Platinum-refractory Disease Research Articles

A phase II randomized study of avelumab plus entinostat versus avelumab plus placebo in patients (pts) with advanced epithelial ovarian cancer (EOC).

5511 Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523.

Utilization and outcomes of high-dose chemotherapy and stem-cell rescue in patient with testicular cancer from 2005 to 2014 in United States.

e18246 Background: Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue. This regimen is commonly used as salvage therapy, third-line or later therapy in patients with platinum-refractory disease. The utilization and real-world outcomes and complications of patients with testicular cancer undergoing autologous hematopoietic stem cell transplant (aHSCT) in United States are unknown. Methods: We queried National Inpatient Sample, a large inpatient data set in the United States, from 2005 to 2014 for male patients with testicular cancer or multiple myeloma (control group) receiving aHSCT and compared outcomes between these groups. The primary outcome was in-hospital mortality rate, and the secondary outcomes included in-hospital complications of aHSCT, length of stay and total charges. Outcomes were assessed by means of univariate analysis, multivariate regression and propensity score matched-pair analysis. Results: A total of 391 patients (weighted N = 1,909) with testicular cancer and 4,809 male patients (weighted N = 23,501) with multiple myeloma who underwent aHSCT from 2005 to 2014 were identified. Mean age of patients with testicular cancer was 32.3 years vs 59 years for multiple myeloma patients (p < 0.001) There were no differences in in-hospital mortality rates (1.5% vs 1.4%, p = 0.85) or rates of intubation (2.3% vs 1.6%, p = 0.36), sepsis (7.7% vs 7.5%, p = 0.94), bacteremia (13.5% vs 15.6%, p = 0.42), or stomatitis (43.8% vs 38.8%, p = 0.87) between patients with testicular cancer and multiple myeloma receiving autologous HSCT. However, utilization of total parenteral nutrition was higher in patients with testicular cancer (12.9% vs 4.7%, p < 0.001). There was no difference in length of stay (17.5 vs 17.5 days, p = 0.77) and total charges (121,120$ vs 123,729$, p = 0.74) between two groups. The results were consistent in multivariate and propensity score matched-pair analysis. Conclusions: The in-hospital outcomes of patients with testicular cancer receiving aHSCT appears to be similar to patients with multiple myeloma. However, overall utilization of aHSCT for testicular cancer appears to be low in United States.

Primary Yolk Sac Tumor of the Liver in an Adult Man.

ABSTRACTPrimary yolk sac tumor of the liver is extremely rare in adults. We report a case of a young man with an unresectable primary yolk sac tumor of the liver, who had a platinum-refractory disease that progressed despite 2 lines of chemotherapy. We review the literature pertaining to primary yolk sac tumor of the liver and its management.

Oral metronomic chemotherapy for recurrent & refractory epithelial ovarian cancer: A retrospective analysis.

Background & objectives:Advanced epithelial ovarian cancer (EOC) is associated with dismal outcome and progression-free survival (PFS) shortens with each subsequent relapse. For patients with recurrent and platinum refractory disease, therapeutic options are limited. Oral metronomic therapy (OMT) is associated with symptomatic relief and stable response in a significant proportion of patients. We retrospectively evaluated the outcome of patients with EOC treated with OMT at a tertiary care hospital in north India.Methods:Between January 2011 to December 2017, 36 EOC patients received OMT. Patients’ median age was 50 yr (range, 38-81 yr) and they had received a median of two lines of prior chemotherapy. OMT regimen included a combination of cyclophosphamide, etoposide (VP-16) and celecoxib with or without pazopanib along with supportive care. Response rates and outcomes were ascertained using the Gynecological Cancer Intergroup Guidelines. The toxicity was graded according to the Common Terminology Criteria for Adverse Events v.4.03.Results:The median CA-125 before initiating OMT was 160 U/ml (range, 42.23-5330 U/ml). The median interval between last chemotherapy and starting OMT regimen was 159 days (range, 1-1211 days). The overall response rate was 50 per cent. The median progression-free survival (PFS) was 8.2 months [95% confidence interval (CI): 5.03-10.33], and the median overall survival was 38 months (95% CI: 25.6-NR). Patients who received two lines of chemotherapy before OMT (P=0.052) and those who received pazopanib-based OMT (P=0.0513) had better PFS.Interpretation & conclusions:For patients with relapse and refractory EOC, OMT could be a reasonable option. A combination of oral etoposide (VP-16) and pazopanib needs further evaluation in a large number of patients in a randomized trial.

