Refractory Germ Cell Tumors Research Articles

Antibody-drug conjugates as a novel therapeutic modality to treat recurrent refractory germ cell tumors.

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy.

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

High Dose Chemotherapy With Autologous Stem Cell Transplant for Patients With Advanced Germ Cell Tumors: Real-World Evidence From a Tertiary Cancer Center in Brazil

BackgroundHigh-dose chemotherapy followed by stem cell transplant (HDCT) is potentially curative for patients with refractory germ cell tumors (rGCT). There is scarce real-world data supporting its implementation in low- and middle-income countries. We described the experience of our tertiary cancer center in Sao Paulo, Brazil. MethodsWe identified male patients ≥18 years-old with rGCT referred to HDCT after board discussion. Clinical data, including delays in HDCT protocol, were extracted from medical records, and survival outcomes were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazard were used to determine effects on overall survival (OS). ResultsFrom January 2013 to January 2023, 34 patients were referred and considered eligible to receive 2 cycles of HDCT. Most patients had primary testicular tumors (82%), nonseminomatous histology (88%), and poor International Germ Cell Collaborative Group (IGCCCG) (79%). Twenty-three patients received HDCT (1 cycle, n = 8; 2 cycles, n = 15). Main reasons for not receiving any HDCT were death due to progressive disease (n = 1), performance deterioration (n = 7), and failure of stem cell mobilization (n = 3). OS at 2 years was 36.7% for the eligible population, 56.1% for patients who underwent at least 1 HDCT, and 77.1% for those who had ≥2 cycles. The 2-year OS rate for patients not given HDCT was 0%. All patients had delays in protocol, and poor-risk patients had longer intervals from referral to protocol initiation (0.7 vs. 1.8 month, P < .01). ConclusionOutcomes of patients who received ≥1 HDCT were encouraging; however, only 15 from 34 eligible patients were able to receive the planned 2 cycles of HDCT. Further strategies to minimize treatment delays in low- and middle-income countries are needed.

Therapeutic efficacy of high-dose chemotherapy with autologous stem-cell transplantation in 44 relapsed or refractory germ-cell tumor patients: A retrospective cohort study.

Despite having a higher mortality risk than conventional chemotherapeutics, high-dose chemotherapy (HDCT) has the potential to be curative in relapsed/refractory germ-cell tumors. Therefore, selecting the best patient group for this treatment is critical. This study aimed to determine the factors that affect survival in our relapsed/refractory GCT cohort who received HDCT and autologous stem-cell transplantation. Between September 2010 and 2020, we included in the study 44 relapsed/refractory male patients with GCT treated with HDCT plus autologous stem-cell transplantation. The patients' demographic features, clinical characteristics, and treatment outcomes were evaluated. Statistical analyses were performed to identify risk factors associated with survival. The median age of all cohorts was 28 years. Thirty-six patients had nonseminomatous tumors, and 8 patients had seminomatous tumors. The most common primary tumor sites were the gonads (75%), followed by the mediastinum (15.9%) and the retroperitoneum (9.1%). After HDCT, 11 patients had a complete response, 12 patients had a partial response, and 17 patients had a progressive disease, respectively. About 23 patients (52.3%) experienced at least 1 treatment-related grade 3 to 4 nonhematological toxicity. About 4 patients (10%) died due to HDCT-related toxicity. The total group's median progression-free survival (PFS) was 7 months, and the median overall survival (OS) was 14.9 months. Primary tumor site (hazard ratio [HR]: 1.84; P = .028), type of HDCT regimen (HR: 0.35; P = .010), and best response to HDCT (HR: 11.0; P < .0001) were independent prognostic risk factors for PFS. The only independent prognostic risk factor associated with OS was the best response to HDCT (HR: 6.62; P = .001). The results of the study promise the best response to HDCT as a primary measure for predicting survival in relapsed/refractory GCT. In contrast, primary mediastinal GCT is not a good candidate for HDCT. Furthermore, a carboplatin-etoposide regimen in combination with cyclophosphamide and paclitaxel may improve PFS.

