Survival of advanced melanoma patients with normal LDH treated with oblimersen, temozolomide, and nab-paclitaxel

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9080-9080
Author(s):  
A. C. Pavlick ◽  
P. Ott ◽  
J. Escalon ◽  
K. Madden ◽  
E. Yepes ◽  
...  
Keyword(s):  
Survival Data ◽  
Caspase 3 ◽  
Subcutaneous Tissue ◽  
Tumor Biology ◽  
Metastatic Tumor ◽  
Advanced Melanoma ◽  
Response To Treatment ◽  
Antisense Therapy ◽  
Melanoma Patients ◽  
Ecog Ps

9080 Background: Oblimersen (OBL), temozolomide (TMZ), and abraxane (ABX) act synergistically in preclinical studies with melanoma cell lines. Bcl-2 antisense therapy in combination with dacarbazine was encouraging in advanced melanoma patients(pts) with normal LDH. Methods: Chemotherapy-naïve advanced melanoma pts (ECOG PS ≤ 2, baseline LDH ≤1.1 × ULN, measurable disease per RECIST) were enrolled on a phase I/II protocol. The treatment regimen consisted of 56-day cycles of OBL (7 mg/kg/d continuous IV infusion, d 1–7 and 22–28), TMZ (75 mg/m2/d, d 1–42), and ABX (175 mg/m2 in Cohort 1, 260 mg/m2 in Cohort 2, d 7 and 28). Immunohistochemical (IHC) staining for Bcl-2, Bcl-XL, BAK and caspase 3 was performed in pre- and post-therapy tumor samples. Serum shed collagen cryptic epitope levels were monitored. Results: 18 pts were treated (Cohort 1 = 14 pts [1–6 cycles];Cohort 2 = 4 pts [2–3 cycles]). Median age was 58 years (range: 34–78). Disease sites included liver (6), other visceral sites (10), skin, subcutaneous tissue, and lymph nodes (2). The overall survival (OS) was 14.7 months and showed a trend towards superiority when compared to both arms of the prior oblimersen trial (DTIC, OS 9.7 months, p = 0.078 and DTIC-OBL, OS 11.4 months, p = 0.31) in pts with the same LDH cut-off (Bedikian et al. JCO. 2006). 50% of pts survived > 1 year. One CR lasted 25+ mo, five PR (>50% tumor reduction) lasted > 2 cycles, and 7 SD lasted > 3 cycles. Five PD after 1 cycle were seen. One ocular melanoma pt survived 15 mo despite PD. Shed cryptic epitopes correlated with clinical response versus disease progression. Alteration of the tumor biology based on phenotypic changes in Bcl-2, Bcl-xL, BAK and caspase 3 correlated with response to treatment. Conclusions: Our data suggest that the combination of OBL, TMZ, and ABX is synergistic in advanced melanoma pts with normal LDH, possibly translating into improved OS compared to prior regimens with dacarbazine ± OBL. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in melanoma cells from metastatic tumor. The survival data in the limited number of pts enrolled in cohort 1 and 2 of this trial are encouraging; further exploration with this combination is underway using 1-hour infusions of OBL. No significant financial relationships to disclose.

Markers of response to PD-1 inhibition.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14505-e14505 ◽  
Author(s):  
Thijo Jeroen Nicolaas Hiltermann ◽  
Lucie Hijmering-Kappelle ◽  
Harry J.M. Groen
Keyword(s):  
Survival Data ◽  
Lymphocyte Count ◽  
Cox Regression ◽  
Tumour Response ◽  
Absolute Lymphocyte Count ◽  
Patient Characteristics ◽  
Predictive Biomarker ◽  
Response To Treatment ◽  
Platinum Based Chemotherapy ◽  
Ecog Ps