Therapeutic Intensification and Induction Chemotherapy for High-Risk Locally Advanced Squamous Cell Carcinoma.

The treatment of HNSCC has rapidly evolved over the past 30years and multidisciplinary management is required, especially for locally advanced disease (LAHNSCC). Concomitant chemoradiation (cCRT) is the standard of care and cetuximab/RT (CET/RT) is an alternative treatment option, especially for patients unfit for concurrent cisplatin. Several intensification strategies have been explored to improve the outcome of the concomitant treatment. The combination of cisplatin plus cetuximab concurrent to RT failed to improve overall survival (OS) in two phase III trials. Induction chemotherapy (IC) has a proven role in organ preservation; however, its ability in prolonging OS has not been clearly demonstrated. Immune checkpoint inhibitors (ICIs), specifically anti PD-1 inhibitors, have been recently approved for the treatment of patients with recurrent/metastatic platinum-refractory disease. Recent clinical trials are exploring the role of immunotherapy at earlier stages of the disease in combination with concomitant treatments. The purpose of this article is to review current evidence regarding treatment intensification strategies for LAHNSCC (except nasopharyngeal carcinomas) with particular emphasis on the role of induction chemotherapy.

Prime time for immunotherapy in advanced urothelial cancer

Metastatic urothelial cancer (UC) is a lethal disease. Until 2016, cytotoxic chemotherapy with substantial toxicity was the only therapeutic option. In the first-line metastatic setting, cisplatin-based combination chemotherapy remains the standard of care. For cisplatin-ineligible patients, carboplatin-based regimens that are less efficacious are often substituted. In platinum-refractory patients, taxanes and vinflunine are the most commonly used. Recently, treatment options have largely expanded with the development of the immune checkpoint inhibitors (ICIs). Here, we review the rationale, clinical trial data and recent advances in biomarker development in the field of immuno-oncology in this disease site. We will also explore future directions of the field with respect to sequencing and combination strategies. A comprehensive literature review was performed using Pubmed, clinicaltrials.gov, and conference proceedings from the European Society of Medical Oncology (ESMO) and the American Society of Oncology (ASCO). ICIs have disease activity in metastatic UC. Five ICIs gained FDA regulatory approval in metastatic UC in patients with platinum-refractory disease. Of these five agents, pembrolizumab has level I evidence based on the KEYNOTE-045 phase III trial showing an overall survival benefit of 3 months over standard chemotherapy. ICIs also play a role in the first-line setting for patients who are cisplatin ineligible. Currently, ICIs are administered to unselected patients as reliable predictive biomarkers are lacking; however, this is a very active area of research. The rapid expansion of ICIs has also led to many upcoming trials, testing ICIs earlier in the disease course and in various combination strategies. Studies on optimal sequencing of therapies are eagerly awaited.

SIU-ICUD recommendations on bladder cancer: systemic therapy for metastatic bladder cancer.

The SIU (Société Internationale d'Urologie)-ICUD (International Consultation on Urologic Diseases) working group on systemic therapy for metastatic bladder cancer has summarized the most recent findings on theaforementioned topic and came to conclusions and recommendations according to the evidence published. In Europe and the United States, treatment for metastatic UC has changed a great deal recently, mainly involving a move from chemotherapy to immune checkpoint blockers. This is particularly true in platinum-refractory disease, where supportive randomized data exist. Five checkpoint blockers have been approved in this setting by the FDA: avelumab, atezolizumab, durvalumab, nivolumab, and pembrolizumab. Nivolumab, pembrolizumab, and atezolizumab have been approved in Europe.