Identification of a panel of microRNA biomarkers for the management of patients with refractory germ cell tumor of the testis.

521 Background: In 1946, nearly 90% of patients diagnosed with metastatic Testicular Germ Cell Tumor (TGCT) succumbed to the disease within a year. In the present day, over 90% of such patients are successfully cured. However, there is a remaining 10% of patients have tumors that consist of chemotherapy-resistant forms of TGCT, such as yolk sac tumors and teratomas. This underlines the need for developing biomarkers that can guide the choice between additional chemotherapy and surgical intervention. MicroRNAs (miRNAs), non-coding RNA molecules that control post-transcriptional modifications, have shown promise in identifying TGCTs. Research has particularly highlighted the overexpression of miR-371a-3p and miR-375-3p in TGCTs. Nevertheless, these miRNAs are not effective in distinguishing between teratomas and other TGCT types. The Cancer Genome Atlas (TCGA), a publicly accessible database, offers clinical and miRNA data on various tumors, including TGCTs. Our objective is to leverage TCGA to identify miRNAs that can be used to classify TGCTs containing teratomas from those that do not. Methods: Between 2001 and 2013, TCGA gathered a total of 135 primary TGCT samples. We group these tumors into those without teratomas and those with any teratomatous components. We used EdgeR, a Bioconductor package designed for differential expression analysis of RNA that accounts for both biological and technical variation. A false discovery rate of less than 1e-8 was applied. A heatmap was generated to display the hierarchical clustering of differentially expressed miRNAs. Results: Based on the above cut-off, a panel of 50 miRNAs of differentially expressed miRNA were used to generate a hierarchical clustering that showed clear clustering between the two groups. Notably, tumor suppressor miRNAs such as hsa-mir-203a, hsa-mir-199, and hsa-mir-152, which are usually downregulated in non-teratoma TCGT, are overexpressed in teratomas. Other miRNA including hsa-mir-146a and hsa-mir-3607, which are downregulated tumor suppressors for non-TCGT are also downregulated in teratomas but not in teratoma-free TGCT. Conclusions: Despite the high cure rate for TGCTs, tumors containing chemotherapy-resistant teratomas still contribute to elevated mortality rates. Utilizing TCGA data, we identified a set of miRNAs that are effective in distinguishing between teratoma-containing and teratoma-free TGCTs. This miRNA panel has the potential to inform decisions related to surgical treatment plans and provide further insight into the biology of the disease.

Doxorubicin, paclitaxel, and cisplatin (ATP) for refractory germ cell tumors.

e17028 Background: Patients with refractory germ cell tumor (GCT) have limited treatment options and poor prognosis. We describe our institutional experience with doxorubicin, paclitaxel, and cisplatin (ATP) as an outpatient chemotherapy regimen for patients with refractory GCT. Methods: We performed a retrospective chart review of all patients who received ATP at our institution between August 2017 and August 2022. ATP consisted of doxorubicin 30 mg/m2, paclitaxel 100 mg/m2 over one hour, and cisplatin 30 mg/m2 every 2-3 weeks. We reviewed patient and disease characteristics including staging, histology, prior therapies, tumor marker and imaging responses. Progression free survival (PFS) and overall survival (OS) were respectively calculated from the first ATP dose date to disease progression/death and to death/last follow up. Results: A total of 39 patients with refractory GCT received ATP. Patients were 95% male, 54% white, with a mean age of 30 years (range 18-63). Prior to ATP administration, 92% of GCTs had elevated tumor markers, including 54% with elevated AFP, 56% with elevated HCG, and 18% with elevated both tumor markers. 8% of GCTs did not have elevated tumor markers at baseline. Further disease characteristics are described in table 1. Patients received a median of 2 lines of prior systemic therapies (range 1-6), including 97% with prior cisplatin-based regimens and 21% with prior high dose chemotherapy with stem cell rescue transplant. Patients received a median of 3 doses of ATP (range 1-8) with 31% for palliative intent and the rest as a bridge to transplant or other therapies. After ATP administration, 77% patients had decreased tumor markers, including 18% with tumor marker normalization. Of the 19 patients with imaging post-ATP, 53% had complete or partial response, 16% had stable disease, and 32% had disease progression. By December 2022, 79% patients had progression or death, with a median PFS of 3.8 months (95% CI: 1.94, 7.16) and median OS of 10.7 months (95% CI: 6.37, 32.69). 18% of patients experienced toxicities requiring admissions. Conclusions: Based on our retrospective single institution experience, ATP has clinical activity in refractory GCT and is associated with decreased tumor markers and imaging response in most patients. ATP is a convenient and feasible outpatient regimen and can be used in the salvage setting and as a bridge to other therapies. [Table: see text]

