Taxane-platinum Combination Research Articles

Phase I study of ombrabulin in combination with paclitaxel and carboplatin in Japanese patients with advanced solid tumors

ObjectivesTo evaluate the maximum tolerated dose/maximum administered dose, safety, pharmacokinetic, and efficacy profiles of ombrabulin combined with paclitaxel and carboplatin in Japanese patients with solid tumors.MethodsOmbrabulin (25, 30, or 35...

Endometrial Carcinoma: Immune Microenvironment and Emerging Treatments in Immuno-Oncology.

Endometrial cancer (EC) can easily be cured when diagnosed at an early stage. However, advanced and metastatic EC is a common disease, affecting more than 15,000 patients per year in the United Sates. Only limited treatment options were available until recently, with a taxane–platinum combination as the gold standard in first-line setting and no efficient second-line chemotherapy or hormone therapy. EC can be split into four molecular subtypes, including hypermutated cases with POLE mutations and 25–30% harboring a microsatellite instability (MSI) phenotype with mismatch repair deficiency (dMMR). These tumors display a high load of frameshift mutations, leading to increased expression of neoantigens that can be targeted by the immune system, including (but not limited) to T-cell response. Recent data have demonstrated this impact of programmed death 1 and programmed death ligand 1 (PD-1/PD-L1) inhibitors on chemo-resistant metastatic EC. The uncontrolled KEYNOTE-158 and GARNET trials have shown high response rates with pembrolizumab and dostarlimab in chemoresistant MSI-high tumors. Most responders experiment long responses that last more than one year. Similar, encouraging results were obtained for MMR proficient (MMRp) cases treated with a combination of pembrolizumab and the angiogenesis inhibitor lenvatinib. Approvals have, thus, been obtained or are underway for EC with immune checkpoint inhibitors (ICI) used as monotherapy, and in combination with antiangiogenic agents. Combinations with other targeted therapies are under evaluation and randomized studies are ongoing to explore the impact of ICI-chemotherapy triplets in first-line setting. We summarize in this review the current knowledge of the immune environment of EC, both for MMRd and MMRp tumors. We also detail the main clinical data regarding PD-1/PD-L1 inhibitors and discuss the next steps of development for immunotherapy, including various ICI-based combinations planned to limit resistance to immunotherapy.

SIENDO/ENGOT-EN5/GOG-3055: A randomized phase 3 trial of maintenance selinexor versus placebo after combination platinum-based chemotherapy in advanced or recurrent endometrial cancer.

TPS5610 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Options for advanced or recurrent EC following platinum-based therapy and/or radiotherapy are limited and prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone is approved for relapsed/refractory multiple myeloma. In addition, selinexor monotherapy has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase 2 study, 50 mg/m2 (̃80 mg) selinexor administered twice weekly demonstrated a disease control rate ( SD ≥ 12 weeks or a PR) of 35% with 2 confirmed partial responses among 23 heavily pretreated EC patients); similar results were observed in 60 pts with platinum resistant or refractory ovarian cancer (median 5 prior regimens, ORR 8%, DCR 30%) (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent EC following platinum-based chemotherapy. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase 3 study in patients in partial (PR) or complete remission (CR) after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 248 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrence at the time of taxane-platinum therapy and disease status after chemotherapy (PR vs CR). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.

Taxane-induced Attenuation of the CXCR2/BCL-2 Axis Sensitizes Prostate Cancer to Platinum-based Treatment

BackgroundTaxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive. ObjectiveTo identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC. Design, setting, and participantsTranscriptomic data from a publicly available mCRPC dataset of taxane-exposed and taxane-naïve patients were analyzed to identify response indicators and emerging vulnerabilities. Functional and preclinical validation was performed in taxane-resistant mCRPC cell lines and genetically engineered mouse models (GEMMs). InterventionMetastatic CRPC cells were treated with docetaxel, cisplatin, carboplatin, the CXCR2 antagonist SB265610, and the BCL-2 inhibitor venetoclax. Gain and loss of function in culture of CXCR2 and BCL-2 were achieved by overexpression or siRNA silencing. Preclinical assays in GEMM mice tested the antitumor efficacy of taxane-platinum combinations. Outcome measurements and statistical analysisProliferation, apoptosis, and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival, and histopathology. Changes in CXCR2, BCL-2, and chemokines were analyzed by reverse transcriptase quantitative polymerase chain reaction and Western blot. Human expression data were analyzed using Gene Set Enrichment Analysis, hierarchical clustering, and correlation studies. GraphPad Prism software and R-studio were used for statistical and data analyses. Results and limitationsTranscriptomic data from taxane-exposed human mCRPC tumors correlate with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated in experimental models that the sensitivity to cisplatin is dependent on CXCR2 and BCL-2, and that targeting them sensitizes prostate cancer (PC) cells to cisplatin. In vivo taxane-platinum combinations are highly synergistic, and previous exposure to taxanes sensitizes mCRPC tumors to second-line cisplatin treatment. ConclusionsThe hitherto unappreciated attenuation of the CXCR2/BCL-2 axis in taxane-treated mCRPC patients is an acquired vulnerability with potential predictive activity for platinum-based treatments. Patient summaryA subset of patients with aggressive and therapy-resistant prostate cancer benefits from taxane-platinum combination chemotherapy; however, we lack the mechanistic understanding of how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell escape mechanisms to chemotherapy-induced cell death, hence making these cells more vulnerable to additional platinum treatment.

Cross-resistance of cisplatin selected cells to anti-microtubule agents: Role of general survival mechanisms

Although the first line of therapy for epithelial ovarian cancer typically consists of taxane-platinum combination therapy, many patients develop a platinum-resistant tumor within a year. Several previous studies have looked at this cross-resistance between cisplatin and anti-microtubule drugs, but their findings have been somewhat conflicting. Here, we developed cisplatin-resistant cell lines that are resistant to low and high levels of cisplatin and explored the effects of three anti-microtubule drugs (paclitaxel, vincristine, and colchicine) on the parental and cisplatin-resistant cells. We found that cells resistant to lower levels of cisplatin were no more resistant to anti-microtubule drugs than parental cells, while cells that were resistant to higher levels of cisplatin had a subpopulation of cells that were cross-resistant to anti-microtubule drugs, clarifying discrepancies within the field. We then isolated this subpopulation by applying selective pressure with anti-microtubule drugs and performed RNA sequencing and gene set enrichment analysis to identify resistance mechanisms. This subpopulation was found to express increased levels of pro-survival TNF/NFκB signaling, among other enriched pathways, suggesting that cross-resistance was due to more general survival mechanisms found in the cisplatin-selected cells.

SIENDO/ENGOT-EN5: A randomized phase III trial of maintenance with selinexor/placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer.

TPS6105 Background: Endometrial cancer is one of the most common gynecologic malignancies with increasing incidence and mortality. Patients with advanced disease that has relapsed or received prior platinum-based therapy or radiotherapy have limited options and the prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone was recently approved for patients with multiple myeloma. In addition, single agent selinexor has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase II study, 50 mg/m2 (~80 mg) selinexor administered twice weekly demonstrated a disease control rate of 35% with 2 confirmed partial responses among 23 patients with heavily pretreated endometrial cancer (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent endometrial cancer. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase III study in patients in partial or complete remission after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 192 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrent disease at the time of taxane-platinum therapy and disease status after chemotherapy (partial versus complete response). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.

Clinical Characteristics of Clear Cell Ovarian Cancer: A Retrospective Multicenter Experience of 308 Patients in South Korea.