Abstract 2817: RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian cancer

Abstract Ovarian cancer (OC) is deadly and incurable for patients who relapse after primary cancer is treated with surgery and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and most recurrent tumors are chemoresistant, causing deaths of nearly 15,000 women from this disease each year in U.S.A., which highlights the need for new therapeutic strategies. Platinum drug resistance and refractory disease pose major challenges in treating this disease and are major factors contributing to the poor survival rate of OC patients. Our studies demonstrated that RAD6 (an E2 ubiquitin conjugating enzyme) signaling is stimulated upon chemotherapeutic treatment and promotes expression of DNA repair proteins including Fanconi anemia (FA) pathway. Analysis of clinical samples revealed upregulation of RAD6 in ovarian tumors compared to normal ovarian tissues and RAD6 inhibition reduces cancer cell survival. In a pilot clinical study (n=26) comparing matched OC tumors from patients before and after carboplatin chemotherapy regimen, we found that RAD6 was upregulated after treatment and correlated with both chemoresistance and poor progression-free survival. Knockdown or inhibition of catalytic activity (small-molecule inhibitor) of RAD6 attenuated carboplatin-induced monoubiquitination of target proteins such as FANCD2, PCNA and histone 2B, thereby sensitizing OC cells to carboplatin. Interestingly, inhibition of RAD6 alone in OC cells induced replication stress and reduced cell survival and proliferation by arresting cells in the G2/M phase. Moreover, RAD6 plays an important role in the activation of the trans-lesion synthesis (TLS) pathway by monoubiquitinating PCNA and in the activation of the FA DNA repair pathway. These are critical mechanisms for cells to repair DNA crosslinks induced by platinum drugs. Together with these observations, our data suggest that inhibition of RAD6 could be a viable therapeutic target for overcoming platinum resistance and disease recurrence induced by FA pathway in ovarian cancer. Citation Format: Chinnadurai Mani, David Clark, Ranganatha Somasagara, Sebastian Spencer, Kaushlendra Tripathi, Komariah Palle. RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2817.

Abstract 3301: Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse

Abstract Despite favorable initial response to platinum chemotherapy, the majority of patients with ovarian cancer will develop recurrent disease and succumb to it within 5 years of diagnosis. Initial recurrence is frequently platinum-sensitive and women can respond to multiple lines of platinum-based chemotherapy before eventually developing platinum-refractory disease. The observation that the tumor cells that survive the initial therapy give rise to a chemosensitive progeny is inconsistent with a simple Darwinian model of selection of genetically resistant clones. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are among the mechanisms hypothesized to mediate re-emergence of platinum-sensitive ovarian cancer. However, given the lack of high-throughput methods to simultaneously track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated a new lentiviral barcode library, termed Watermelon. Unlike existing barcoding libraries that enable the tracking of multiple cancer cells solely at the DNA level, the Watermelon library encodes transcribed barcodes, which allows one to map the lineage to the transcriptional profile of each individual cell. This unique barcoding scheme, which is coupled with a genetic H2B retention system, enables simultaneous tracing of lineage as well as the transcriptional and proliferative states of each cell in the population during drug treatment. We have established and characterized an in vitro platinum-sensitive relapse model and are applying the Watermelon system together with time-lapse imaging to study the mechanisms underlying time-to-relapse variation and cell-fate decisions. By broadening our knowledge of the cellular and molecular pathways that affect noninherited drug resistance, our work will facilitate the future development of novel therapies that delay or even prevent the emergence of platinum-refractory ovarian cancer. Citation Format: Yaara Oren, Aviv Regev, Joan Brugge. Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3301.

A phase II study of pembrolizumab and paclitaxel in refractory extensive disease small cell lung cancer.

8575Background: Patients with platinum refractory extensive disease (ED) small cell lung cancer (SCLC) have a poor prognosis and a little progress have been made. We aimed to investigate the effica...

Survival outcomes of patients with germ cell tumors treated with high-dose chemotherapy for refractory or relapsing disease.

