First-line Cisplatin-based Chemotherapy Research Articles

High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included 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. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Prognostic factors for overall survival in patients with advanced digestive neuroendocrine carcinoma treated with first-line cisplatin-based chemotherapy: A post-hoc analysis of JCOG1213.

594 Background: Advanced digestive neuroendocrine carcinoma (ADNEC) is a rare and aggressive malignancy without evidence of prognostic factors assessed in prospective studies. We aimed to evaluate prognostic factors in patients with ADNEC receiving first-line cisplatin-based chemotherapy. Methods: This is a post-hoc analysis of JCOG1213, which is a phase 3 randomized trial showing equivalent overall survival (OS) for cisplatin plus etoposide versus cisplatin plus irinotecan as first-line chemotherapy for patients with ADNEC. The primary endpoint of JCOG1213 was OS. For this post-hoc analysis of prognostic factors, patients who had ineligible histology based on the central pathological review or who lacked the necessary clinical data for analysis were excluded. A Cox proportional hazard model was used to assess the effect of independent variables on OS. Priori variables selected on previous reports (performance status (PS), Ki-67 index, and serum LDH level), as well as variables that remained at a level of p-value <0.20 by backward stepwise selection, were incorporated in the final model of OS. Results: Among 170 patients enrolled in JCOG1213, a total of 129 patients with ADNEC were included in this analysis. In multivariable analysis, serum LDH level (> upper normal limit vs. normal) was identified as a significant prognostic factor for OS (HR = 1.721, 95% CI: 1.144–2.589, p = 0.009). Other clinicopathological factors were not found to be significant, including PS (1 vs. 0; HR = 0.784, 95% CI: 0.507–1.214, p = 0.276), Ki-67 (≥ 55% vs. < 55%; HR = 1.475, 95% CI: 0.588–3.698, p = 0.407), liver metastasis (present vs. absent; HR = 1.434, 95% CI: 0.968–2.124, p = 0.072), sex (female vs. male; HR = 1.387, 95% CI: 0.937–2.053, p = 0.102), and serum ALP level (> upper normal limit vs. normal; HR = 0.948, 95% CI: 0.639–1.406, p = 0.789). OS of patients with elevated serum LDH levels was shorter than those with normal serum LDH levels (median: 9.5 months vs. 15.6 months, p = 0.0019). No statistically significant differences were observed between the two groups regarding objective response rate (58.8% vs. 54.1%, p = 0.594) and progression-free survival (median: 4.5 months vs. 5.9 months, p = 0.141). A numerically lower proportion of patients with elevated serum LDH levels received second-line chemotherapy than those with normal serum LDH levels (76.5% vs. 88.3%). Conclusions: Serum LDH level may serve as a prognostic factor in the daily practice of patients with ADNEC and as a risk stratification factor in future randomized clinical trials. Clinical trial information: UMIN000014795 .

Concomitant Immunotherapy and Metastasis-Directed Radiotherapy in Upper Tract Urothelial Carcinoma: A Biomarker-Driven, Original, Case-Based Proof-of-Concept Study.

Metastatic upper tract urothelial carcinoma (mUTUC) has a poor prognosis. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in patients with metastatic urothelial carcinoma. However, data supporting the use of ICIs in patients with mUTUC are limited. A promising synergy between ICI and concomitant radiotherapy (RT) has been reported in patients with mUTUC. Our research involved a case-based investigation and emphasized the successful integration of different specialists' skills. Observed after partial urethrectomy procedures for muscle-invasive upper tract urothelial carcinoma (UTUC), the radiological detection of lung metastases prompted us to implement cisplatin-based first-line chemotherapy and molecular characterization in the treatment process. We uncovered alterations in the ERBB2 and FGFR3 genes and mismatch repair deficiency at a molecular level. First-line chemotherapy treatment led to a stable disease, and the patient was started on maintenance immunotherapy with Avelumab. Subsequently, an increase in the size of the lung nodules was described, and the patient received radiotherapy for three lung lesions in combination with immunotherapy. After 3 months, a restaging CT scan reported a complete response, which is still ongoing. We discuss the mechanisms driving RT/ICI synergy and the molecular profile of mUTUC as factors that should be considered in therapeutic strategy planning. Molecular insight enhances the originality of our study, providing a nuanced understanding of the genetic landscape of mUTUC and paving the way for targeted therapeutic strategies. The therapeutic armamentarium expansion encourages the design of a multimodal and personalized approach for each mUTUC patient, taking into account tumor heterogeneity and molecular profiling.