PurposeThe purpose of this study was to evaluate clinical characteristics and treatment pattern of ovarian clear cell carcinoma (OCCC) in Korea and the role of adjuvant chemotherapy in early-stage.Materials and MethodsMedical records of 308 cases of from 21 institutions were reviewed and data including age, performance status, endometriosis, thromboembolism, stage, cancer antigen 125, treatment, recurrence, and death were collected.ResultsRegarding stage of OCCC, it was stage I in 194 (63.6%), stage II in 34 (11.1%), stage III in 66 (21.6%), and stage IV in 11 (3.6%) patients. All patients underwent surgery. Optimal surgery (residual disease ≤ 1 cm) was achieved in 89.3%. Majority of patients (80.5%) received postoperative chemotherapy. The most common regimen was taxane-platinum combination (96%). Median relapse-free survival (RFS) was 138.5 months for stage I, 33.4 for stage II, 19.3 for stage III, and 9.7 for stage IV. Median overall survival (OS) were not reached, 112.4, 48.7, and 18.3 months for stage I, II, III, and IV, respectively. Early-stage (stage I), endometriosis, and optimal debulking were identified as favorable prognostic factors for RFS. Early-stage and optimal debulking were also favorable prognostic factors for OS. Majority of patients with early-stage received adjuvant chemotherapy. However, additional survival benefit was not found in terms of recurrence.ConclusionMajority of patients had early-stage and received postoperative chemotherapy regardless of stage. Early-stage and optimal debulking were identified as favorable prognostic factors. In stage IA or IB, adding adjuvant chemotherapy did not show difference in survival. Further study focusing on OCCC is required.

Chemotherapy for advanced gastric cancer.

Chemotherapy for advanced gastric cancer.

Cisplatin to induce cancer stem cell state in ovarian cancer.

e17098Background: Ovarian cancer (OC) is the most lethal gynecological cancer. Despite high rates of response to initial cytoreductive surgery and taxane-platinum combination therapy, vast majority...

Use of panomic assessment to reveal DNA repair alterations and to predict potential therapeutic response to taxane-platinum combination therapy in prostate cancer.

5040Background: Patients with PC have limited treatment options after failure of hormonal and taxane therapy. Androgen receptor (AR) signaling may exert therapeutic effects on the DNA repair pathwa...

Taxane platinum combination chemotherapy versus single agent platinum for the first line treatment of epithelial ovarian cancer

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Clinical Significance of ABCG2 Haplotype-tagging Single Nucleotide Polymorphisms in Patients With Unresectable Non–Small Cell Lung Cancer Treated With First-line Platinum-based Chemotherapy

The ATP-binding cassette (ABC) ABCG2, involved in multidrug resistance (MDR) in cancer cells, plays an integral role in drug resistance. Single nucleotide polymorphisms (SNPs) have been identified in many MDR-associated ABC genes that seem to influence drug sensitivity/resistance through various mechanisms. Therefore, we investigated whether ABCG2 haplotype-tagging SNPs (htSNPs) were associated with clinical outcomes in patients with unresectable non-small cell lung cancer (NSCLC) treated with front-line platinum-based chemotherapy. We genotyped 4 ABCG2 htSNPs for 129 unresectable NSCLC cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of the htSNPs in patient response, survival, and adverse events related to platinum-based chemotherapy were analyzed according to each ABCG2 htSNP using the χ test, Kaplan-Meier method, and Cox proportional hazard model. The rs2725264 was significantly related to overall survival (OS) (P=0.018, log-rank test). The median survival duration (in months) for patients with the rs2725264 T/T, T/C, and C/C genotypes was 35.75 (95% confidence interval [CI], 24.25-47.25), 34.25 (hazard ratio [HR] 1.27 [0.68 to 2.35]; 95% CI, 27.16-41.34), and 14.89 (HR 3.22 [1.26 to 8.24], 95% CI, 13.86-15.92), respectively. The rs2725264 was identified as an independent factor by Cox proportional hazard model analysis (P=0.028). In the taxane-based groups, OS was associated with rs2725264 (P=0.041), whereas in the gemcitabine-based groups, OS was associated with rs4148149 (P=0.014). Our data suggest ABCG2 htSNPs rs2725264 (overall group and taxane-platinum combination group) and rs4148149 (gemcitabine-platinum combination group) were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. Thus, the ABCG2 htSNP rs2725264 may be independently associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy.

