Context Venous thromboembolism is one of the leading causes of morbidity and mortality in patients with cancer. Concerns have arisen regarding the risk of venous thromboembolism with the novel antiangiogenic agent bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial. Objective To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, a systematic review and meta-analysis of published randomized controlled trials was performed. Data Sources The databases of PubMed and Web of Science were searched for articles published in the English language from January 1966 until January 2008 and abstracts presented at American Society of Clinical Oncology conferences held between January 2000 and January 2008 were searched to identify relevant clinical trials. Study Selection and Data Extraction Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab and data on venous thromboembolism were available. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Data Synthesis A total of 7956 patients with a variety of advanced solid tumors from 15 randomized controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively. Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with an RR of 1.33 (95% CI, 1.13-1.56; P  Conclusion The use of bevacizumab was significantly associated with an increased risk of developing venous thromboembolism in cancer patients receiving this drug.

https://jamanetwork.com/journals/jama/articlepdf/182924/jrv80016_2277_2285.pdf

Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis.

This article reviews resistance to chemotherapy in metastatic castration-resistant prostate cancer (CRPC), which is a result of mechanisms of resistance specific to prostate cancer and to general mechanisms common to different cancer types. New therapies targeting these mechanisms are outlined and their potential impact in future and ongoing clinical trials is discussed. Knowledge of the mechanisms of drug resistance offers great hope for future effective therapy; however, drug resistance in metastatic CRPC is multifactorial and complex and the development of new medical therapies remains challenging.

Drug resistance in metastatic castration-resistant prostate cancer

PURPOSE: Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen. EXPERIMENTAL DESIGN: The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells. RESULTS: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control. CONCLUSION: This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

https://clincancerres.aacrjournals.org/content/clincanres/12/4/1260.full.pdf

A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer.

Purpose: In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC). Experimental Design: Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants. Results: Growth rate constants ( g ) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10 −3.17 ) relative to single-agent thalidomide (log g = 10 −2.08 ) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration. Conclusion: Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials. Clin Cancer Res; 17(4); 907–17. ©2010 AACR .

/pdf/tumor-regression-and-growth-rates-determined-in-five-s3wtz2lxlx.pdf

Tumor Regression and Growth Rates Determined in Five Intramural NCI Prostate Cancer Trials: The Growth Rate Constant as an Indicator of Therapeutic Efficacy

Purpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC).

Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles.

Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration ( C max) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration ( t max) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively.

Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.

https://clincancerres.aacrjournals.org/content/clincanres/14/1/209.full.pdf

A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer


 Background: Inflammatory breast cancer (IBC) is a rare but aggressive tumor type accounting for up to 10% of breast cancer deaths. One-third of IBCs express high PD-L1 that can be targeted by atezolizumab (Az). MEK inhibitor cobimetinib (Co) not only inhibits the RAS-MAPK pathway but can further enhance immune-mediated killing. Thus, we hypothesize that Az+Co may enhance the efficacy of chemotherapy in metastatic IBC (mIBC). We opened a trial to test this hypothesis with a comprehensive multi-omics biomarker assessment. Patients and Methods: In a single-center, open-label phase II study, cohort 1 received one cycle of Az+ Co, followed by four cycles of Az+Co+eribulin (E) to induce a maximum clinical response, followed by Az+Co maintenance. Pre and Post one cycle of Az+Co tumors were collected for immunohistochemistry (IHC), multiplex immunofluorescence (mIF), whole-exome sequencing (WES), and RNA sequencing (RNAseq). Blood was collected for circulating tumor DNA (ctDNA). Results: Seventeen patients were enrolled in cohort 1. Seven had PR, and three had SD as the best responses. Fourteen had pre, and six had pre/post tumors. The levels of PD-L1 expression at pre/post were not associated with responses. WES revealed the median tumor mutation burden at pre- was 9mt/Mb. More than 50% had TP53 and PI3K pathway mutations at pre. RTK-RAS and Notch pathways were altered in 4/9 cases. PRDM9 and DPY19L2 single-gene mutations were commonly noted in pre. No cancer-associated gene aberration, including potential biomarkers of anti-PDL1 agent response was associated with clinical outcomes. Transcriptomic gene set enrichment analysis demonstrated a greater degree of TNFa and TGFb signaling, Oxphos, angiogenesis, and epithelial-to-mesenchymal transition (EMT) processes in tumors from patients with poor response. Immune profiling by RNAseq revealed two responders to have elevated effector memory T cells, NK T cells, myeloid dendritic cells, and M1 macrophage signatures in pre-samples, but post-samples were not available. mIF confirmed a higher frequency of NK-T cells. The ctDNA analysis from serially collected blood samples is ongoing. Discussion: In this comprehensive multi-omics analysis of pre-and-post-Az+Co, we observed several novel findings, while conventional biomarkers for Az and Co did not correlate with clinical responses. EMT, Oxphos, Notch, and chronic inflammation pathways, which are not previously well reported, were observed in this IBC cohort. These markers warrant further validation to see if they carry significance as therapeutic targets in IBC.
 Citation Format: Bora Lim, Angela Alexander, Jie S. Willey, Huiming Sun, Suyu Liu, Anisha B. Patel, Edwin Roger Parra, Cara Haymaker, Luisa Solis Soto, Alejandra Serrano, Baohua Sun, Cibelle Freitas Pinto Lima, Auriole Tamegnon, Renganayaki K. Pandurengan, Dzifa Douse, Jessica Lan, Luthra Raja, Randy Chu, Mark Knafl, Scott E. Woodman, Haifeng Zhu, Katja Shulze, Katherine Fedenko, Walter Darbonne, Naoto T. Ueno, Vicente Valero. Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-19.

Abstract P4-08-19: Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer

Purpose Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. Methods Seventy-five patients with chemotherapy-naive metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m2 intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. Results After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the...

https://ascopubs.org/doi/pdf/10.1200/JCO.2004.05.074

Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer

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Abstract P4-08-19: Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer

Randomized Phase II Trial of Docetaxel Plus Thalidomide in Androgen-Independent Prostate Cancer