Risk Factors for Relapse in Nonseminomatous Testicular Cancer After Postchemotherapy Retroperitoneal Lymph Node Dissection With Viable Residual Cancer.

No consensus exists on the management of men with nonseminoma and viable nonteratomatous germ cell tumor in the postchemotherapy retroperitoneal lymph node dissection (pcRPLND) specimen after first-line chemotherapy. We analyzed surveillance versus different adjuvant chemotherapy regimens and the influence of time to pcRPLND on oncologic outcomes. Data on 117 men treated with cisplatin-based first-line chemotherapy between 1990 and 2018 were collected from 13 institutions. All patients had viable nonteratomatous germ cell tumor in the pcRPLND specimen. Surgery was performed after a median of 57 days, followed by either surveillance (n = 64) or adjuvant chemotherapy (n = 53). Primary end points were progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). After controlling for International Germ Cell Cancer Cooperative Group risk group and percent of viable malignant cells found at RPLND, no difference was observed between men managed with surveillance or adjuvant chemotherapy regarding PFS (hazard ratio [HR], 0.72 [95% CI, 0.32 to 1.6]; P = .4), CSS (HR, 0.69; 95% CI, 0.20 to 2.39; P = .6), and OS (HR, 0.78 [95% CI, 0.25 to 2.44]; P = .7). No statistically significant differences for PFS, CSS, or OS were observed on the basis of chemotherapy regimen or in men treated with pcRPLND ≤57 versus >57 days after first-line chemotherapy. Residual disease with <10% versus ≥10% viable cancer cells were associated with a longer PFS (HR, 3.22 [95% CI, 1.29 to 8]; P = .012). Relapse in the retroperitoneum was observed in 34 (29%) men. Men with a complete resection at pcRPLND and <10% viable cells have favorable outcomes without further treatment. Complete retroperitoneal resection seems more important than early pcRPLND.

The usage of Pembrolizumab in Metastatic Urothelial Carcinoma

Bladder cancer is common cancer threatening countless people’s lives. Urothelial carcinoma contributes to 90% of bladder cancer cases and has a low average five-year relative survival rate of 6% if metastasized. Finding appropriate therapy for those with metastatic urothelial carcinoma (MUC) is therefore crucial. Most patients cannot get first-line cisplatin-based chemotherapy, and a small number cannot receive any platinum-based treatment. The immune checkpoint inhibitor pembrolizumab blocking the PD-1 with the PD-L1 protein expressed on urothelial carcinoma cells. This blockade reduces immunosuppressive effects and restores effective neoplastic cell eradication. Compared to conventional chemotherapy strategies, pembrolizumab had significant improvement in the safety profile, reduction of adverse effect rate, and elongation of survival under certain conditions. It offers an alternative treatment option for those who are ineligible for chemotherapy. Pembrolizumab has been given the approval to be used in first-line settings for patients who are ineligible for platinum and second-line settings for patients who have already had chemotherapy. This paper summarizes the mechanism and application of pembrolizumab for treating MUC. The drug’s efficacies under different conditions, advantages, current issues, and future investigation directions are discussed.

Prevalence and risk factors for ototoxicity after cisplatin-based chemotherapy.

Ototoxicity is a prominent side effect of cisplatin-based chemotherapy. There are few reports, however, estimating its prevalence in well-defined cohorts and associated risk factors. Testicular cancer (TC) survivors given first-line cisplatin-based chemotherapy completed validated questionnaires. Descriptive statistics evaluated the prevalence of ototoxicity, defined as self-reported hearing loss and/or tinnitus. We compared patients with and without tinnitus or hearing loss using Chi-square test, two-sided Fisher's exact test, or two-sided Wilcoxon rank sum test. To evaluate ototoxicity risk factors, a backward selection logistic regression procedure was performed. Of 145 TC survivors, 74% reported ototoxicity: 68% tinnitus; 59% hearing loss; and 52% reported both. TC survivors with tinnitus were more likely to indicate hypercholesterolemia (P = 0.008), and difficulty hearing (P < .001). Tinnitus was also significantly related to age at survey completion (OR = 1.79; P = 0.003) and cumulative cisplatin dose (OR = 5.17; P < 0.001). TC survivors with hearing loss were more likely to report diabetes (P = 0.042), hypertension (P = 0.007), hypercholesterolemia (P < 0.001), and family history of hearing loss (P = 0.044). Risk factors for hearing loss included age at survey completion (OR = 1.57; P = 0.036), hypercholesterolemia (OR = 3.45; P = 0.007), cumulative cisplatin dose (OR = 1.94; P = 0.049), and family history of hearing loss (OR = 2.87; P = 0.071). Ototoxicity risk factors included age, cisplatin dose, cardiovascular risk factors, and family history of hearing loss. Three of four TC survivors report some type of ototoxicity; thus, follow-up of cisplatin-treated survivors should include routine assessment for ototoxicity with provision of indicated treatments. Survivors should be aware of risk factors associated with ototoxicity. Referrals to audiologists before, during, and after cisplatin treatment is recommended.

