent with prior studies.

Clear as mud, right?  love, c

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

It goes without saying that over the years I have posted a zillion reports about all things immunotherapy:  anti-PD-1 ~ Pembrolizumab (also referred to as Pembro and Keytruda) as well as Nivolumab (also called nivo and Opdivo) both of which have very similar side effect profiles and a roughly 40% response rate when used alone; anti-CTLA-4 ~ ipilimumab (also called ipi and Yervoy) which has similar side effects but with greater frequency and intensity than the anti-PD-1 products {though many tolerate it well} with about a 15% response rate when used alone; as well as the ipi/nivo combo which has a response rate of 50+%. (Here's a link:  ASCO 2016: Checkmate 069 - ipi/nivo combo in Stage IV melanoma demonstrated a 68% ORR)  Consistently, treatment naive patients have responded best to all of the above, responses are the most durable we have ever had in any melanoma treatments, many folks continue to respond even if they have to stop treatment due to side effects.  We have also learned that side effects need to be treated as soon as possible, often with steroids, so as to save lives and prevent greater damage than has already occurred, AND the use of steroids, if needed, DOES NOT IMPEDE RESPONSE!!!!  Feel free to use the blog's search bubble to find more info and data on all of this.  Now researchers are looking at:

Pembro plus ipi:

Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.

ASCO 2017. J Clin Oncl, 35, 2017. Carlino, Atkinson, Cebon, et al.

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAF^V600mutant, and 13% received greater than/= to 1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61%; the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

Here 153 Stage IV melanoma patients (no brain mets) but some with increased LDH were given Pembro 2mg/kg and ipi at only 1mg/kg, together every three weeks for 4 doses and then pembro alone q 2 wks.  There were no treatment related deaths, though ALL patients had side effects, but were grade 3/4 in only 45%.  The way the data was examined ~ with one near endpoint and another 7 months later...proved...AGAIN...that responses can occur late....and as per Weber and Agarwala, when it comes to immunotherapy, "Give the patient time!" ~ for an ultimate ORR of 61% and CR of 15%.  So....these responses are no better than those demonstrated in the ipi/nivo combo.  But...what is interesting is that ipi was dosed at only 1mg/kg whereas in the ipi/nivo combo it is used at 3mg/kg. (AGAIN!!!  Why can't researchers [and Big Pharma!!!!] construct trials so that you can REALLY compare results!!!) At any rate, this tidbit of data may prove important in decreased side effects and it would be important/interesting to see if nivo with ipi at only 1m/kg would continue to do as well as the combo does currently.  I'm betting it would....but that's just me.

While the next couple of articles did not come out of ASCO this year...they pertain to the topic at hand...so I've included them here.

Here, researchers looked at the response to ipi after patients have progressed on pembro:

Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma  KEYNOTE-006 Poster Spotlight: G. Long (Australia).  European Cancer Conference, Jan 2017.

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti–PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab.

Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported.

Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAF^V600-mutant tumors at baseline. Best response to pembrolizumab was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks, and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks. Median duration of ipilimumab was 8 weeks. The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received greater/= to 1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months.

Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.

So in 97 patients, most of whom had taken pembro for about 18 weeks with a PR in 16% and SD in 12%, PD in 62% (clearly, these were folks who were not responding to pembro as well as the usual data) were, in about 5 weeks placed on ipi at 3mg/kg, with most folks taking it for 8 weeks.  At that point, the ORR to ipi was 14% (which is what responses to ipi usually run at).  Additional data showed:  CR in 3%, PR in 11%, SD in 33%, PD in 33%.  While not great, this certainly shows that if you are not a responder to pembro....switching ASAP to ipi can gain a response of about 15%.  A similar response was attained in the last abstract noted in this post from ASCO 2015:  ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Here researchers looked at how tumors, and subsequently the patients!!!, responded to pembro:

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Nishino, Giobbie-Hurder, Manos, et al. Clin Cancer Res. 2017 June 7.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.
Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained less than 20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with less than 20% tumor burden increase from baseline had longer OS than patients with greater than/= to 20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with less than 20% tumor burden increase during therapy had significantly reduced hazards of death.  Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of less than 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention.