TANDEM HIGH DOSE CHEMOTHERAPY WITH AUTOLOGOUS BONE MARROW TRANSPLANTATION IN GERM CELL TUMOR— EXPERIENCE FROM A TERTIARY CARE CENTER FROM SOUTH INDIA

Background: The use of high-dose chemotherapy with autologous hematopoietic cell transplantation is well established as a potentially curative approach in patients with relapsed or refractory disease in testicular Germ cell tumours after initial cisplatin-based chemotherapy. The use of tandem transplant with high-dose carboplatin and etoposide conditioning has been a tried and is a feasible option in relapse setting.Overall, HDCTand Autologous stem cell transplant can offer cure rates of up to 60% in the relapsed GCTsetting. Data on Tandem HDCTand ASCTis very limited in Indian subcontinent. Hence we report our experience with respect to safety, efcacy and tolerability, survival outcomes of HDCT/ ASCT in patients with relapsed GCT. Methods: Patients who were diagnosed with relapsed or refractory Germ cell tumours and underwent Tandem HDCT and ASCT were analysed from patient records from 2013 to 2020. Results: Both our patients received BEP (bleomycin, etoposide, and cisplatin) as rst-line therapy. HDCT was done after 2nd line salvage chemotherapies in both patients. Both patients were treated with 2 courses of High-dose carboplatin (700mg/m2) and etoposide(750mg/m2) as conditioning regimen followed by stem cell rescue(CD34+ stem cells yield – 5 to 6x106 cells/kg ) 3-4 weeks apart. Grade ¾ toxicities including myelosuppression, diarrhea, mucositis were observed in both patients. After ASCT both patients were followed up with imaging and serial monitoring of tumour markers. 1st patient died 3 months after ASCT due to disease relapse and our 2nd patient was disease free for 22 months, after which he developed progressive disease in brain and succumbed to disease. Conclusion: This is the rst report from India on tandem HDCT with ACST in relapsed GCTs. Tandem HDCT/ASCT seems to be safe and feasible option in relapsed/ refractory testicular GCT's.

Paclitaxel, gemcitabine, oxaliplatin regimen in induction therapy of patients with relapsed and refractory germ cell tumors before high-dose chemotherapy: results of a pilot study

Purpose: to evaluate the efficacy of TGO (paclitaxel, gemcitabine, oxaliplatin) regimen as induction therapy for hematopoietic stem cells mobilization (HSC) before high-dose chemotherapy (HDCT) in patients with recurrent nonseminomatous germ cell tumors (NSGCT).Patients and methods: the study enrolled patients with relapsed and/or refractory NSGCT after frontline chemotherapy. Modified TGO regimen (paclitaxel 100 mg/m2 on day 1 + gemcitabine 1000 mg/m2 on day 1 + oxaliplatin 130 mg/m2 on day 1, once every 14 days) was administered with filgrastim support 10 mcg/kg subcutaneous from day 8 and until the completion of leukapheresis. Maximum 3 cycles of TGO regimen was administered. After harvesting the required volume of CD34+ cells, HDCT was initiated which consisted of 3 cycles of the CE regimen (carboplatin AUC8 on day 1–3 + etoposide 400 mg/m2 on day 1–3) with further HSC autologous stem cell transplantation (ASCT).Results: Five patients with NSGCT with poor IGCCCG prognosis according were enrolled. All of them received ifosfamide-containing chemotherapy as initial treatment. The required HSC were collected for three cycles of HDCT in all patients (100 %); in four (80 %) patients the required number of cells was collected after the 1st cycle of TGO. Four (80 %) patients started the HDCT phase, one patient prematurely terminated treatment due to the rapid progression. One patient who received full planned therapy demonstrated complete and durable tumor regression at the time of data analysis (with 37 months follow-up).Conclusions: the TGO regimen can be used to collect PBSC from patients with relapsed and/or refractory NSGCT before HDCT, further study of this approach is required.

