Assessment of a novel immunological biomarker SNP panel from a phase III trial of Bacillus Calmette-Guérin (BCG) adjuvant treatment in stage III melanoma patients.

2519 Background: Melanoma is an immunogenic cancer, whereby immunotherapy in stage III patients has shown some success. However, there are no effective immune biomarker tests to identify patients most likely to benefit from immunotherapy. BCG (Bacillus Calmette-Guérin) therapy is a form of immunomodulation. The objective was to assess the predictive clinical effect of a single nucleotide polymorphism(SNP) immune biomarker panel in stage III resected melanoma patients treated with BCG. Methods: MMAIT-III was a phase III prospective randomized international multicenter trial of BCG+melanoma vaccine vs BCG+placebo after complete resection of stage III melanoma patients (NIH #NCT00052130). 120/292 patients with palpable disease treated with resection and BCG+placebo had lymphocytes(PBL) from USA sites available for analysis. Endpoints were overall survival(OS) and disease-free survival(DFS), with a 10-yr follow-up. PBL DNA was assessed by MassARRAY MALDI-TOF for 28 SNPs associated with macrophage/monocyte-related immune response pathways to BCG/tuberculosis. A pilot study(n=34) from phase II BCG trial confirmed presence of the SNPs. A logistic regression determined a SNP score, and a cutoff was identified by ROC and used as a predictor in a Cox proportional hazard model in a verification study(n=120). Results: 9 SNPs in 6 genes had prognostic value: NRAMP1 and CD14, 18, 195, 209, 282. The 9-SNP panel distinguished patients in 2 survival groups(OS median 4.9-yrs vs 1.5-yrs, p=0.0008), AUC=0.77. SNP biomarker positivity demonstrates significant association with 10-yr OS (59.7% vs 15.7%; HR 1.97, CI 1.11-3.50, p=0.018) and DFS (47.2% vs 12.3%; HR 2.35, CI 1.43-3.92, p=0.0007). In Cox model, the SNP panel was a significant predictor of OS(HR 2.69, CI 1.56-9.00, p=0.0052) and DFS(HR 2.33, CI 1.49-5.16, p=0.0003) independent of known melanoma prognostic factors. Conclusions: The 9-SNP panel identified patients with an exceptionally favourable disease outcome, and may represent a stratifying predictive SNP panel for identifying patients that are inherently responsive to BCG therapy and potentially other immunomodulating agents in melanoma.

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Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.18_suppl.lba1 ◽

2017 ◽

Vol 35 (18_suppl) ◽

pp. LBA1-LBA1 ◽

Cited By ~ 19

Author(s):

Qian Shi ◽

Alberto F. Sobrero ◽

Anthony Frank Shields ◽

Takayuki Yoshino ◽

James Paul ◽

...

Keyword(s):

Cox Model ◽

Disease Free Survival ◽

Standard Of Care ◽

Pooled Analysis ◽

Phase Iii ◽

Stage Iii ◽

Differential Outcomes ◽

Phase Iii Trials ◽

Stratified Cox Model

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

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Prognostic value of tumor deposits for disease free survival in patients with stage III colon cancer: A post hoc analysis of IDEA France phase III trial (PRODIGE-GERCOR).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3519 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3519-3519

Author(s):

Jean Francois Delattre ◽

Romain Cohen ◽

Julie Henriques ◽

Antoine Falcoz ◽

Jean-François Emile ◽

...

Keyword(s):