e14505 Background: Nivolumab (Nivo) has a durable tumour response in 20 % of patients. While a PD-L1 IHC complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Serum biomarkers predicted by the cancer immunogram (Blake Science 2016) and response to Nivo defined by a clinical benefit ≥6 month (DR) and response by CR, PR or SD according to RECIST v1.1 are shown. Methods: Advanced NSCLC pts progressing after 1L platinum-based chemotherapy were treated with Nivo. Baseline blood markers drawn: CRP, absolute lymphocyte count, plasma glucose and LDH. Kaplan-Meier used to estimate survival data. Cox regression was used to predict associations with possible (bio-) markers and survival (age, gender, ECOG PS, histology, presence of brain metastasis, CRP, LDH, glucose, lymphocyte count). Results: Patient characteristics see table. 20% showed a DR with CR (n = 3), PR (n = 31 of 33) and SD (n = 9 of 20). Only ECOG PS was associated with OS and PFS. Soluble biomarkers were not. When tumour response (RECIST or DR) was added to the regression model ECOG PS was no longer significant but responses were. HR for PFS for DR was 0.07 (0.03-0.14) and HR according to the classical RECIST1.1 was 0.22 (0.16-0.32). HR for OS for DR 0.09 (0.03-0.21) and for classical RECIST1.1 0.26 (0.17-0.40). Conclusions: Serum blood markers at baseline were not associated with survival. Response to treatment as DR seems a stronger predictor for survival than RECIST. 45% of pts with SD had a DR. [Table: see text]

scholarly journals 673 Precision microbiome mapping identifies a microbiome signature predictive of Immune checkpoint inhibitor response across multiple research study cohorts

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Matthew Robinson ◽  
Kevin Vervier ◽  
Simon Harris ◽  
David Adams ◽  
Doreen Milne ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Advanced Melanoma ◽  
List Type ◽  
Metagenomic Sequencing ◽  
Genome Database ◽  
Sequencing Platform ◽  
Melanoma Patients

BackgroundThe gut microbiome of cancer patients appears to be associated with response to Immune Checkpoint Inhibitor (ICIs) treatment.1–4 However, the bacteria linked to response differ between published studies.MethodsLongitudinal stool samples were collected from 69 patients with advanced melanoma receiving approved ICIs in the Cambridge (UK) MELRESIST study. Pretreatment samples were analysed by Microbiotica, using shotgun metagenomic sequencing. Microbiotica’s sequencing platform comprises the world’s leading Reference Genome Database and advanced Microbiome Bioinformatics to give the most comprehensive and precise mapping of the gut microbiome. This has enabled us to identify gut bacteria associated with ICI response missed using public reference genomes. Published microbiome studies in advanced melanoma,1–3renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC)4 were reanalysed with the same platform.ResultsAnalysis of the MELRESIST samples showed an overall change in the microbiome composition between advanced melanoma patients and a panel of healthy donor samples, but not between patients who subsequently responded or did not respond to ICIs. However, we did identify a discrete microbiome signature which correlated with response. This signature predicted response with an accuracy of 93% in the MELRESIST cohort, but was less predictive in the published melanoma cohorts.1–3 Therefore, we developed a bioinformatic analytical model, incorporating an interactive random forest model and the MELRESIST dataset, to identify a microbiome signature which was consistent across all published melanoma studies. This model was validated three times by accurately predicting the outcome of an independent cohort. A final microbiome signature was defined using the validated model on MELRESIST and the three published melanoma cohorts. This was very accurate at predicting response in all four studies combined (91%), or individually (82–100%). This signature was also predictive of response in a NSCLC study and to a lesser extent in RCC. The core of this signature is nine bacteria significantly increased in abundance in responders.ConclusionsAnalysis of the MELRESIST study samples, precision microbiome profiling by the Microbiotica Platform and a validated bioinformatic analysis, have enabled us to identify a unique microbiome signature predictive of response to ICI therapy in four independent melanoma studies. This removes the challenge to the field of different bacteria apparently being associated with response in different studies, and could represent a new microbiome biomarker with clinical application. Nine core bacteria may be driving response and hold potential for co-therapy with ICIs.Ethics ApprovalThe study was approved by Newcastle & North Tyneside 2 Research Ethics Committee, approval number 11/NE/0312.ReferencesMatson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359(6371):104–108.Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359(6371):91–97.