Here 96 patients with measureable disease were given pembro.  ORR was the expected 44%.  Folks whose tumor burden increased less than 20% from their baseline, once therapy was started, did best, and this was 55% of the peeps in the study.  They ended up with a longer OS than those whose known tumor burden increased more than 20% from baseline while on pembro.  Of course!  If your tumors mostly just shrink while on treatment...you do better!!!   BUT!  The pseudoprogression thing is real for some...albeit in small numbers...3 patients had target lesions increase in size but went on to gain a response and 1 patient that didn't have measureable disease when they started treatment developed a new lesion that then regressed.

Well, there you have it.  Things remain about as clear as mud if you are a melanoma patient who is progressing on immunotherapy as to trying to decide what to do next!!!  But....it is clear...that there is hope.  Love and luck to all the ratties - c

Important stuff floating in our blood - tumor DNA, micro RNA, cytokines - can determine tumor burden, predict response, and side effects for melanoma patients!!!

Continuing from yesterday.....  Our blood is a fairly accessible information rich soup that can tell us all sorts of things about our bodies!!!  One important ingredient for melanoma patients is circulating tumor DNA.  Here's a load of prior reports: Circulating tumor DNA - to determine diagnosis, disease burden, response to therapy, etc  Here are a couple more reports:

Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients.  McEvoy, Warburton, Al-Ogaili, et al. BMC Cancer. 2018 Jul 9.

Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB).  Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).  CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB. CtDNA was not detectable in patients with an MTB of greater than/= to 10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.  We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.

From validity to clinical utility: the influence of circulating tumor DNA on melanoma patient management in a real-world setting. Rose, Luber, Makell, et al. Mol Oncol. 2018 Aug 16.

Melanoma currently lacks a reliable blood-based biomarker of disease activity, although circulating tumor DNA (ctDNA) may fill this role. We investigated the clinical utility (i.e., impact on clinical outcomes and interpretation of radiographic data) of measuring ctDNA in patients with metastatic or high-risk resected melanoma. Patients were prospectively accrued into greater than/= to 1 of 3 cohorts, as follows. Cohort A: patients with radiographically-measurable metastatic melanoma who underwent comparison of ctDNA measured by a BEAMing digital PCR assay to tissue mutational status and total tumor burden; when appropriate, determinations about initiation of targeted therapy were based on ctDNA data. Cohorts B and C: patients with BRAF- or NRAS-mutant melanoma who had either undergone surgical resection of high-risk disease (cohort B) or were receiving or had received medical therapy for advanced disease (cohort C). Patients were followed longitudinally with serial ctDNA measurements with contemporaneous radiographic imaging to ascertain times to detection of disease activity and progressive disease, respectively. The sensitivity and specificity of the ctDNA assay was 86.8% and 100%, respectively. Higher tumor burden and visceral metastases were found to be associated with detectable ctDNA. In 2 patients in cohort A, ctDNA test results revealed a targetable mutation where tumor testing had not; both patients experienced a partial response to targeted therapy. In 4 of 30 patients with advanced melanoma, ctDNA assessments indicated evidence of melanoma activity that predicted radiographic evidence of disease progression by 8, 14, 25 and 38 weeks, respectively. CtDNA was detectable in 3 of these 4 patients coincident with radiographic evaluations that alone were interpreted as showing no evidence of neoplastic disease. Our findings provide evidence for the clinical utility of integrating ctDNA data in managing patients with melanoma in a real-world setting.

Among the many bio-markers present in our blood, there's also circulating RNA.   Prior reports:  RNA and biomarkers generally  Now, this:

Extracellular microvesicle microRNAs as predictive biomarkers for targeted therapy in metastastic cutaneous malignant melanoma.  Svedman, Loncharoenkal, Bottaj, et al. PLoS One. 2018 Nov.

