Pharmacogenomic analysis of the triplet combination of gemcitabine, oxaliplatin, and cetuximab as salvage therapy for metastatic colorectal cancer (mCRC) patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14531-e14531
Author(s):  
A. Hernandez ◽  
E. Bandres ◽  
J. Rodriguez ◽  
N. Bitarte ◽  
N. Ramirez ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Germ Line ◽  
Univariate Analysis ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Median Number ◽  
Rank Test ◽  
Exact Test ◽  
Combination Methods

e14531 Background: We have previously reported that biweekly gemcitabine-based therapy was active in pretreated mCRC pts (De la Cruz et al, ASCO GI 2008, abstr 377). We aimed to investigate whether germ line polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: We evaluated SNPs of genes involved in gemcitabine metabolism (CDA, dCDK, RRM1, DCTD, SLC28A1), DNA repair (XRCC1, XRCC 3, ERCC1, XPD) and two IgG Fcγ R polymorphisms (Fcγ RIIa- H131R and Fcγ RIIIa-V158F), reported to be predictive of cetuximab-based therapy, even in K-ras mutated pts. Whole blood was collected and DNA extracted from peripheral lymphocytes using a DNA isolation Kit (Qiagen, CA). Polymorphisms were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Clinical response was evaluated according to RECIST criteria. Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples of 35 out of 39 enrolled pts were tested for genomic analysis. Patient‘s characteristics are as follows; M/F: 26/13, median age: 59 years, median number of prior chemotherapy lines: 2 (1–4), Köhne risk groups; low: 8 pts, intermediate: 18 pts, high: 13 pts. After a median follow-up of 20 months, median progression-free survival (PFS) is 6.7 months (95% CI; 5.2–8.3) and median overall survival 15.4 m (95% CI; 14.7–16.1). Overall response rate (ORR) was 53.8%. RRM1 R284R SNPs (p=0.06), T741T (p=0.02) and RRM1–524CT (p=0.04) were linked to clinical responsiveness. All pts possessing 2 or 3 favourable RRM1 SNPs responded. ORR was 53.3% for pts with no favourable SNPs versus 85% for pts with any favourable SNP (p=0.04). ORR was also significantly higher in pts with any histidine allele in the Fcγ RIIa polymorphism (93% vs. 60%, p=0.034). Median PFS was adversely affected in pts harbouring no favourable RRM1 SNPs (4.2m versus 6.7 months, p=0.019) and in those pts with homozygous Fcγ RIIa-131R allele (4.4 vs. 7.5 months, p=0.007). Conclusions: Polymorphic variants of RRM1 and Fcγ RIIa may play a key role in the efficacy of gemcitabine and cetuximab-based therapy for mCRC pts. No significant financial relationships to disclose.

Predictive value of Ile105Val polymorphism of the gluthatione-S-transferase P1 in patients with metastatic colorectal cancer (m CRC) treated with the triplet combination of irinotecan, oxaliplatin, and capecitabine

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
R. N. Zarate ◽  
J. Rodriguez ◽  
E. Bandres ◽  
N. Bitarte ◽  
N. Ramirez ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Response Rate ◽  
Strong Predictor ◽  
Univariate Analysis ◽  
Haematological Toxicity ◽  
Median Number ◽  
Rank Test ◽  
Exact Test ◽  
Combination Methods ◽  
Gstp1 Ile105val