Treatment beyond progression with immune checkpoint inhibitors in advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21541-e21541
Author(s):  
Pawel Sobczuk ◽  
Anna Malgorzata Czarnecka ◽  
Mateusz Spalek ◽  
Pawel Teterycz ◽  
Monika Dudzisz-Śledź ◽  
...  
Keyword(s):  
Multimodal Treatment ◽  
Multidisciplinary Treatment ◽  
Objective Response ◽  
Real Life ◽  
Tumor Burden ◽  
Advanced Melanoma ◽  
Disease Stage ◽  
Treatment Beyond Progression ◽  
Melanoma Patients ◽  
Metastatic Sites

e21541 Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.

Patient human leukocyte antigen (HLA) genotype may predict response to anti-programmed death receptor 1 (anti-PD1) in advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21512-e21512
Author(s):  
Oliver Oey ◽  
Muhammad Adnan Khattak ◽  
Afaf Abed ◽  
Tarek Meniawy ◽  
Anna Reid ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Prognostic Value ◽  
Cox Regression ◽  
Multivariate Analyses ◽  
Locally Advanced ◽  
White Blood Cells ◽  
Advanced Melanoma ◽  
Hla B27 ◽  
Melanoma Patients ◽  
Hla Genotype

e21512 Background: Anti-PD-1 therapy has improved the outcome of advanced melanoma patients with a 5-year survival rate of about 40-45%. However, biomarkers predictive of response to immune checkpoint blockade therapy are lacking. There is limited data on the utility of host germline human leucocyte antigen (HLA) genotype as a predictor of response to anti-PD-1 therapy in advanced melanoma. Here, we investigate the prognostic value of HLA in predicting survival outcomes of patients with unresectable locally advanced, metastatic melanoma on anti-PD-1 therapy. Methods: Blood was collected from 113 metastatic melanoma patients who were treated with anti-PD-1 therapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and subsequently HLA-I and HLA-II typed using clinically validated assay. Univariate analyses were conducted using Cox regression model correlating homozygosity at HLA-I and HLA-II loci with overall survival (OS). HLA-A and HLA-B were classified into 12 supertypes and correlated with OS. Multivariate analyses were performed while controlling for age, gender, prior therapy, BRAF mutation status, ECOG performance status and presence of liver and brain metastases. Results: Homozygosity at HLA-I or HLA-II loci was not associated with OS. However, the absence of HLA-B62 supertype was associated with a trend towards improved OS (HR: 0.53 [95% CI:0.25-1.10]; P = 0.09) as reported previously. Notably, the absence of HLA-B27 supertype was associated with improved OS which was statistically significant (HR: 0.45 [95% CI:0.24-0.85]; P = 0.01). In multivariate analyses, the prognostic value of HLA-B27 supertype (HR: 0.38 [95% CI:0.19-0.76]; P = 0.006) was maintained, whereas the prognostic value of HLA-B62 supertype significantly improved (HR: 0.42 [95% CI:0.19-0.94]; P = 0.03). Conclusions: Our results suggest a limited role of HLA homozygosity in predicting survival of melanoma patients treated with anti-PD-1 therapy. However, we identified that the absence of HLA-B62 and HLA-B27 supertype is associated with improved survival benefit. Therefore, HLA-B27 and HLA-B62 supertype may be used as adjunct biomarkers of response to anti-PD-1 therapy in patients with melanoma in addition to PD-L1 status, pending validation in prospective randomised clinical trials.

scholarly journals Serum CEACAM1 Elevation Correlates with Melanoma Progression and Failure to Respond to Adoptive Cell Transfer Immunotherapy

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
R. Ortenberg ◽  
S. Sapoznik ◽  
D. Zippel ◽  
R. Shapira-Frommer ◽  
O. Itzhaki ◽  
...  
Keyword(s):  
Strong Predictor ◽  
Xenograft Model ◽  
Tumor Burden ◽  
Adoptive Cell Transfer ◽  
Screening Tools ◽  
Response To Treatment ◽  
Tumor Biomarker ◽  
Melanoma Patients ◽  
First Time