IntroductionMale patients with metastatic germ cell tumors can be cured in up to 96% of cases depending on stage and IGCCCG prognosis group. Treatment in relapse consists of conventional or high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) combined with local treatment modalities.ResultsMost patients were classified as poor risk according to IGCCCG (n = 24; 52%) and as intermediate (n = 12), high (n = 16), or very high risk (n = 9) at time of first relapse according to IPFSG criteria. In 67% of patients (n = 31) HDCT/ASCT was performed as first salvage treatment in relapse or for primary refractory disease following first line chemotherapy. In 46% of patients (n = 21) progressive disease was documented after mobilization and prior to HDCT/ASCT. Median progression free survival (mPFS) was 7.4 months (95% confidence interval (CI): 1.3–13.6) while median overall survival (mOS) was 22.2 months (95% CI: 8.9–35.5). When stratified for IPFSG risk group, mPFS (p < 0.001) and mOS (p = 0.009) differed significantly between risk groups (very low vs. low vs. intermediate vs. high vs. very high). Metastases to liver/bone/brain and platinum refractory disease were independent risk factors for inferior PFS (p = 0.024; p = 0.008) but not OS.Materials and MethodsForty-six patients treated with HDCT/ASCT at the university clinics in Heidelberg and Nuremberg between 2000–2016 were identified and analyzed. Data was collected retrospectively.ConclusionsHDCT/ASCT offers a potential curative strategy for patients with relapsed GCT. Improvement is still needed in patients with intermediate, high, and very high IPFSG risk group.

Phase II trial of afatinib in patients with advanced/metastatic urothelial carcinoma (UC) with genetic alterations in ERBB receptors 1-3 who failed on platinum-based chemotherapy (CT).

TPS540 Background: First-line treatment of patients (pts) with advanced/metastatic UC consists of platinum-based CT, with no well-established subsequent therapy for platinum-refractory disease. Although checkpoint inhibitors have shown promising results recently, targeted agents have generally not demonstrated significant clinical activity in this setting. Around 20% of UC harbor ERBB family genetic alterations, as such it may be a suitable therapeutic target (Knowles, Nat Rev Cancer 2015;15:25–41). The irreversible ERBB family blocker, afatinib, has shown activity in a Phase II trial in a subset of pts with UC who had ERBB2/ERBB3 aberrations (Choudhury, J Clin Oncol 2016;34:2165–71). This Phase II trial will evaluate afatinib in pts with UC molecularly selected for ERBB receptor alterations. Methods: This single-arm trial will assess the efficacy and safety of afatinib in pts with UC harboring ERBB2/ERBB3 mutations or ERBB2 amplification (Cohort A), or EGFR (ERBB1) amplification (Cohort B). Eligible pts are ≥18 years of age with ECOG PS 0–1, histologically confirmed advanced/metastatic UC of the bladder, upper tract or urethra, not amenable to surgery and progressing during or after platinum-based CT, with available archival tissue samples for pre-screening biomarker analysis. Pts will receive oral afatinib 40 mg/day until disease progression or discontinuation. Cohort A is enrolling in two stages, with Stage 2 enrollment based on anti-tumor activity observed. The primary endpoint is progression-free survival (PFS) rate at 6 months; secondary endpoints include objective response rate, PFS, overall survival, disease control rate, duration of response and tumor shrinkage. Trial objectives will be analyzed separately for the two cohorts. Safety and biomarker assessments will also be performed. The trial commenced in June 2016; as of October 4, 2017, 201 samples have been analyzed, with 24.3% and 8% of pts with genetic alterations potentially eligible for inclusion in Cohort A and B, respectively. To date, 12 pts have received study treatment in Cohort A and 6 in Cohort B; recruitment is ongoing. Clinical trial information: NCT02780687.