2544 Background: Several phase I/II trials have shown that the triplet combination of oxaliplatin, irinotecan and capecitabine is a feasible and active in solid tumors. We aimed to investigate whether germline polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: The following genetic polymorphisms were analysed: glutathione S-transferase (GSTP1-Ile105Val, GSTT1 and GSTM1 deletion), TYMS (TS-5´UTR 2R/3R; TS-5´G/C; TS-3´UTR 6-bp deletion), MTHFR 1298A>C, UGT1A1, ERCC1, XPD. Polymorphisms from peripheral lymphocytes were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples for 63 out of 72 prospectively enrolled pts were tested for genomic analysis. Median age was 57 (32–78), median ECOG 1(0–2), median number of cycles administered 6 (1–13), median number of metastatic sites was 1 (1–4). M/F: 50/22. Risk according to Köhne classification was low (52.8% of pts), intermediate (26.4%) and high (8.3%). Overall response rate (ORR) was 62.5%. Median progression-free survival (PFS) was 9.87 months (95% CI; 7.6–12) and median overall survival was 24.6 months (95% CI; 19.5–29.7). A significant association was observed between MTHFR 1298A>C and haematological toxicity, with C/C genotype pts being at higher risk of grade 3–4 neutropenia (50% vs. 28%, p = 0.035) and leucopenia (50% vs. 15%, p = 0.04). Heterozygous and homozygous GSTP-105Val showed a significant superior response rate (80%) compared to only 40% in pts harbouring the GSTP1–105Ile/Ile genotype (p = 0.008, Fisher´s exact test). PFS was also adversely affected in pts with GSTP1–105Ile/Ile (5.2 months vs. 12.3 months in those pts with at least one GSTP1–105Val allele, p = 0.001). In the multivariate analysis, the relative risk for progression was 3.4 (95% CI; 1.3–9.1) for the GSTP1–105Ile/Ile genotype (p = 0.01). Conclusions: The GSTP1-Ile105Val polymorphism is a strong predictor of clinical outcome for XELOXIRI therapy in mCRC pts. No significant financial relationships to disclose.

Association of HER2 and IGF1 germline polymorphisms with outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR) with or without cetuximab (CB): The EPIC experience.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3615-3615 ◽  
Author(s):  
Dongyun Yang ◽  
Pierre Oliver Bohanes ◽  
Wu Zhang ◽  
Christopher Harbison ◽  
Ovidiu C. Trifan ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Second Line ◽  
Exact Test ◽  
Fisher's Exact Test ◽  
Fisher’S Exact Test

3615 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated 6 functional germline polymorphisms involved in the IGF1 and HER2 for their potential role as molecular predictors of clinical outcome in pts treated in the EPIC study. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the EPIC trial. Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Univariate analysis (Fisher's exact test for RR; log-rank test for PFS and OS) was performed to examine associations between polymorphisms and clinical outcome. Multivariate analysis (Logistic regression or Cox regression model) was conducted to control baseline patient characteristics and treatment. Results: 186 pts with available samples were treated either with IR/CB (arm A, 84 pts) or IR alone (arm B, 102 pts). Median age was 59 yrs (range 34-85yrs) for arm A and 61 yrs (range 25-90 yrs) for arm B. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS for arm A was 3.0 months (95%CI 2.4- 4.1 months) vs 2.7 months (95%CI 2.2-2.9 months) for arm B; median OS was 9.3 months (95%CI 7.1-21.1 months) for arm A vs 12.3 months (95%CI 10.4- 17.9 months) for arm B. KRAS mutation status was not significantly associated with outcome in our patient cohort. We found that HER2 rs 1136201 was significantly associated with response (RR: AA 6.5%, AG 12.5%, and GG 27.3%, Fisher’s exact test p=0.045). IGF1 rs 2946834 was significantly associated with PFS in both univariate and multivariate analyses (median PFS was 2.8 months in patients with CC or CT vs 1.8 months in patients with TT; log-rank p=0.009; Wald test p=0.008). Conclusions: Our study suggests the prognostic value of polymorphisms in the IGF1 and HER2-pathway in mCRC pts treated with IR± CB. Prospective validation of these findings in clinical trials is warranted.