Patient-Reported Functional Impairment Due to Hearing Loss and Tinnitus After Cisplatin-Based Chemotherapy.

Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score (P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

Changes in CoQ10/Lipids Ratio, Oxidative Stress, and Coenzyme Q10 during First-Line Cisplatin-Based Chemotherapy in Patients with Metastatic Urothelial Carcinoma (mUC).

Oxidative stress plays an important role in cancer pathogenesis, and thiobarbituric acid-reactive substance level (TBARS)-a parameter of lipid peroxidation-has prognostic significance in chemotherapy-naive patients with metastatic urothelial carcinoma (mUC). However, the effect of cisplatin (CDDP)-based chemotherapy on oxidative stress, coenzyme Q10, and antioxidants remains unknown. The objective of this prospective study was to determine possible changes in the CoQ10 (coenzyme Q10)/lipids ratio, antioxidants (α-tocopherol, γ-tocopherol, β-carotene, CoQ10), total antioxidant status (TAS), and TBARS in plasma at baseline and during first-line chemotherapy based on CDDP in mUC subjects. In this prospective study, 63 consecutive patients were enrolled. The median age was 66 years (range 39-84), performance status according to the Eastern Cooperative Oncology Group (ECOG) was 2 in 7 subjects (11.1%), and visceral metastases were present in 31 (49.2%) patients. Plasma antioxidants were determined by HPLC and TAS and TBARS spectrophotometrically. After two courses of chemotherapy, we recorded significant enhancements compared to baseline for total cholesterol (p &lt; 0.0216), very low-density lipoprotein (VLDL) cholesterol (p &lt; 0.002), triacylglycerols (p &lt; 0.0083), α-tocopherol (p &lt; 0.0044), and coenzyme Q10-TOTAL (p &lt; 0.0001). Ratios of CoQ10/total cholesterol, CoQ10/HDL-cholesterol, and CoQ10/LDL-cholesterol increased during chemotherapy vs. baseline (p &lt; 0.0048, p &lt; 0.0101, p &lt; 0.0032, respectively), while plasma TBARS declined (p &lt; 0.0004). The stimulation of antioxidants could be part of the defense mechanism during CDDP treatment. The increased index of CoQ10-TOTAL/lipids could reflect the effect of CDDP protecting lipoproteins from peroxidation.

Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors

BackgroundWe conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).Patients and methodsFor dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with previous anti-PD-1/PD-L1 therapy. Patients received eprenetapopt 4.5 g/day intravenously (IV) on days 1-4 with pembrolizumab 200 mg IV on day 3 in each 21-day cycle. Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and recommended phase II dose (RP2D) of eprenetapopt.ResultsForty patients were enrolled (median age 66 years; range 27-85) and 37 received eprenetapopt plus pembrolizumab. No DLTs were reported and the RP2D for eprenetapopt in combination was 4.5 g/day IV on days 1-4. The most common eprenetapopt-related AEs were dizziness (35.1%), nausea (32.4%), and vomiting (29.7%). AEs leading to eprenetapopt discontinuation occurred in 2/37 patients (5.4%). In efficacy-assessable patients (n = 29), one achieved complete response (urothelial cancer), two achieved partial responses (NSCLC, urothelial cancer), and six patients had stable disease.ConclusionsThe eprenetapopt plus pembrolizumab combination was well tolerated with an acceptable safety profile and showed clinical activity in patients with solid tumors.

Second-line therapy in testicular germ cell tumours: results from a tertiary cancer care centre in India.