Colon Cancer ◽

Cox Model ◽

Multivariable Analysis ◽

Disease Free Survival ◽

Tnm Staging ◽

Phase Iii ◽

Stage Iii ◽

Free Survival ◽

Stage Iii Colon Cancer ◽

Disease Free

3519 Background: Tumor deposits (TDs) are isolated tumor foci in the pericolic, perirectal or mesocolic fat without residual lymph node (LN) tissue. TDs seem to impact the prognosis of stage III colon cancer (CC) patients (pts) but are only considered in TNM staging in the absence of LN metastases (LNM). We aimed at evaluating the prognosis value for disease free survival (DFS)of TDs in International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France phase III study (NCT00958737) that compared 3 versus 6 months of adjuvant FOLFOX or CAPOX for stage III CC pts. Methods: All pathological reports of pts included in IDEA France trial were retrospectively analyzed. DFS according to the presence or absence of TDs was evaluated using Kaplan-Meier estimator. Multivariable Cox model analysis was performed to evaluate the association between TDs and DFS. This analysis did not included immunohistochemical biomarkers. Results: Among the 2022 pts included in IDEA France study, 1942 (96%) were analyzed. 80 pts were excluded: no pathological report (n = 68), pts without treatment (n = 12). TDs were found in 184 pts (9.47%), of whom 74 with N1a/b (40%), 55 with N1c (30%) and 55 with N2 LN stage (30%). All characteristics were similar according to the presence of TDs, except for tumor/node (TN) stage (T4 and/or N2 are more frequent in pts with TDs; p = .0046). The 3-year DFS rates were 65.59% [95% confidence interval (95%CI) 58.04-72.12] and 74.71% [95%CI 72.57-76.71] for pts with and without TDs, respectively (p = 0.0079). In multivariable analysis, TDs were associated with higher risk of recurrence or death (hazard ratio (HR) = 1.36, 95%CI 1.05-1.75, p = .0201), as well as T4 and/or N2 (HR = 2.21, 95%CI 1.03-1.59, p < .001), 3 months of adjuvant treatment (HR = 1.29, 95%CI 1.09-1.52, p = .0029), obstruction (HR = 1.28, 95%CI 1.03-1.59, p = .0233) and male (HR = 1.24, 95%CI 1.04-1.46, p = .0151). Adding TDs count to the LNM count, 35 out of 1454 N1a/b/c CC pts (2.4%) were reclassified as N2 and experienced worse 3 years DFS than confirmed N1 CC pts (p = .0151). Conclusions: TD is an independent and valuable prognostic factor for DFSin stage III CC pts and should be considered whatever the LNM status.

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Genetic Variants in Immune Related Genes as Predictors of Responsiveness to BCG Immunotherapy in Metastatic Melanoma Patients

Cancers ◽

10.3390/cancers13010091 ◽

2020 ◽

Vol 13 (1) ◽

pp. 91

Author(s):

Romela Irene Ramos ◽

Misa A. Shaw ◽

Leland Foshag ◽

Stacey L. Stern ◽

Negin Rahimzadeh ◽

...

Keyword(s):

Immune Responses ◽

Disease Free Survival ◽

Phase Iii ◽

Stage Iii ◽

Immune Gene ◽

Nucleotide Polymorphisms ◽

Predictive Tool ◽

Immune Genes ◽

Ajcc Stage ◽

Melanoma Patients

Adjuvant immunotherapy in melanoma patients improves clinical outcomes. However, success is unpredictable due to inherited heterogeneity of immune responses. Inherent immune genes associated with single nucleotide polymorphisms (SNPs) may influence anti-tumor immune responses. We assessed the predictive ability of 26 immune-gene SNPs genomic panels for a clinical response to adjuvant BCG (Bacillus Calmette-Guérin) immunotherapy, using melanoma patient cohorts derived from three phase III multicenter clinical trials: AJCC (American Joint Committee on Cancer) stage IV patients given adjuvant BCG (pilot cohort; n = 92), AJCC stage III patients given adjuvant BCG (verification cohort; n = 269), and AJCC stage III patients that are sentinel lymph node (SLN) positive receiving no immunotherapy (control cohort; n = 80). The SNP panel analysis demonstrated that the responder patient group had an improved disease-free survival (DFS) (hazard ratio [HR] 1.84, 95% CI 1.09–3.13, p = 0.021) in the pilot cohort. In the verification cohort, an improved overall survival (OS) (HR 1.67, 95% CI 1.07–2.67, p = 0.025) was observed. No significant differences of SNPs were observed in DFS or OS in the control patient cohort. This study demonstrates that SNP immune genes can be utilized as a predictive tool for identifying melanoma patients that are inherently responsive to BCG and potentially other immunotherapies in the future.

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S-100B Concentrations Predict Disease-Free Survival in Stage III Melanoma Patients

Annals of Surgical Oncology ◽

10.1245/s10434-009-0629-8 ◽

2009 ◽

Vol 16 (12) ◽

pp. 3455-3462 ◽

Cited By ~ 34

Author(s):

S. Kruijff ◽

E. Bastiaannet ◽

A. C. Muller Kobold ◽

R. J. van Ginkel ◽

A. J. H. Suurmeijer ◽

...