Quality-of-life (QoL) in RANGE: A phase 3 study of ramucirumab (RAM) plus docetaxel (DOC) versus placebo (P) plus DOC in platinum-refractory locally advanced or metastatic urothelial carcinoma (UC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 419-419 ◽  
Author(s):  
Andrea Necchi ◽  
Hiroyuki Nishiyama ◽  
Nobuaki Matsubara ◽  
Jae-Lyun Lee ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Median Number ◽  
Rank Test ◽  
Point Change ◽  
Exact Test ◽  
Eortc Qlq C30 ◽  
Platinum Refractory ◽  
Eortc Qlq

419 Background: RAM + DOC in RANGE (NCT02426125) improved progression free survival (hazard ratio [HR] = 0.757) with a higher objective response rate (24.5% vs 14%) and an acceptable safety profile (Petrylak, et al Lancet 2017). QoL was a secondary objective. Methods: Patients (pts) whose UC progressed following platinum-based therapy were randomized to receive RAM (10 mg/kg) + DOC (75 mg/m2) or P + DOC on Day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity with a maximum of 10 cycles for DOC. Pts completed the EORTC QLQ-C30 (v3) prior to each cycle & at the 30-day follow up visit. QoL scales were analyzed for: 1) rates of improved/stable scores (compared with Fisher’s exact test) & 2) time to sustained deterioration (TtD), defined as randomization to first worsening with no subsequent non-worsened assessment (compared with unstratified log-rank test). A ≥10 point change (on 100-point scale) was deemed clinically meaningful. Results: 530 pts were randomized. 254/263 (97%) RAM-DOC & 260/267 (97%) P-DOC pts provided baseline (BL) QoL data & ≥85% for post-BL, on-therapy assessments. Median number of cycles was 4 for RAM-DOC & 3 for P-DOC. Mean BL scores were similar between arms & indicated greatest impairment for global QoL, fatigue, pain, & insomnia. For all scales, rates of improved/stable scores were not different, except for pain at Cycles 4 & 7 where rates were higher for RAM-DOC (p < 0.05). Relative to other QoL scales, pain generally had highest rates of improved scores in both arms (14-25% for RAM-DOC & 8-24% for P-DOC for Cycles 1-4). In a post hoc analysis, Cycles 1-4 rates of improved pain scores were 31-32% for RAM-DOC & 14-26% for P-DOC in tumor responders, but 17-29% for RAM-DOC & 16-28% for P-DOC in pts with stable disease. For TtD, 14/15 QoL scales had HRs < 1, indicating similar or numerically longer TtD in QoL for RAM-DOC (HRs 0.67- 1.06; all 95% confidence intervals included 1). Conclusions: The addition of RAM to DOC for platinum-refractory UC pts did not adversely impact QoL relative to P-DOC. Trends in improved TtD and improved rates of pain associated with tumor response favored RAM-DOC. Clinical trial information: NCT02426125.

Polymorphisms correlated with the clinical outcome of locally advanced or metastatic colorectal cancer patients treated with ALIRI vs. FOLFIRI

Pteridines ◽  
2013 ◽  
Vol 24 (1) ◽  
pp. 69-79 ◽  
Author(s):  
Ana Barcelos ◽  
Elisa Giovannetti ◽  
Robert de Jonge ◽  
Mina Maftouh ◽  
Pieter Griffioen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Outcome ◽  
Metastatic Colorectal Cancer ◽  
Topoisomerase I ◽  
Univariate Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Copy Number Variations ◽  
Rank Test ◽  
Functional Polymorphisms