937PD - PD-L1 expression and prognosis significance in advanced ovarian cancer

Background: Recent data suggest that programmed death ligand 1 (PD-L1) expression may predict response to anti–programmed death 1 (PD-1) therapy. This retrospective observational study evaluated the prognostic effect of PD-L1+ expression in patients with histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube cancer (OCa). Methods: Patients diagnosed with FIGO stages II-IV OCa from 2004-2012, at Aarhus University Hospital and Rigshospitalet, Copenhagen, Denmark, were included. PD-L1 expression was measured in tissue collected at OCa surgery, using immunohistochemistry with anti–PD-L1 22C3 antibody. PD-L1+ expression was defined as staining in ≥ 1% of tumor or inflammatory cells. Patients partially sensitive (PPS; treatment-free interval [TFI] of 6-12 mo) or fully sensitive (FPS; TFI >12 mo) to platinum therapy were considered platinum sensitive, whereas those refractory (TFI <3 mo) or resistant (TFI of 3-6 mo) to platinum were platinum insensitive. Data were analyzed using Cox proportional hazard model, adjusting for age, stage, histology, residual tumor, surgery type, performance status, and/or TFI. Results: Median age of the 376 patients at diagnosis was 63 years (range, 26-86). 77% had histologic grade 2/3 serous adenocarcinoma, 46% had residual tumor after surgery, and 9%, 70%, and 21% had FIGO stages II, III, and IV disease, respectively. FPS, PPS, platinum-resistant, and platinum-refractory disease comprised 49%, 27%, 15%, and 9% of patients, respectively. 50.5% of patients were PD-L1+, with prevalence increasing with increased platinum sensitivity (P for linear trend <0.05). Median overall survival (OS) was 43 mo (50.4 mo in PD-L1+ vs 38.3 mo in PD-L1– patients). A statistically significant association was seen between PD-L1+ tumors and longer OS (adjusted hazard ratio [aHR], 0.71 [95% CI, 0.55-0.91]). The association was not significant in platinum-insensitive patients (aHR, 0.82 [0.50-1.36]), but there was a tendency towards significance in platinum-sensitive patients (0.77 [0.57-1.06]), driven by those with a TFI of 6-12 mo. Conclusions: PD-L1 was frequently expressed in advanced OCa patients, and expression may be prognostic, particularly in those with partially platinum-sensitive OCa. Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: T.T. Vo: Employed by, own stock in, and have received research grants from Merck & Co., Inc. W. Zhou, M. Busch-Sørensen, D. Chappell: Employed by and own stock in Merck & Co., Inc. T. Steiniche: Received research funding from and have been reimbursed for travel and accommodation expenses by Merck & Co., Inc. All other authors have declared no conflicts of interest.

High-Dose Chemotherapy and Autologous Peripheral-Blood Stem-Cell Transplantation for Relapsed Metastatic Germ Cell Tumors: The Indiana University Experience.

Purpose Patients with relapsed metastatic germ cell tumor (GCT) can be cured with second-line and even third-line regimens. We report survival outcomes of patients treated with high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplantation (PBSCT) at Indiana University between 2004 and 2014. Patients and Methods We conducted a retrospective analysis of 364 consecutive patients with GCT who progressed after cisplatin-based combination chemotherapy and were subsequently treated with HDCT and PBSCT. Three hundred forty-one patients received two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. Twenty-three patients received only a single course of HDCT because of progressive disease or toxicity. Cox proportional hazards models were used to test predictors of disease progression. Results The median age was 32 years (range, 17 to 70 years). With a median follow-up of 3.3 years, the 2-year progression-free survival (PFS) was 60% (95% CI, 55% to 65%) and the 2-year overall survival was 66% (95% CI, 60% to 70%). Three hundred three patients received HDCT as second-line therapy with a 2-year PFS of 63% (95% CI, 57% to 68%), and 61 patients received HDCT as third-line or later therapy with a 2-year PFS of 49% (95% CI, 36% to 61%). In a multivariable analysis, factors associated with disease progression included use of HDCT as third-line or later therapy, platinum-refractory disease, mediastinal primary tumor site, nonseminoma histology, intermediate- or poor-risk disease at the time of GCT diagnosis, and human chorionic gonadotropin ≥ 1,000 mIU/mL at initiation of HDCT. There were nine treatment-related deaths. Secondary leukemia developed in five patients. Conclusion This large single-institution study demonstrates that patients with relapsed metastatic GCT are curable by HDCT plus PBSCT even when used in third-line or later therapy.