Mitogen activated-protein kinase pathway inhibitors (MAPKis) improve treatment outcome in patients with disseminated BRAFV600 mutant cutaneous malignant melanoma (CMM) but responses are of limited duration due to emerging resistance. Although extensive research in mechanisms of resistance is being performed, predictive biomarkers for durable responses are still lacking. We used miRNA qPCR to investigate if different levels of extracellular microvesicle microRNA (EV miRNA) in matched plasma samples collected from patients with metastatic IV BRAFV600 mutated CMM before, during and after therapy with MAPKis could serve as predictive biomarkers.  EV miRNAs were extracted from plasma samples from 28 patients collected before and during therapy, measured by quantitative PCR-array and correlated to therapy outcome. Increased levels of EV let-7g-5p during treatment compared to before treatment were associated with better disease control with MAPKis. Elevated levels of EV miR-497-5p during therapy were associated with prolonged progression free survival (PFS).  EV miRNAs let-7g-5p and miR-497-5p were identified as putative novel predictive biomarkers of MAPKi treatment benefit in metastatic CMM patients highlighting the potential relevance of assessing EV miRNA during and after treatment to unravel novel mechanisms of resistance.

Circulating cytokines are substances like interleukin, interferon, and growth factors, that cells in our immune system secrete in order to affect other cells. Here's a report for a little background:  Eosinophilia with Nivo and Pembro - A predictor of success?!!
Here they are being examined as predictors of toxicity to immunotherapy:

Circulating cytokines predict immune-related toxicity in melanoma patients receiving anti-PD-1-based immunotherapy. Lim, Lee, Gide, et al. Clin Cancer Res. 2018 Nov 8.  

Combination PD-1 and CTLA-4 inhibitor therapy has dramatically improved the survival of patients with advanced melanoma but is also associated with significant immune-related toxicities. This study sought to identify circulating cytokine biomarkers of treatment response and immune-related toxicity.  The expression of 65 cytokines was profiled longitudinally in 98 melanoma patients treated with PD-1 inhibitors, alone or in combination with anti-CTLA-4, and in an independent validation cohort of 49 patients treated with combination anti-PD-1 and anti-CTLA-4. Cytokine expression was correlated with RECIST response and immune-related toxicity, defined as toxicity that warranted permanent discontinuation of treatment and administration of high dose steroids.

Eleven cytokines were significantly upregulated in patients with severe immune-related toxicities at baseline and early during treatment. The expression of these eleven cytokines was integrated into a single toxicity score, the CYTOX score, and the predictive utility of this score was confirmed in the discovery and validation cohorts. 

The CYTOX score is predictive of severe immune-related toxicity in melanoma patients treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy. This score, which includes pro-inflammatory cytokines such as IL-1a, IL-2 and IFNa2, may help in the early management of severe, potentially life-threatening immune-related toxicity.

Hoping for much more consistency and use of these relatively simple tests in order to reap better treatment outcomes for melanoma patients in 2019!!! - c

Measuring cell-free DNA in melanoma patient's blood to determine tumor burden and prognosis

I have spent years yelling about finding a reasonable marker through a simple blood draw to determine disease burden, response to therapy, and prognosis for melanoma patients.  Here's a zillion reports - Markers for melanoma- looking at utilizing everything from progression on scans, t-cell exhaustion, lymphocytes, circulating CD8 and CD4 t cells, eosinophils, LDH, melanoma antigens, to circulating tumor cells to determine the status of a melanoma patient's disease burden.

On the topic of circulating tumor DNA alone there are these:  Circulating tumor DNA in melanoma
It can be used to determine level of disease, progression, BRAF status and response to treatment.
Now there's this:

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients. Valpione, Gremel, Mundra, et al.  Eur J Cancer. 2017 Nov 23.

Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients.

A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients.

Baseline cfDNA concentration correlated with pre-treatment tumour burden. Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/μl identified two distinct prognostic groups. Patients with cfDNA greater than/= to 89 pg/μl had shorter OS (10.0 versus 22.7 months) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden. In addition, the ratio between baseline cfDNA and tumour burden was prognostic.

We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

These tests work!  It is time to make them a reality for those with melanoma! - c

In melanoma, if you are worried about your PD-L1 level....DON'T wig out yet!!!!