BackgroundMalignant testicular neoplasms constitute about 1% of all cancers in males. This is one of the most common tumours in adolescents and young adult males. After the introduction of cisplatin-based chemotherapy, the survival of germ cell tumour patients, even those with poor prognostic risk factors, has significantly improved over the years. Second-line chemotherapy in patients who have progressed over the first-line cisplatin-based chemotherapy has shown convincing 5 years of overall survival (OS).MethodologyThis study is a retrospective analysis of testicular cancer patients from 2014 to 2020 who have received salvage chemotherapy treatment at Tata Memorial Centre. Patient demographics, tumour characteristics and treatment details were recorded in a specific format, and progression-free survival and OS were analysed along with response to therapy.ResultsA total of 46 testicular cancer patients from 2014 to 2020, who received second-line chemotherapy, were analysed from the database maintained at our hospital. The median age at diagnosis was 29.5 (18–60) years. Most of the patients (30, 65.2%) presented with lung metastasis and 11 (23.9%) patients with liver metastasis. Most of the patients (21, 45.6%) received vinblastine, ifosfamide and cisplatin, whereas 13 (28.2%) patients received paclitaxel, ifosfamide and cisplatin regimen and 7 (15.2%) patients received GemOx regimen as the second-line chemotherapy. Median OS was observed to be 33.97 months and median progression-free survival was 29.01 months.ConclusionSecond-line chemotherapy in testicular germ cell tumours can result in long-term disease control and all patients who are fit to tolerate second-line therapy should be offered it. Patients with relapsed seminoma did better than relapsed non-seminomatous germ cell tumours.

Impact of adverse health outcomes (AHOs) on self-reported physical and mental health in U.S. testicular cancer survivors (TCS).

12080 Background: No study has systematically evaluated the impact of AHOs on PROMIS-validated measures of physical and mental health in TCS. Patient-reported outcomes are increasingly recognized as crucial in TCS follow-up, given their young age at diagnosis and high cure rates. Methods: Eligible TCS (age &lt; 60 yr at diagnosis, given first-line cisplatin-based chemotherapy (CHEM)) completed comprehensive health surveys, prescription drug usage, and PROMIS global physical health and global mental health measures. PROMIS scores were compared to US subpopulation norms for similar-age men. 2017-2018 NHANES data were compared with select survey responses. Linear regression examined the relationship between individual AHOs (pain, obesity, cisplatin-induced peripheral neuropathy (CIPN)), cisplatin-related AHOs (CIPN, hearing loss, vertigo, tinnitus, renal disease), cardiovascular (CVD) AHOs (7 AHO), and all AHOs taken together (24 AHOs), with PROMIS global physical and mental health measures. Regression models were adjusted for age, cisplatin dose, time since CHEM, education, income, smoking, and alcohol. Results: Among 213 TCS (median age at evaluation: 46 yr; IQR: 38-52 yr; median time since CHEM completion: 10.6 yr; IQR: 6.8-16.6 yr), the most common AHOs were tinnitus (60%), self-reported hearing loss (60%), CIPN (55%), and Raynaud Phenomenon (43%). The median number of AHOs was 5 (IQR: 3-7), and 12% of TCS had ≥10 AHOs. Only 1.4% of TCS had no AHOs. Compared to NHANES men without cancer, controlling for age, education, and race, fewer TCS currently smoked (3% vs. 22%; P&lt;.001) and fewer were obese (31% vs. 43%, P=.026) but alcohol intake was comparable. However, TCS had significantly lower physical (mean: 48.5 vs. 51.2, P&lt;.001) and mental health (mean: 48.4 vs. 50.8, P&lt;.001) than US men. Increasing numbers of AHOs were significantly associated with decreasing physical ( P&lt;.001) and mental health ( P&lt;.001) after adjustment. The magnitude of effect was strongest for the number of cisplatin-related AHOs with both physical (β: -1.3; 95% CI: -1.9, -0.7; P&lt;.001) and mental health (β: -1.3; 95% CI: -2.1, -0.4; P=.003) after adjustment. In individual AHO adjusted models, CIPN (β: -1.8; 95% CI: -3.3, -0.4), pain (β: -5.0; 95% CI: -6.8, -3.2) and obesity (β: -2.7; 95% CI: -4.3, -1.1) were significantly associated with decreased physical health. Only pain (β: -5.9; 95% CI: -8.4, -3.4) and CIPN (β: -2.0; 95% CI: -4.0, -0.1), but not obesity, were associated with decreased mental health. Conclusions: At a median of 11 years after CHEM completion, 50% of TCS have ≥5 AHOs, and over 1 in 10 have ≥10 AHOs. AHO following cisplatin chemotherapy have major deleterious impacts on patient-reported measures of physical and mental health. Future survivorship research should focus on developing preventive and interventional strategies to care for TCS most vulnerable for impaired physical and mental health after CHEM.