Efficacy of ifosfamide, carboplatin and etoposide chemotherapy protocol in relapsed refractory germ cell tumors

Efficacy of ifosfamide, carboplatin and etoposide chemotherapy protocol in relapsed refractory germ cell tumors

Efficacy of Gemcitabine, Paclitaxel, and Oxaliplatin Protocol in the Treatment of Relapsed or Refractory Germ Cell Tumours.

To determine the survival endpoints and treatment-related adverse events after the use of the gemcitabine, paclitaxel, and oxaliplatin (GemPOx) protocol in relapsed/refractory germ cell tumours (GCTs) who had previously received multi-line systemic treatments including high-dose chemotherapy. Observational study. Clinic of Medical Oncology, Gulhane School of Medicine, Ankara, Turkey, between January 2017 and August 2021. Clinical characteristics of adult patients with relapsed/refractory GCTs treated with the GemPOx protocol were recorded from the hospital's patient registry database. Patients without a medical record were not included in the study. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), one-year PFS rate, one-year OS rate, and treatment-related haematological side effects were determined after GemPOx. Fifty-three adult patients were included (47 of them were male). Seventy-eight percent had Stage 3 at initial diagnosis. Twenty-four percent of the patients received more than four lines of systemic chemotherapy. Ninety-six percent of the patients received high-dose chemotherapy prior to GemPOx. ORR, which is the sum of the complete and partial response rates, was 69.8%. PFS was determined as 8.5 ± 5.4 months. The one-year PFS rate was 30.3%. OS was 15.9 ± 10.6 months. The one-year OS rate was 72.6%. Febrile neutropenia was observed in 15.1% of the patients. In patients with relapsed/refractory GCTs receiving multi-line systemic chemotherapy, significant PFS and OS are achievable, and a manageable spectrum of haematological side effects is observed with GemPOx. Gemcitabine, Paclitaxel, Oxaliplatin, Germ cell tumour.

Phase II study of disulfiram (D) and cisplatin (P) in refractory germ cell tumors (GCTs).

e17013 Background: Multiple relapsed/refractory GCTs patients have extremely poor prognosis, therefore, new treatment strategies are warranted. Previously, we showed, that cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory germ cell cancer. Methods: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. All patients were pretreated with at least 2 cisplatin-based therapies (median 4, range 2 – 7); 6 tumors (50.0%) were absolutely refractory to cisplatin and 9 patients (75.0%) had visceral non-pulmonary metastases. Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in the this report. Results: Median age was 36 years (range: 29 – 48 years). Median number of treatment cycles was 2 (range 1 – 6). During a median follow-up period of 3.1 months (range: 1.3 – 13.9), all (100%) patients experienced disease progression and died. None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival (PFS) was 1.4 months, 95% CI (0.7 – 1.5 months), and median overall survival (OS) was 2.9 months 95% CI (1.5 – 4.7 months). Disease stabilization for at least 6 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT03950830.

Overcoming Chemotherapy Resistance in Germ Cell Tumors.

Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

A phase II trial evaluating the efficacy of cabozantinib in the treatment of patients with refractory germ-cell tumors (GCT).