Evolution of Chemosensitivity and Resistance Assays as Predictors of Clinical Outcomes in Epithelial Ovarian Cancer Patients.

Epithelial ovarian cancer (EOC) is responsible for more cancer-related deaths than any other malignancy of the female reproductive system. The standard of care for advanced EOC involves a combination of cytoreductive surgery and platinum-based chemotherapy. Although a majority of patients respond to a platinum-containing regimen, many fail to respond to first-line treatment (platinum-refractory disease) or experience disease progression within 6 months of completing treatment (platinum-resistant disease). Even in patients who initially respond to platinum-based therapy, secondary development of platinum resistance is common. Many chemotherapeutic regimens with comparable efficacy and toxicities are available, leaving the determination of optimal therapy to the physician's discretion. There have been many efforts over the years to develop accurate predictors of outcomes in patients treated with chemotherapy to help inform treatment decisions. Predictive treatment markers are particularly relevant in a disease such as EOC, where a large number of similarly efficacious chemotherapy regimens are available. Chemosensitivity and resistance assays (CSRAs) are attractive approaches to interrogate the efficacy and complex biology of EOC. Some early predictive cellular tests, such as the early clonogenic assays, were limited by technical and logistical issues. Over time, changes in these assays have improved their prognostic and predictive value, but there is still a lack of widespread adoption due to methodological difficulties or limited clinical validation. Herein, we provide an overview of the evolution of CSRAs used to predict outcomes in patients treated with chemotherapy that have been evaluated for use in EOC, with a focus on the latest generation chemoresponse assay.

Platinum-refractory germ cell tumors: an update on current treatment options and developments.

In general, 50% up to 80% of metastasized germ cell tumor patients can be cured by platinum-based chemotherapy. However, 3-5% of patients will still die of platinum-refractory disease and new systemic treatment options are needed to improve treatment success in this difficult setting. This review aims to give an overview on treatment options and current developments in the field of platinum-refractory male germ cell tumors. A comprehensive literature search was conducted searching PubMed, Medline, Cochrane and Embase to identify clinical trials regarding the treatment of platinum-refractory disease. ASCO, EAU and ESMO conference proceedings were searched to identify unpublished results of relevant trials. Comprehensive review papers were hand searched for additional references. Clinicaltrials.gov was checked for ongoing clinical trials in the field of platinum-refractory germ cell tumors. Outcome of platinum-refractory disease remains poor. Single-agents with reasonable activity are gemcitabine, oxaliplatin and paclitaxel, but complete remissions resulting in long-term survival could not be achieved. The triple-combination of gemcitabine, oxaliplatin and paclitaxel followed by resection of residual masses provides the best outcomes with objective responses in 51% of patients and long-term survival in approximately 10-15%. To date, no molecularly targeted agent has shown reasonable activity. Treatment options for platinum-refractory disease are limited, but a small subset of patients may achieve long-term disease-free survival by multimodal treatment. The potential of novel targeted agents, i.e. by immune-checkpoint-inhibition remains to be defined.

Abstract 3734: Preclinical evaluation of Rad6 inhibition to overcome platinum resistance in ovarian cancer