Malignant melanoma is a devastating disease whose incidences are continuously rising. The recently approved antimelanoma therapies carry new hope for metastatic patients for the first time in decades. However, the clinical management of melanoma is severely hampered by the absence of effective screening tools. The expression of the CEACAM1 adhesion molecule on melanoma cells is a strong predictor of poor prognosis. Interestingly, a melanoma-secreted form of CEACAM1 (sCEACAM1) has recently emerged as a potential tumor biomarker. Here we add novel evidences supporting the prognostic role of serum CEACAM1 by using a mice xenograft model of human melanoma and showing a correlation between serum CEACAM1 and tumor burden. Moreover, we demonstrate that serum CEACAM1 is elevated over time in progressive melanoma patients who fail to respond to immunotherapy as opposed to responders and stable disease patients, thus proving a correlation between sCEACAM1, response to treatment, and clinical deterioration.

scholarly journals Immune-Escape Markers in Relation to Clinical Outcome of Advanced Melanoma Patients Following Immunotherapy

2014 ◽  
Vol 2 (6) ◽  
pp. 538-546 ◽  
Author(s):  
Esther P.M. Tjin ◽  
Gabrielle Krebbers ◽  
Kimberley J. Meijlink ◽  
Willeke van de Kasteele ◽  
Efraim H. Rosenberg ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Escape ◽  
Advanced Melanoma ◽  
Melanoma Patients

BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response

2017 ◽  
Vol 27 (3) ◽  
pp. 281-287 ◽  
Author(s):  
Céline Desvignes ◽  
Henry Abi Rached ◽  
Carole Templier ◽  
Elodie Drumez ◽  
Pauline Lepesant ◽  
...  
Keyword(s):  
Treatment Response ◽  
Initial Treatment ◽  
Braf Inhibitor ◽  
Advanced Melanoma ◽  
Melanoma Patients

scholarly journals Prospective, Multicenter Clinical Impact Evaluation of a 31-Gene Expression Profile Test for Management of Melanoma Patients

2018 ◽  
Vol 2 (2) ◽  
pp. 111-121 ◽  
Author(s):  
Larry D Dillon ◽  
Joseph E Gadzia ◽  
Robert S Davidson ◽  
Michael McPhee ◽  
Kyle R Covington ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Tumor Biology ◽  
Primary Melanoma ◽  
Risk Class ◽  
Class 1 ◽  
Post Test ◽  
Melanoma Patients ◽  
And Performance

Objective: A 31-gene expression profile (GEP) test that has been clinically validated identifies melanoma patients with low (Class 1) or high (Class 2) risk of metastasis based on primary tumor biology.  This study aimed to prospectively evaluate the test impact on clinical management of melanoma patients.Methods:  Physicians at 16 dermatology, surgical or medical oncology centers examined patients to assess clinical features of the primary melanoma.  Recommendations for clinical follow-up and surveillance were collected.  Following consent of the patient and performance of the GEP test, recommendations for management were again collected, and pre- and post-test recommendations were assessed to determine changes in management resulting from the addition of GEP testing to traditional clinicopathologic risk factors.   Results:  Post-test management plans changed for 49% (122 of 247) of cases in the study when compared to pre-test plans. Thirty-six percent (66 of 181) of Class 1 cases had a management change, compared to 85% (56 of 66) of Class 2 cases.  GEP class was a significant factor for change in care during the study (p<0.001), with Class 1 accounting for 91% (39 of 43) of cases with decreased management intensity, and Class 2 accounting for 72% (49 of 68) of cases with increases.Conclusions: The reported study show that the 31-gene GEP test improves net health outcomes in the management of cutaneous melanoma.  Physicians used test results to guide risk-appropriate changes that match the biological risk of the tumor, including directing more frequent and intense surveillance to high-risk, Class 2 patients.

scholarly journals Metabolic Tumor Volume for Early Response Assessment in Early-Stage Unfavorable Hodgkin Lymphoma Treated with Nivolumab in the GHSG Nivahl Phase II Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4020-4020
Author(s):  
Conrad-Amadeus Voltin ◽  
Jasmin Mettler ◽  
Horst Mueller ◽  
Michael Fuchs ◽  
Christian Baues ◽  
...  
Keyword(s):  
Survival Data ◽  
Research Funding ◽  
Early Stage ◽  
Response Assessment ◽  
Early Response ◽  
Percentage Change ◽  
Response To Treatment ◽  
Deauville Score ◽  
Group A ◽  
Group B