TPS428 Background: While the majority of patients with metastatic testicular cancer are cured with first-line cisplatin-based chemotherapy, 20-30% of patients will relapse following initial treatment. Many will still be cured with second and even third-line chemotherapy options, but there remains a need for new therapeutic approaches for patients with relapsed/refractory disease. Cabozantinib is an oral tyrosine-kinase inhibitor (TKI) with multiple targets including c-MET, VEGF, RET, and AXL. Testicular GCT have low rates of somatic mutations, though have been shown to be associated with a gain of chromosome 7, a portion of which encodes c-MET. When hepatocyte growth factor (HGF) binds to its c-MET receptor, cell proliferation, migration, invasion, and apoptosis escape occurs. In addition, compared to normal testicular tissue, testicular GCT have been shown to have higher rates of VEGF expression. Based on these findings, we proposed a phase 2 trial with cabozantinib in patients with relapsed/refractory GCT. Methods: This phase II, single arm, open label trial with a Simon two-stage design is evaluating cabozantinib 60mg daily in patients with relapsed/refractory GCT. Eligible patients are adult men and women with GCT (seminoma, non-seminoma, or ovarian GCT) that have progressed after first-line cisplatin-based combination chemotherapy in addition to at least 1 salvage regimen and are considered incurable with standard therapies. Patients with primary mediastinal non-seminoma, late relapse, and treated stable brain metastases are eligible. 12 patients will be enrolled initially in the first stage of the Simon two-stage design. If at least one complete response (CR), partial response (PR), or stable disease (SD) for ≥3 months is achieved, the trial will be deemed worthy of further investigation and 9 additional patients will be enrolled. Patients will be treated daily with cabozantinib until time of progression or unacceptable toxicity. Primary outcome is clinical benefit rate (proportion of CR, PR, and SD for ≥3 months using RECIST 1.1, modified to include tumor markers, AFP and hCG). Secondary outcomes include objective response rate, progression-free survival, overall survival, and tolerability and toxicity of cabozantinib. Exploratory evaluation of MET overexpression by IHC and amplification by next generation sequencing in correlation with response will be performed. This study is currently enrolling patients. As of September 20, 2021, the prespecified goal for the Simon stage 1 has been met, and 7 of planned 21 patients have enrolled. Clinical trial information: NCT04876456.

Proteomic profiling of cisplatin-resistant and cisplatin-sensitive germ cell tumour cell lines using quantitative mass spectrometry

PurposeAdvanced testicular germ cell tumours (GCT) generally have a good prognosis owing to their unique sensitivity towards cisplatin-based chemotherapies. However, cisplatin-resistant GCT have a poor outcome. Further studies are mandatory to better understand resistance mechanisms and develop therapeutic strategies for refractory GCTs.MethodsProtein levels in cisplatin-resistant GCT cell lines of NTERA-2, NCCIT and 2102EP were analyzed by quantitative proteomic mass spectrometry (MS) in combination with stable isotope labelling by amino acids in cell culture (SILAC). Differentially abundant protein markers of acquired cisplatin resistance were validated by Western blotting. Comprehensive bioinformatical annotation using gene set enrichment analyses (GSEA) and STRING interaction analysis were performed to identify commonly affected pathways in cisplatin resistance and the data were compared to the GCT cohort of the ‘The Cancer Genome Atlas’.ResultsA total of 4375 proteins were quantified by MS, 144 of which were found to be differentially abundant between isogenic resistant and sensitive cell line pairs (24 proteins for NTERA-2, 60 proteins for NCCIT, 75 proteins for 2102EP). Western blotting confirmed regulation of key resistance-associated proteins (CBS, ANXA1, LDHA, CTH, FDXR). GSEA revealed a statistically significant enrichment of DNA repair-associated proteins in all three resistant cell lines and specific additional processes for individual cell lines.ConclusionHigh resolution MS combined with SILAC is a powerful tool and 144 significantly deregulated proteins were found in cisplatin-resistant GCT cell lines. Our study provides the largest proteomic in vitro library for cisplatin resistance in GCT, yet, enabling further studies to develop new treatment options for patients with refractory GCT.

Current Management of Refractory Germ Cell Tumors.

Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20-30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs. Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs. Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.

