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Nintedanib plus mFOLFOX6 as second-line treatment of metastatic, chemorefractory colorectal cancer: The randomised, placebo-controlled, phase II TRICC-C study (AIO-KRK-0111).
Ettrich, TJ, Perkhofer, L, Decker, T, Hofheinz, RD, Heinemann, V, Hoffmann, T, Hebart, HF, Herrmann, T, Hannig, CV, Büchner-Steudel, P, et al
International journal of cancer. 2021;(6):1428-1437
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Abstract
Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor-a/-b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC-C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC-C is a randomised controlled, double-blinded, phase II trial in mCRC patients that received a first-line non-oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1-d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty-three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32-1.30; P = .2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48-2.23; P = .9387; DCR: F + P: 50% vs F + N: 66,7%; P = .2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second-line therapy of mCRC.
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Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S.
Di Bartolomeo, M, Raimondi, A, Cecchi, F, Catenacci, DVT, Schwartz, S, Sellappan, S, Tian, Y, Miceli, R, Pellegrinelli, A, Giommoni, E, et al
Tumori. 2021;(2):150-159
Abstract
BACKGROUND No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III β-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.
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Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance).
Innocenti, F, Sibley, AB, Patil, SA, Etheridge, AS, Jiang, C, Ou, FS, Howell, SD, Plummer, SJ, Casey, G, Bertagnolli, MM, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(1):267-275
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Abstract
PURPOSE Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405. EXPERIMENTAL DESIGN Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models. RESULTS The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10-6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10-6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced. CONCLUSIONS This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.
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A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab-resistant head and neck cancer: The MAESTRO study.
Seiwert, TY, Kochanny, S, Wood, K, Worden, FP, Adkins, D, Wade, JL, Sleckman, BG, Anderson, D, Brisson, RJ, Karrison, T, et al
Cancer. 2020;(14):3237-3243
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Abstract
BACKGROUND Patients with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) have poor outcomes. This study hypothesized that dual blockade of mammalian target of rapamycin and epidermal growth factor receptor (EGFR) would overcome cetuximab resistance on the basis of the role of phosphoinositide 3-kinase signaling in preclinical models of EGFR resistance. METHODS In this multicenter, randomized clinical study, patients with recurrent/metastatic HNSCC with documented progression on cetuximab (in any line in the recurrent/metastatic setting) received 25 mg of temsirolimus weekly plus cetuximab at 400/250 mg/m2 weekly (TC) or single-agent temsirolimus (T). The primary outcome was progression-free survival (PFS) in the TC arm versus the T arm. Response rates, overall survival, and toxicity were secondary outcomes. RESULTS Eighty patients were randomized to therapy with TC or T alone. There was no difference for the primary outcome of median PFS (TC arm, 3.5 months; T arm, 3.5 months). The response rate was 12.5% in the TC arm (5 responses, including 1 complete response [2.5%]) and 2.5% in the T arm (1 partial response; P = .10). Responses were clinically meaningful in the TC arm (range, 3.6-9.1 months) but not in the T-alone arm (1.9 months). Fatigue, electrolyte abnormalities, and leukopenia were the most common grade 3 or higher adverse events and occurred in less than 20% of patients in both arms. CONCLUSIONS The study did not meet its primary endpoint of improvement in PFS. However, TC induced responses in cetuximab-refractory patients with good tolerability. The post hoc observation of activity in patients with acquired resistance (after prior benefit from cetuximab monotherapy) may warrant further investigation.
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FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
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Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.
Llovet, JM, Decaens, T, Raoul, JL, Boucher, E, Kudo, M, Chang, C, Kang, YK, Assenat, E, Lim, HY, Boige, V, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;(28):3509-16
Abstract
PURPOSE Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.
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New pharmacological developments in the treatment of hepatocellular cancer.
Gusani, NJ, Jiang, Y, Kimchi, ET, Staveley-O'Carroll, KF, Cheng, H, Ajani, JA
Drugs. 2009;(18):2533-40
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and fourth leading cause of cancer death worldwide. The survival for patients with advanced HCC is extremely poor. This is largely attributed to the lack of effective screening methods, advanced stage at presentation, limited utility of surgical intervention and ineffective medical therapy. Over the past 30 years, many conventional cytotoxic agents have been tested and have failed to confer a survival benefit. Recently, sorafenib, a multi-tyrosine kinase inhibitor, was approved by the US FDA as first-line therapy in HCC as the first agent demonstrating survival benefit in this disease. Although the survival benefit demonstrated by sorafenib is moderate, molecular targeted therapy has brought new hope in the management of HCC.
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Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study.
Ryan, CJ, Halabi, S, Ou, SS, Vogelzang, NJ, Kantoff, P, Small, EJ
Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;(7):2030-7
Abstract
PURPOSE Adrenal androgens activate the androgen receptor and stimulate prostate cancer growth. Ketoconazole is used as an inhibitor of adrenal androgen synthesis in men with androgen-independent prostate cancer. This study analyzes the relationship between pretreatment androgen levels and outcome following ketoconazole treatment. EXPERIMENTAL DESIGN Baseline levels of three adrenal androgens (androstenedione, dehydroepiandrostenedione, and dehydroepiandrostenedione-sulfate) and testosterone were measured. Regression models (logistic and proportional hazard) were used to assess the prognostic significance of these levels in predicting overall survival and prostate-specific antigen (PSA) response defined by Consensus Criteria. RESULTS In 103 patients with available levels, PSA response rate was 28% and median response duration was 4.8 months. The median baseline androstenedione level was 0.64 ng/mL and was 0.88 ng/mL versus 0.53 ng/mL for those with and without a PSA response, respectively (P = 0.034). In univariate analysis, elevation of baseline androstenedione levels was predictive of PSA response [odds ratio, 2.26; 95% confidence interval (95% CI), 1.03-4.96; P = 0.043]. In multivariate analysis, both the uppermost and the middle tertile of baseline androstenedione level were associated with an improved overall survival compared with those in the lower tertile (hazard ratio, 0.59; 95% CI, 0.36-0.98; P = 0.40; hazard ratio, 0.53; 95% CI, 0.32-0.90; P = 0.018, respectively). A linear correlation was observed among all androgen levels. CONCLUSIONS Higher androstenedione levels predict likelihood of response to ketoconazole and improved survival compared with patients with lower levels. These data suggest that therapy with ketoconazole is less effective in patients with low levels of androgen at baseline.
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Relapse of acute promyelocytic leukemia with PML-RARalpha mutant subclones independent of proximate all-trans retinoic acid selection pressure.
Gallagher, RE, Schachter-Tokarz, EL, Zhou, DC, Ding, W, Kim, SH, Sankoorikal, BJ, Bi, W, Livak, KJ, Slack, JL, Willman, CL
Leukemia. 2006;(4):556-62
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Abstract
Relapse of acute promyelocytic leukemia (APL) following all-trans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARalpha, but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the nonmutant pretreatment APL cell population by a PML-RARalpha mutant subclone. Two patients relapsed in proximity of ATRA treatment; however, in four patients there was a 6-48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested > or = 3 months before relapse at > or = 1 in 10(2) (10(-2)) sensitivity. In one patient, a functionally weak mutation was detected at 10(-4) sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARalpha mutant subclones and suggest that APL subclones harboring PML-RARalpha mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/survival advantage.