AbstractLeucovorin-modulated 5-fluorouracil (5-FU) plus irinotecan (FOLFIRI) is the most common treatment of metastatic colorectal cancer (CRC). 5-FU inhibits thymidylate synthase (TS) and irinotecan topoisomerase I, leading to inhibition of DNA replication and repair. FOLFIRI efficacy suggested that other TS inhibitors might synergize with irinotecan, and Phase I/II studies for second-line treatment showed promising results of combinations with the multitargeted antifolate pemetrexed (PMX), which exerts its effects primarily via TS inhibition. However, a randomized Phase II trial of PMX + irinotecan (ALIRI) showed similar efficacy and safety, but significantly shorter progression-free survival (PFS) compared with FOLFIRI in locally advanced or metastatic CRC. In our previous aCGH study, we evaluated genome-wide copy number variations, whereas in the current study we evaluated relationships between functional polymorphisms and PFS. Candidate polymorphisms were studied by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) (TSER-2R/3R) or Taqman-PCR (MTHFR-1958G>A, MTR-2756A>G, MTHFR-1298A>C, SHMT1-1420C>T, ATIC-347C>G, AMPD-134C>T, MTRR-66A>G and SLC-19A180G>A) in 84 patients (40 FOLFIRI, 44 ALIRI). The Kaplan-Meier method was used to plot PFS, and the log-rank test to compare curves. At univariate analysis the homozygous variants of both MTR-2756A>G and SHMT1-1420C>T were associated with significantly shorter PFS. Conversely, a significantly longer PFS (7.3 months) was observed when ATIC-347C>G CC+CG genotypes were grouped vs. GG. At multivariate analysis the genotypes MTR-2756A>G AA+AG, SHMT1-1420C>T TT+CT and ATIC-347C>G CC+CG emerged as significant predictors for PFS. Because MTR, SHMT1 and ATIC are all involved in folate pathways, we further explored the effect of a combination of their risk genotypes on PFS, showing that patients carrying two risk genotypes had a significantly shorter PFS (3.9 months, p<0.001). The correlations of polymorphisms in genes with clinical outcome underscore the importance of a candidate gene-based approach. Ultimately, the validation of the role of these polymorphisms in prospective multicenter trials might optimize currently available treatments in selected CRC patients (e.g., FOLFIRI) or PMX-based treatments in other tumor types.

Pharmacogenomic analysis of a randomized phase II trial (BOND 2) of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4128-4128 ◽  
Author(s):  
W. Zhang ◽  
D. Yang ◽  
M. Capanu ◽  
E. Hollywood ◽  
M. Lue-Yat ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Median Survival ◽  
Phase Ii ◽  
Tumor Response ◽  
Univariate Analysis ◽  
Rank Test ◽  
Exact Test ◽  
Metabolism Pathway ◽  
Neuropilin 1 ◽  
Angiogenesis Pathway

4128 Background: Phase II CBI VS CB trial has shown that bevacizumab added the efficacy of cetuximab and cetuximab/irinotecan in irinotecan-refractory bevacizumab-naïve CRC patients. We tested the germline polymorphisms involved in angiogenesis pathway(VEGF, IL-8, TGF-β), EGFR pathway (EGFR, COX-2, CyclinD1,E-cadherin,FCGR2A,3A), DNA repair pathway(ERCC1, XRCC1, XPD) and drug metabolism pathway (GSTP1, UGT1A1) to evaluate their association with clinical outcome. Here we expand our gene polymorphisms data involving EGFR pathway (EGF, FCGR2B, Survivin, ADAMS10/17), Angiogenesis pathway (Neuropilin-1, HIF-1, Tissue factor) and irinotecan metabolism pathway(ABCB1,OATPC). Methods: Genomic DNA was extracted from blood samples. 65 out of 81 patients enrolled in the BOND 2 trial were available for molecular correlates study. these 65 patients include 44 men, 21 women, median age 58 years (range 24–86). Patients received either with CBI (n=31) (Arm A) or with CB (n=34) (Arm B). In Arm A, 12 pts (43%) had PR, the median TTP was 7.1 months, and the median survival was 18.0 months. In Arm B, 9 pts (27%) had PR, the median TTP was 4.6 months, and the median survival was 10.3 months. PCR-RFLP based technique was used to determine polymorphisms. Univariate analysis (Fisher’s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: For Arm B, we found significant associations between HIF-1 polymorphism and tumor response (P=0.017), between HIF-1, FCGR2B polymorphisms and TTP, and between OATPC polymorphism and OS (P values < 0.05). For Arm A, we found a trend in association between EGF polymorphism and tumor response (P=0.08). Conclusions: These data suggest that germline polymorphisms may be potential molecular markers for clinical outcome for patients with mCRC treated with CBI or CB. Prospective studies are needed to confirm these preliminary findings. [Table: see text]