Efficacy of TIP (paclitaxel, ifosfamide and cisplatin) as salvage chemotherapy for relapsed germ cell cancer patients stratified by the modified International Prognostic Factors Study Group (IPFSG) score: The Northern Ireland (NI) Experience.

5028 Background: Salvage therapy for relapsed or refractory germ cell tumours (GCTs) after first-line treatment (1LT) failure remain controversial. The ongoing TIGER trial aims to compare conventional-dose chemotherapy (CDCT) using TIP with high-dose chemotherapy (HDCT) and to validate a modified version of the IPFSG stratification system as a secondary objective. We retrospectively analysed data from patients treated with TIP at our institution and stratified by the modified IPFSG (mIPFSG) groupings, correlating this with clinical outcomes. Methods: Data from all GCT patients who received TIP in NI between 2005 and 2014 was collected. Patients were scored using known IPFSG factors including progression-free interval (0-1), metastasis site (0-3), response to 1LT (0-2), primary tumour site (0-3), HCG (0-1), AFP (0-2), and histology (-1 to 0), and categorised into the modified strata. Descriptive and inferential statistics using SPSS compared survival measure outcomes and the favourable response rate (FRR) i.e the proportion of patients achieving either a complete response or partial response with normal serum tumour markers, according to mIPFSG group. Results: Thirty patients were identified, all of whom received 4 cycles of TIP. The median age was 37 years (range 17-57), 28 patients were non-seminoma histology with 2 patients seminoma. The cohort comprised predominantly of patients with more adverse mIPFSG features and the FRR of the group was 30%, with a median progression-free survival (PFS) of 9 months and 2-year overall survival (OS) of 50%. Clinical outcomes differed by mIPFSG score as shown below. Conclusions: Our study shows TIP efficacy comparable to published data, and to our knowledge is the first to show correlation between clinical outcomes with the regimen and the new mIPFSG model. The differences in outcomes to CDCT using TIP across risk groups in real world practice shows potential for a stratified approach to patient selection for salvage therapy, as is under investigation by the TIGER study.[Table: see text]

Expression of programmed death ligand-1 (PD-L1) in metastatic and postchemotherapy viable testicular germ cell tumors

IntroductionChemotherapy for testicular germ cell tumors (GCT) is highly effective, with few patients who do not respond. Clinical studies to evaluated novel treatments are challenging given the rarity of these patients. Therefore, we sought to evaluate PD-L1 staining on metastatic and postchemotherapy viable testicular GCTs as a surrogate for potential benefit for immunotherapy targeting the PD-1/PD-L1 axis. MethodsEthics research committee approval for this retrospective study was obtained by four participating institutions (CHU de Québec, St. Joseph's Health Care, Halifax Health Science Centre, Johannes Gutenberg University). Patients with viable metastatic testicular GCTs pathology samples were included. Patients with pure teratoma were excluded. PD-L1 staining with the 22C3 clone was evaluated on samples with >100 viable tumor cells using the combined positive score (CPS). ResultsFrom 51 patients identified at participating institutions, 24 postchemotherapy and 18 chemotherapy-naive metastatic samples were available for PD-L1 staining, with 9 matched prechemotherapy samples and 7 matched orchiectomy pathology samples, respectively. The median CPS score was 55.6 (IQR 16–100) for all metastatic samples, 44.9 (IQR 13–100) for postchemotherapy metastatic samples, and 68.8 (IQR 38–100) for chemotherapy-naïve metastatic samples, with the median number of viable tumor cells at 545, 500, and 550, respectively. Differences were not significant between chemotherapy-naïve and postchemotherapy samples (P = 0.07), though among non-seminoma GCT metastatic samples, CPS scores were significantly lower postchemotherapy (P = 0.02). Significant differences among postchemotherapy metastatic tumors were also seen according to predominant subtype, with lower CPS scores for predominant yolk sac and higher values for predominant seminoma and choriocarcinoma. In 7 patients with matched specimens pre- and postchemotherapy, a significant increase in CPS was observed for seminoma (26.7 vs. 81.7, P = 0.045), but not nonseminoma GCTs. Comparing all chemotherapy naïve-samples, PD-L1 expression was higher in metastatic samples versus testicular samples (mean CPS 68.8 vs. 39.8, P = 0.02). This was also seen in matched chemotherapy-naïve samples (mean CPS 77.9 vs. 33.1, P = 0.01). ConclusionOur results suggest that most patients with refractory GCTs postchemotherapy will not benefit from PD-1/PD-L1 immunotherapy. However, the high PD-L1 expression in patients with predominant or pure seminoma post-chemotherapy suggests this may represent a subgroup for whom further trials may be considered.