While a wide variety of folks have been gettin' folks fired up about the presence or absence of PD-L1 expression in relation to response to immunotherapy (checkpoint inhibitors)...there's this:

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.  Morrison, Pabla, Conroy, et al.  J Immunother Cancer. 2018 May 9.  

Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.  

Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8⁺ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

PD-L1 positivity greater than or equal to 1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

Immunotherapy works in about 40% of melanoma patients, if you are talking about anti-PD-1 (Nivo/Opdivo or Pembro/Keytruda) and we REALLY need to figure out how to make that response rate better.  Here, researchers from 8 facilities looked at a lot of factors ~ PD-L1 expression, CD8 T cell infiltration, tumor mutational burden and other funky immune factors.  After examination of 231 patients (as best as I can tell), while PD-L1 positivity "correlated with response and OS...but demonstrated limited predictive performance."  "Comprehensive immune profiling demonstrated higher sensitivity (72%) compared to PD-L1 (34%) and tumor mutational burden (32%)."

Clearly, the presence of PD-L1 on your tumor is not the end all be all in determining response to immunotherapy.  Would that it were that simple!  But, y'all know melanoma don't play that way!!  Hang in there ratties!  - c

ASCO 2017: Circulating DNA to measure response in melanoma

Wouldn't it be great if we could do a simple lab draw to determine the type of tumor, as well as tumor burden a patient has??  With such a test we could minimize use of painful biopsies, decrease repeated exposure to radiation via scans, and could much more rapidly determine whether a patient's tumor burden is decreasing in a positive response to a given therapy....or not!

I've been posting studies addressing these possibilities for a while...
From 2014:  With immunotherapy tumors can grow or reappear...even though it is working. Will DNA analysis clarify response???

From 2015:  PCR testing for melanoma

PCR testing for circulating melanoma DNA....one mo one!!

Circulating Tumor Cells...how they may eventually impact melanoma diagnosis and response to therapy

From 2016:  Here, I actually broke down all the various biomarkers, what they are and what they mean ~ Biomarkers - blood components, circulating tumor cells AND of the tumor itself

Then there were these:  BRAF testing via blood rather than tumor tissue

Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma!

From 2017:  Circulating DNA predicts response to anti-PD-1

Circulating tumor DNA provide valid way to monitor response to anti-PD-1 therapy for melanoma....AGAIN!!!

Now...there's this:

Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.

ASCO 2017. J Clin Oncol 35, 2017. Braune, Buboff, Follo, et al.

Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS. A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS. Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 and LDH. Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. 

Here, using a blood test to check for bits of circulating tumor DNA for BRAF V600E and wild type, the researchers looked at 89 previously drawn blood samples from 32 patients along with 158 blood samples from 12 patients in this trial.  These samples were collected at baseline, and in roughly 1 week, 1 month and then q 3 months for up to 2 years.  Examination of the previously drawn samples showed that 23 of the 31 Stage IV patients were positive for BRAF V600E circulating tumor cells in their blood at least once (74%).  The presence of circulating DNA from tumor cells at baseline was a poor indicator for PFS (progression free survival), while decreasing levels of same was a favorable prognostic factor for PFS.  Patients that still had circulating DNA from tumor cells in their blood "early after a change or institution of treatment predicted tumor progression at first clinical response assessment".  If the test changed from being positive for the ctDNA to negative for it, or if there was a decrease in the level measured, the patients had a more favorable course.

Makes sense, right?  If you have a lot of circulating tumor DNA in your blood...that's not good.  If you still have ctDNA floating around after you have started a new treatment...it doesn't bode well for you to respond well to that treatment.  However, if you have little ctDNA period, or if the amount you have is decreasing with your treatment...it is likely that you will do well!!!  Think how much more quickly we could get a patient on the treatment that works for them with a tool like this!!!  I think we've beat around this bush for long enough!!!  Let's make peripheral blood sample testing for circulating tumor DNA a reality!! - c

Clinical condition of melanoma peeps and associated outcomes when treated with anti-PD-1 vs anti-PD-1 and ipi

While this report is not exactly news...it is interesting and confirms prior data:

Clinical Correlates of Response to Anti-PD-1-based Therapy in Patients With Metastatic Melanoma.  Davis, Perez, Avoubi,...Sosman...et al. J Immunother. 2019 Mar 13. 