Abstract Ovarian cancer (OC) is the most lethal gynecological cancer in women in the United States. Advances in surgery and chemotherapy have not significantly changed the overall survival rate of OC for the last few decades, which highlights the need for new therapeutic strategies. Platinum drug resistance and refractory disease pose major challenges in treating this disease and are major factors contributing to the poor survival rate of OC patients. Although most patients initially respond to platinum based chemotherapy, about 80% of cases present with recurrent disease, develop platinum resistance, and die with the advanced disease. Considering the heterogeneity, small fractions of the cells could be inherently resistant to chemotherapy and/or dormant and exhibit stem-like cell properties, contributing to the resistant phenotype and disease recurrence. Although the Cancer stem cell (CSC) theory of therapeutic resistance proposes that the proportion of CSCs correlate to enhanced chemoresistance and early disease recurrence, the specific molecular mechanisms that regulate tumor cell behavior (stemness) and integrate signaling networks with aberrant oncogenic signaling in OC cells are not known. Our analysis of clinical samples revealed upregulation of Rad6, an E2 ubiquitin conjugating enzyme, in more than 80% of ovarian tumors compared to normal ovarian tissues. Upregulation of Rad6 also correlated well with tumor progression. Further analysis of molecular pathways in OC cells revealed a strong correlation between Rad6 upregulation and increased β-catenin and hedgehog signaling, stem cell like characteristics and platinum resistance. Downregulation of Rad6 using siRNAs or inhibition of its catalytic activity by a small molecule inhibitor, attenuated carboplatin induced monoubiquitination of its target proteins such as histone 2B, PCNA and proteins of the Fanconi anemia pathway thereby sensitizing OC cells to carboplatin. Interestingly, inhibition of Rad6 alone in OC cells induced replication stress and reduced cell survival and proliferation by arresting cells in the G2/M phase. Moreover, inhibition of Rad6 in various OC cell lines reduced expression of β-catenin, Gli1 and several OC stem cell markers. Moreover, Rad6 plays an important role in the activation of the trans-lesion synthesis (TLS) pathway by monoubiquitinating PCNA and in the activation of the Fanconi Anemia (FA) DNA repair pathway. These are critical mechanisms for cells to repair DNA crosslinks induced by platinum drugs. Together with these observations, our data suggest that inhibition of Rad6 could be a viable therapeutic target for overcoming platinum resistance and disease recurrence in ovarian cancer. Citation Format: Sebastian M. Spencer, Ranganatha R. Somasagara, Kaushlendra Tripathi, David W. Clark, Hend Kothayer, Andrew D. Westwell, Rodney P. Rocconi, Komaraiah Palle. Preclinical evaluation of Rad6 inhibition to overcome platinum resistance in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3734.

Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients.

High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10–0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-016-0238-7) contains supplementary material, which is available to authorized users.

Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141.

6009Background: Patients (pts) with R/M SCCHN have poor prognosis, and median OS for pts with platinum-refractory disease is ≤6 mo. We investigated if nivo, a fully human IgG4 anti-PD-1 mAb improve...

Routine Clinical Practice for Patients With Recurrent Ovarian Carcinoma

Treatment options for patients with recurrent ovarian carcinoma are diverse, and different therapies are recommended based on platinum-free interval (PFI). Data examining the association between platinum sensitivity, treatment strategy, and outcomes are limited, particularly for partially platinum-sensitive (PPS) patients. This study characterized clinical features and outcomes in patients with recurrent ovarian carcinoma in the context of sensitivity to platinum-based therapy. Anonymized case records were obtained from eligible European medical sites. Eligible patients were 18 years or older with epithelial ovarian carcinoma who had received 1 or more platinum-based therapies and had 1 or more subsequent relapses. Patient records were categorized by PFI and analyzed based on demographic and clinical data using descriptive statistics. There was no difference between PFI in PPS patients receiving platinum versus nonplatinum therapy (8.9 [range, 6.0-12.0] and 8.3 [range, 6.0-11.3] months, respectively). Overall survival in patients with platinum-sensitive, PPS, platinum-resistant, and platinum-refractory disease was 43.0 (95% confidence interval [95% CI], 25.1-42.3), 20.5 (95% CI, 17.7-24.8), 12.7 (95% CI, 10.4-14.2), and 9.8 (95% CI, 6.6-14.9) months, respectively. Among PPS patients, overall survival was 23.5 (95% CI, 18.4-37.3) and 18.7 (95% CI, 11.0-23.5) months for those who received platinum and nonplatinum-based therapy, respectively. No demographic or clinical characteristics were identified that indicated a difference between PPS patients who received platinum-based therapy versus those who did not. Partially platinum-sensitive patients with recurrent ovarian carcinoma who received platinum-based therapy had improved outcomes compared with those who did not. No clear demographic criteria for choosing platinum- versus nonplatinum-based therapy for PPS patients were identified from patient records.