Australia and New Zealand (ANZ) outcomes of high-dose chemotherapy and stem cell transplantation for relapsed or refractory germ cell tumors (GCT) from 1999 to 2019: Multicenter registry-based study with ABMTRR.

382 Background: High dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) is effective in advanced germ cell tumours (GCT) that are refractory to, or progress after, first-line therapies. Five-year overall survival in North American and European series range from 48-60%1,2,3. This study aimed to assess ANZ outcomes for quality assurance. Methods: Retrospective multi-centre audit of all male patients with GCT who underwent HDCT and ASCT from 1999-2019. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. Primary outcomes included overall and progression- free survival (OS, PFS). Results: 111 patients were identified at 13 centres, each treating a median (range) of 7 (1-27) patients. Median (range) age was 30 (14-68) years. 88 (79%) had testicular primary. 16% were pure seminoma. Median time from first diagnosis to first stem cell cycle was 11 months (range 3 months-38 years). Prior to ASCT, 35% had primary refractory disease and 65% had relapsed. IPFSG risk score was very low in 5%, low in 13%, intermediate in 36%, high in 25%, and very high in 21%. HDCT regimen was CE in 78% (as part of TI-CE regimen in 38%), Carbop-EC-T in 6%, ICE in 6%, CEC in 5% and other in 4%. 89% completed all planned HDCT and ASCT cycles. Five treatment related deaths occurred. Progressive disease on treatment occurred in 14%. At median follow-up time 4.4 years (95% CI: 2.9 to 6.0), 51% were disease-free, 13% alive with disease, 34% deceased. 3 patients displayed late progression over 2 years after ASCT. The estimated 1, 2 and 5-year PFS rates were 62%, 57% and 52% respectively and OS rates were 73%, 65% and 61%. Survival by IPFSG and IGCCG risk categories are displayed in the table below. Conclusions: This is the first registry-based audit of HDCT for metastatic GCT from ANZ, which has demonstrated our outcomes are comparable with best international practice.

Gemcitabine, Oxaliplatin and Paclitaxel (GemPOx) in Patients with Relapsed or Refractory Germ Cell Tumors After High Dose Chemotherapy, A Retrospective Single-Center Experience

Germ cell tumors are chemosensitive tumors, and patients with metastatic germ cell tumors can be cured even in the metastatic setting. There are limited treatment options for the patients who have refractory or recurrent disease after high dose chemotherapy (HDCT) with autologous stem cell transplantation. We aimed to show real-life data on health outcomes in adult patients with recurrent or refractory germ cell tumor who received the gemcitabine, oxaliplatin, and paclitaxel (GemPOx) combination regimen.We analyzed the data of 33 patients receiving GemPOx regimen after HDCT in our department between January 2016 and January 2020. Primary objectives were overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The mean age of the study group was 31.5 ± 8.2 years. Of the 33 patients, 27 (81.8%) were men. The median OS and PFS were 16 months (95% CI: 7.33-24.7) and 10 months (95% CI: 5.1-14.9), respectively. The one-year OS and PFS were 65.7% and 40%, respectively. ORR was 42.4%. Toxicity was managable.Our study demonstrates acceptable safety and efficacy of GemPOx regimen for relapsed refractory patients with germ cell tumors. GemPOx remains one of the best determined systemic treatment options for progressive germ cell tumors patients after HDCT. Keywords: Gemcitabine, Oxaliplatin, Paclitaxel, Germ cell tumors, High dose chemotherapy