Background: Metabolic tumor volume (MTV) measured by FDG-PET/CT is becoming established as an independent risk factor for treatment failure in Hodgkin lymphoma (HL). Moreover, response to treatment with novel agents including checkpoint inhibitors may be better reflected by a decrease in MTV than by currently used response criteria. Our aim was to evaluate the early response to first-line HL treatment with the PD-1 inhibitor nivolumab using MTV. Methods: The analysis set included 59 patients with newly diagnosed, early-stage unfavorable HL treated within the prospective, multicenter, open label, randomized, phase II NIVAHL trial of the German Hodgkin Study Group (GHSG). Patients in NIVAHL were randomized to receive either four double cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine (4x Nivo-AVD, group A, n=31) or a sequential therapy starting with 4x nivolumab monotherapy followed by 2xNivo-AVD and 2x AVD (group B, n=28). Early response to treatment was assessed at a 1st interim restaging after either 2x Nivo-AVD or 4x nivolumab. All NIVAHL patients who underwent PET at both initial staging and early response assessment, with images available to the central review panel for quantitative analysis before April 30th 2019, were included. MTV was calculated using a fixed SUV threshold of 4 for both staging and restaging. Results: Patient characteristics of the MTV analysis subset presented here did not differ in any relevant way from the overall NIVAHL trial population. Median age of the 59 patients was 27 years (range 18-57) with a female predominance (61%). All patients presented with stage II disease (IIB 27%) and ≥3 involved areas was the most common risk factor (75%) followed by elevated erythrocyte sedimentation rate (51%), extranodal disease (17%) and large mediastinal mass (14%). Mean MTV at initial staging was 124 ml (range 4 - 578 ml) and 177 ml (11 - 581 ml) in groups A and B, respectively. In both groups a marked decrease in MTV was observed at the 1st interim restaging (Figure 1): After 2x Nivo-AVD all patients in group A showed a reduction of MTV >80% (mean percentage change in MTV -99.8%). In group B a reduction of MTV >80% was observed in 26/28 patients (93%), while in 2/28 patients an increase <10% was observed (mean percentage change in MTV -91%; Figure 1). The mean residual MTV at interim restaging after 2x Nivo-AVD was 0.4 ml (range 0 - 8) in group A and 11 ml after 4x nivolumab in group B (range 0 - 176). The reduction of MTV was observed irrespective of initial MTV with a similar mean percentage change in patients above and below the median MTV in both groups. When applying the Deauville score, however, the number of patients presenting with a Deauville score ≥4 was higher in the group with an initial MTV above the median MTV than in the group where initial MTV lay below the median value. Using the Lugano criteria and a Deauville score of 4 or higher as cut-off for PET-positivity, early interim complete remission was observed in 81% of patients after 2xNivo-AVD, as compared to 51% after 4x nivolumab monotherapy. Further analyses regarding MTV and response at the 2nd and end-of-treatment restaging as well as survival data are not yet available due to limited follow-up. These data will be available at the time of presentation and shown at the meeting. Conclusions: Marked reductions of MTV demonstrate an excellent early efficacy for both 2x Nivo-AVD and 4x nivolumab as 1st-line therapy for early-stage unfavorable HL. The unexpectedly and previously unreported high MTV reduction with nivolumab monotherapy indicates a relevant potential of anti-PD1 mono- or debulking-therapy in the 1st-line treatment of early-stage unfavorable HL. Early interim response assessment based on MTV may help to identify HL patients treated with anti-PD1 antibodies in whom a significant reduction or even omission of chemotherapy could be considered. MTV appears to have the potential to accurately measure response to immune checkpoint inhibition. However, correlation of early MTV reduction with response at the end of treatment or with survival data is pending. Disclosures Borchmann: Novartis: Honoraria, Research Funding. Bröckelmann:Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding.

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