Aberrant promoter methylation of caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC.

PurposeAberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancer-associated gene loci and correlated results with clinical outcomes.MethodsWe studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.ResultsCav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03–0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.ConclusionsCAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.

Phase II study of topotecan and carboplatin in the treatment of platinum-sensitive recurrent ovarian and peritoneal cancer

15001 Background: The aim of this trial was to investigate the efficacy and toxicity of the combination of Topotecan (T) and Carboplatinum (C) in the management of recurrent platinum sensitive ovarian and peritoneal cancer. Methods: T (1 mg/m2) was given as a 30-minute infusion daily × 3 days and C (AUC 5) was given as a 30-minute infusion following T on day 3 on a 21-day cycle. Results: Thirty patients (pts) were enrolled and all pts were evaluable for response and toxicity. Mean age was 63.2 (range = 44–84). One hundred eighty five cycles (mean/pt = 6, range 2–10) were evaluable for toxicity. Dose escalation (T = 1.25 mg/m2) was possible in 25 (83.3%) pts. Hematologic toxicity grade 3 and 4 neutropenia was seen in 60 (32.4%) and 10 (5.4%) cycles, respectively. Grade 3 thrombocytopenia was encountered in 24 (13%) cycles. Grade 3 Hgb was observed in 4 (2.2%) cycles. No grade 4 thrombocytopenia/Hgb or neutropenic fever was encountered. Blood transfusions were required in 9 (4.9%) cycles. Bone marrow support with erythropoiten (40% pts), and filgrastim (43.3% pts) were utilized. No neuropathy > grade 1 was encountered. Fourteen pts (46.6%) pts had a hypersensitivity reaction to C and successful desensitization was carried out in 8 (57.1%). Mean follow-up interval was 16.9 months (mos) (Range 1.7–43). To date, 6 (20%) pts are alive without disease, 16 (53.3%) are alive with disease, and 8 (26.7) have died of disease. The overall response rate was 83.3% (5 CR and 20 PR). Five (16.6%) pts had SD. Median progression-free interval was 8.2 mos. Overall mean survival for the cohort was 31.2 mos (95% CI: 24.47–37.71). Conclusions: Given the ICON-4 data, supporting combination therapy in recurrent platinum-sensitive patients, this regimen provides an effective and tolerable alternative to Taxane-platinum combination with no significant neuropathy. This regimen is especially attractive in patients who have significant residual neuropathy after initial treatment. Carboplatinum desensitization was feasible in previously pre-treated patients. No significant financial relationships to disclose.

Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132.

First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane-platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy - a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early 'pre-emptive' crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide 'dose-dense' platinums followed by 'dose-dense' paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of 'dose-dense' strategies, and these should be considered in the design of future trials in ovarian cancer.

Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132

First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane–platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy – a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early ‘pre-emptive’ crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide ‘dose-dense’ platinums followed by ‘dose-dense’ paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of ‘dose-dense’ strategies, and these should be considered in the design of future trials in ovarian cancer.

Platinum-taxane combinations in metastatic breast cancer: an evolving role in the era of molecularly targeted therapy.

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Docetaxel appears to be the most active single agent for this condition. The platinum coordination complexes are also active, but are seldom used. An emerging literature suggests that taxane-platinum combinations have substantial activity. Trastuzumab, a molecularly targeted therapy for metastatic breast cancer is active as a single agent in HER2-overexpressing disease, and has been demonstrated to augment the activity of other agents in random assignment trials. Preclinical data suggest a powerful synergistic interaction between trastuzumab and both platinum and docetaxel. In early trials, platinum-taxane-trastuzumab combinations have exhibited promising clinical activity. The potential for cardiac toxicity when trastuzumab is combined with the anthracyclines suggests a further rationale for the development of non-anthracycline regimens, especially in the adjuvant setting. Randomized, multicenter, phase III trials in the metastatic and adjuvant setting are currently underway to test the hypothesis that synergistic combinations of docetaxel, platinums, and trastuzumab will result in superior safety as well as efficacy.