Keyword(s):

Disease Free Survival ◽

Stage Iii ◽

Free Survival ◽

Melanoma Patients ◽

Stage Iii Melanoma ◽

Disease Free

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Erratum to: S-100B Concentrations Predict Disease-Free Survival in Stage III Melanoma Patients

Annals of Surgical Oncology ◽

10.1245/s10434-009-0828-3 ◽

2010 ◽

Vol 18 (S3) ◽

pp. 331-331

Author(s):

S. Kruijff ◽

E. Bastiaannet ◽

A. C. Muller Kobold ◽

R. J. van Ginkel ◽

A. J. H. Suurmeijer ◽

...

Keyword(s):

Disease Free Survival ◽

Stage Iii ◽

Free Survival ◽

Melanoma Patients ◽

Stage Iii Melanoma ◽

Disease Free

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Final DFS results of the SCOT study: An international phase III randomised (1:1) non-inferiority trial comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3502 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3502-3502 ◽

Cited By ~ 2

Author(s):

Timothy Iveson ◽

Rachel Kerr ◽

Mark P. Saunders ◽

Niels Henrik Hollander ◽

Josep Tabernero ◽

...

Keyword(s):

Colorectal Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Cox Model ◽

Disease Free Survival ◽

Patient Choice ◽

Stage Ii ◽

Phase Iii ◽

Stage Iii ◽

Duration Of Treatment

3502 Background: Six months of oxaliplatin-based treatment has been the mainstay of adjuvant chemotherapy for colorectal cancer for the last 13 years. Neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. A shorter duration of treatment would save patients significant toxicity/time and substantially reduce the costs of the drug, its administration, and treatment of adverse effects. Methods: SCOT is a non-inferiority randomised study designed to determine whether 3 months of adjuvant chemotherapy with OxMdG or Xelox (physician/patient choice) in Stage III/high risk Stage II colorectal cancer is as effective as 6 months treatment. Non-inferiority was determined to be a maximum 2.5% fall in 3-year disease-free survival (DFS) on the 3 month arm (from 78% on the 6 month arm) corresponding to a hazard ratio upper limit of 1.13. The study was designed with 90% power at the 2.5% 1-sided level of statistical significance and aimed to recruit 9500 patients to observe 2,750 DFS events (relapses/deaths/new colorectal cancers). Analysis used a Cox model adjusted for study minimisation factors. Results: 6088 patients (60% male, median age 65) with Stage III/high risk Stage II cancers of the colon or rectum were randomised between 27th March 2008 and 29th November 2013. The arms were balanced for clinical and pathological factors. Intended treatment was OxMdG for 1981 and Xelox for 4107 patients. There were 1469 DFS events (734 in 3 month arm and 735 in 6 month arm) giving the study 66% power. 3 year DFS was 76.8% (se = .8%) for the 3 month arm and 77.4% (se = .8%) for the 6 month arm (HR 1.008, 95% CI 0.910-1.117, test for non-inferiority p = 0.014). Non-inferiority appeared stronger for Xelox than OxMdG (test for heterogeneity, p = .059). Results will be shown broken down by stage, site, age, gender and achieved duration of treatment. Conclusions: The SCOT study has shown that 3 months adjuvant treatment is not inferior to 6 months treatment. However the SCOT study is part of the IDEA consortium and the results from the 6 studies in the IDEA consortium addressing the same duration question will also be presented at ASCO 2017. Clinical trial information: ISRCTN59757862.

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Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3501 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3501-3501 ◽

Cited By ~ 16

Author(s):

Timothy Iveson ◽

Alberto F. Sobrero ◽

Takayuki Yoshino ◽

Ioannis Sougklakos ◽

Fang-Shu Ou ◽

...

Keyword(s):

High Risk ◽

Cox Model ◽

Statistical Significance ◽

Disease Free Survival ◽

Pooled Analysis ◽

Stage Ii ◽

Phase Iii ◽

Stage Iii ◽

Primary Analysis ◽

Nodal Harvest

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.

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