Anti-PD-1 agents, alone or in combination with ipilimumab, produce durable responses in some melanoma patients. Tumor features that correlate with response are not well defined. We collected clinical data from metastatic melanoma patients treated at 2 centers who received anti-PD-1 (n=303) or anti-PD-1+ipilimumab (n=57). We correlated number of metastases, diameter of largest tumor (tumor bulk), and organ involvement with response rate (RR), progression-free survival (PFS), and overall survival (OS). Patients with diameter of largest tumor less than or equal to 2 cm had a 53% RR, whereas those with largest tumor greater than 2 cm had a 38% RR. Those with liver metastases had lower RR (25% vs. 43%). RR to anti-PD-1 was greater in patients with less than or equal to 10 metastases compared with those with greater than 10 (39% vs. 27%). In multivariable analyses, size of the largest tumor was independently associated with PFS, OS, and RR, whereas AJCC stage, lactate dehydrogenase, liver metastases, ECOG performance status, number of metastases, and prior therapies were not. In patients treated with anti-PD-1+ipilimumab, however, tumor bulk was not associated with outcomes, although number of metastases was associated with PFS  and RR but not OS. Pathologic analysis did not reveal differences in T-cell infiltration in bulky versus small tumors. Tumor bulk, defined by diameter of largest tumor, was strongly and independently associated with clinical outcomes in anti-PD-1 but not in anti-PD-1+ipilimumab. In conjunction with molecular biomarkers, clinical predictors may help guide selection of immunotherapy agents.

So....this study looked at 360 metastatic melanoma peeps.  303 were given anti-PD-1 alone and 57 were treated with the anti-PD-1 plus ipi.  The researchers looked at response rate (RR), progression-free survival (PFS) and overall survival in the groups to see if there were any clinical consistencies between those results.  They found that (not surprisingly) patients whose largest tumor was less than or equal to 2 cm had a 53% RR while those whose largest tumor measured more than 2 cm had a 38% response rate.  Patients with less than 10 mets had a better RR than those who had more than 10 (39% vs 27%).  Folks with liver mets did less well, with RR of 25% vs 43%.  In a separate, overarching analysis, size of the largest tumor was independently associated with all parameters (PFS, OS, and RR) - while LDH, liver mets, # of mets, and prior therapies were not.  HOWEVER, with the ipi/anti-PD-1 combo, tumor size was NOT associated with out comes, though the NUMBER of mets was still associated with PFS and RR, but not OS.  Analysis of tumor pathology did not reveal any differences in T-cell action in bulky vs small tumors.

We have long known that immunotherapy works best with the lowest tumor burden.  Lots of research indicates that LDH is not a very reliable marker.  We know that liver mets are difficult to treat (early research link here).  We also know that there are no crystal clear parameters (YET!!!) that tell us who will do well on anti-PD-1 as a single agent vs those who need to be treated with anti-PD-1 combined with ipi.  AND ~ that is a hard decision, given the desire to rid ourselves of melanoma versus the unfortunate side effects the combo can trigger that are more easily avoided with anti-PD-1 alone.  BUT ~ given what we have long known and the information presented here....if I had lots of mets, large mets or liver involvement...I would be opting for the combo.  Just saying.  For what it's worth. - c

Study on Intralesional Rose Bengal out of Moffitt...we know a bit more about HOW it works!!!

In 2013 I wrote this:  "I first wrote about PV-10 (also known as Rose Bengal, a pretty cheap derivative of fluorescein, that has been used for over 80 years to stain necrotic tissue in the cornea when corneal abrasions are suspected and as an IV diagnostic of liver impairment) being used in melanoma patients in October of 2012.  The study I reported on was one in which Stage 3-4 melanoma patients had up to 4 courses of PV-10 injections into up to 20 cutaneous and subcutaneous tumors.  The cool thing was that not only did many of the injected tumors respond and shrivel, but some tumors at distant sites (even in the lungs) that were NOT injected, shriveled as well!!!"