Chemoradiotherapy is an Alternative Choice for Patients with Primary Mediastinal Seminoma

2021 ◽  
Author(s):  
Yirui Zhai ◽  
Bo Chen ◽  
Xiaoli Feng ◽  
Kan Liu ◽  
Shulian Wang ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Rank Test ◽  
Clinicopathologic Characteristics ◽  
Cancer Specific Survival ◽  
Adjacent Structures ◽  
Significant Difference ◽  
Mediastinal Seminoma ◽  
Alternative Choice

Abstract Background: The low incidence of primary mediastinal seminomas has precluded the development of clinical trials on mediastinal seminomas. We investigated the clinicopathologic characteristics, prognosis of patients with primary mediastinal seminomas as well as the efficiency of nonsurgical treatments compared with treatments containing surgery.Methods: We retrospectively collected data on the clinicopathologic characteristics, treatments, toxicities, and survival of 27 patients from a single center between 2000 and 2018. Patients were divided into two groups according to whether they received operation. Survivals were assessed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test.Results: The median age was 28 (13-63) years. The most common symptoms were chest pain (29.6%), cough (25.9%), and dyspnea (22.2%). There were 13 and 14 patients in surgery and non-surgery group. Patients in the non-surgical group were more likely to be with poor performance scores (100% vs.76.9%) and disease invaded to adjacent structures(100% vs.76.9%) especially great vessels(100% vs.46.2%).The median follow-up period was 32.23 (2.7-198.2) months. There was no significant difference of overall survival (5-year 100% vs 100%), cancer-specific survival (5-year 100% vs.100%), local regional survival (5-year 91.7% vs.90.0%, p=0.948) , distant metastasis survival (5-year 100.0% vs. 90.9%, p=0.340) and progression-free survival (82.5% vs.90.0%, p=0.245) between patients with and without surgery. Conclusions: Primary mediastinal seminoma was with favorable prognosis, even though frequently invasion into adjacent structures brings difficulties to surgery administration. Chemoradiotherapy is an alternative treatment with both efficacy and safety.

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21032-e21032
Author(s):  
Xuanzong Li ◽  
Linlin Wang
Keyword(s):  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Exact Test ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Tumor Mutational Burden ◽  
The Difference ◽  
Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

Single-arm, phase 2 study of regorafenib plus nivolumab in patients with mismatch repair-proficient (pMMR)/microsatellite stable (MSS) colorectal cancer (CRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3560-3560
Author(s):  
Marwan Fakih ◽  
Kanwal Pratap Singh Raghav ◽  
David Z. Chang ◽  
Johanna C. Bendell ◽  
Timothy Larson ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Progression Free Survival ◽  
Maculopapular Rash ◽  
Median Number ◽  
North American Population ◽  
Immunomodulatory Activity ◽  
Multikinase Inhibitor ◽  
Primary Tumor Site ◽  
Combination Methods ◽  
Biomarker Analysis

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 341-341
Author(s):  
Matthew D Tucker ◽  
Katy Beckermann ◽  
Kristin Kathleen Ancell ◽  
Kerry Schaffer ◽  
Renee McAlister ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Progression Free Survival ◽  
Rank Test ◽  
Cancer Center ◽  
Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

Impact of tumor site on the prognosis of small bowel adenocarcinoma

2019 ◽  
Vol 105 (6) ◽  
pp. 524-528 ◽  
Author(s):  
Rosa Falcone ◽  
Adriana Romiti ◽  
Marco Filetti ◽  
Michela Roberto ◽  
Riccardo Righini ◽  
...  
Keyword(s):  
Small Bowel ◽  
Clinical Outcome ◽  
Primary Tumor ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Rank Test ◽  
Small Bowel Adenocarcinoma ◽  
Tumor Site ◽  
Primary Tumor Site ◽  
Early Stage Disease

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution. Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis. Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P=0.09). Primary tumor site and stage were independent predictors of OS. Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

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