And this in 2014:  "Intralesional melanoma therapy (A procedure in which the "treatment" is directly injected into superficial tumors and in theory, not only does that tumor die, but "by stander" tumors at more distant sites die too!!!) was first recorded back in 1975.  A 75 year old male with 64 melanoma mets just below the skin, as well as junk in his lungs, had 17 superficial lesions injected with Bacille Calmette-Guerin over a period of 8 months. (BCG is a vaccine against some strains of tuberculosis, but does contain a weakened version of the bacteria itself within it.) In the end, all 17 tumors injected resolved and his pulmonary mets diminished by more than 50%!  However, enthusiasm for BCG as a melanoma treatment waned as patients in subsequent trials experienced anaphylactic reactions and death due to disseminated BCG, and randomized trials failed to replicate significant clinical benefit.

Later, intralesional therapy was tried using all sorts of things.  More recently Allovectin-7, OncoVEX, and PV-10 have demonstrated positive results, killing melanoma at the injected site and systemically.  [Now we also have CAVATAK, an intralesional derived from the Coxsackievirus:  CAVATAK: intralesional therapy derived from the Coxsackievirus]

Allovectin-7, is a soup of DNA, that attempts to change the gene make-up of tumor cells. In a study reported in 2012, it provided a 12% overall response rate with no grade 3 or higher toxicities in patients with stage III/IV melanoma with injectable cutaneous lesions.

OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (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.) But, in OncoVEX, it is thought to only replicate in the tumor cells.  The white cells produced in the process kill off the tumor cells.  In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response.  92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months.  Responses were found in patients with all stages and systemic tumors were eradicated in some patients.

Rose Bengal was first utilized in the 1800's to dye fabrics and color the feet of Bengali women red for weddings and celebrations. Later it was used as a staining agent to find corneal lesions and then as an IV preparation to check for impaired liver function.  The "Aha!" moment came in the 1980's when Japanese tests of a "food dye" to determine tumor origin, found dose-dependent survival increases. After a few other sundry studies....PV-10 was born.  It is a 10% Rose Bengal solution, with a 30-minute half-life, excreted via bile. PV-10 is excluded from normal cells, but slips through the cell membrane of cancer cells (liver, breast, melanoma, and others) because their cell walls have a higher lipid content. Once inside, PV-10 triggers lysosomal release (the part of the cell that digests waste), killing the cell in 30-60 minutes. Antigenic tumor fragments are believed to produce the 'bystander effect' leading to immediate reduction in tumor burden and concomitant immunologic activation."

Here is a link to the entire report and others I've posted here:  Info from ASCO 2014 on Rose Bengal (PV-10) and links to more reports

And now....researchers have learned a little more about how it actually works....

Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1.  Liu, Innamarato, Kodumudi, Weber, et al.  Oncotarget. 2016 May 9.

"Intralesional (IL) therapy is under investigation to treat dermal and subcutaneous metastatic cancer. Rose Bengal (RB) is a staining agent that was originally used by ophthalmologists and in liver function studies. IL injection of RB has been shown to induce regression of injected and uninjected tumors in murine models and clinical trials. In this study, we have shown a mechanism of tumor-specific immune response induced by IL RB. In melanoma-bearing mice, IL RB induced regression of injected tumor and inhibited the growth of bystander lesions mediated by CD8+ T cells. IL RB resulted in necrosis of tumor cells and the release of High Mobility Group Box 1 (HMGB1), with increased dendritic cell (DC) infiltration into draining lymph nodes and the activation of tumor-specific T cells. Treatment of DC with tumor supernatants increased the ability of DCs to stimulate T cell proliferation, and blockade of HMGB1 in the supernatants suppressed DC activity. Additionally, increased HMGB1 levels were measured in the sera of melanoma patients treated with IL RB. These results support the role of IL RB to activate dendritic cells at the site of tumor necrosis for the induction of a systemic anti-tumor immune response."

Bentie has always believed that dendritic cells are going to hold some important keys to understanding and perhaps treating melanoma!  Way to go ratties (and little melanoma-bearing mice)! - c