First-line salvage treatment options for germ cell tumor patients failing stage-adapted primary treatment

PurposeIn this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors.MethodsThis work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety.ResultsRelapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10–15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success.ConclusionsPatients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients’ survival.

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.

Randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor.

TPS429 Background: High-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) is effective salvage therapy in patients with relapsed germ-cell tumors (GCT). Utilizing HDCT and PBSCT in the 2nd line setting, cures can be achieved in about 60% of patients with relapsed non-seminoma. Maintenance daily oral etoposide after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the efficacy and safety of maintenance daily oral etoposide after HDCT+PBSCT in patients with relapsed non-seminoma. Methods: This randomized phase II open label trial is evaluating maintenance oral etoposide after HDCT+PBSCT. Eligible patients are adults with metastatic non-seminomatous GCT who have progressive disease after first-line cisplatin-based combination chemotherapy. All patients will complete initial salvage with HDCT+PBSCT with the carboplatin/etoposide Indiana protocol x2 tandem cycles. All patients should have normal or declining tumor markers (AFP and/or hCG) at time of randomization and absence of progressive disease on imaging. Adverse events from prior therapy, including hematologic toxicity, should be recovered to grade≤2 at time of randomization. Randomization should occur within ≤16 weeks from time of the 2nd cycle of HDCT. Patients with primary mediastinal non-seminoma are eligible. Patients with relapsed pure seminoma are excluded. Patients are randomized in 1:1 ratio to receive maintenance etoposide vs. standard of care surveillance post HDCT. Randomization will be stratified by platinum refractory status defined as progression within 4 weeks of first-line chemotherapy (yes vs no). Patients randomized to treatment arm will receive oral etoposide 50mg/m2 daily for 21 consecutive days of 28 day cycles. A total of 3 cycles will be delivered. Weekly labs including CBC w differential will be checked to detect hematological toxicity. The primary objective is to compare the 12-month progression-free survival (PFS) for maintenance etoposide vs observation in patients with relapsed non-seminoma post HDCT. Secondary objectives include to assess the toxicity and tolerability of maintenance etoposide, and 12-month overall survival. Exploratory analysis of the biomarker micro-RNA371 at time of randomization and correlation with disease progression/relapse will be performed. As of September 20, 2021, 5 of the total sample (N = 64) have been enrolled and randomized. Clinical trial information: NCT04804007.

Impact of FDA label change on immunotherapy for metastatic urothelial cancer (mUC) and subsequent changes in mortality.

459 Background: In May 2017, atezolizumab and pembrolizumab (IO) received accelerated approval for first-line treatment of cisplatin-ineligible patients with mUC, irrespective of PDL1 test status. In June 2018, the FDA and EMA restricted IO to cisplatin-ineligible patients with PDL1 positive tumors based on early review of data from confirmatory trials which suggested decreased overall survival in patients with PDL1 negative tumors treated with IO. We assessed the impact of the FDA label change on clinical outcomes of mUC patients in routine care. Methods: We conducted a controlled interrupted time series analysis using the US Flatiron Health electronic health record-derived de-identified database. The study sample included patients from 280 cancer clinics nationwide diagnosed with mUC and compared patients potentially impacted by the label change (cisplatin ineligible patients initiating first-line IO or carboplatin-based chemotherapy) to a comparator group who would have been unaffected by the label change (patients initiating first-line cisplatin-based chemotherapy) from 01 April 2017 to 17 May 2018 (pre-label change) and 20 June 2018 to 01 March 2020 (post-label change), excluding a 30-day wash out period encompassing the time-period between the initial FDA safety alert (18 May 2018) and the official FDA label change (19 June 2018). We used Cox regression to estimate adjusted pre-/post-label change related mortality differences in patients receiving carboplatin-chemotherapy or IO, accounting for secular changes in survival through comparison with the cisplatin comparator group. Results: The study included 829 patients with mUC initiating treatment in the pre-label change period (582 IO or carboplatin, 247 cisplatin) and 1,184 patients in the post-label change period (849 IO or carboplatin, 336 cisplatin), respectively. The use of IO, carboplatin, and cisplatin was similar across time-periods (pre-label change: 44.4%, 25.8%, and 29.8%; post-label change: 48%, 23.6%, 28.4%); while PD-L1 testing increased (6.6% to 28.1%). In adjusted models, there were no differences in survival in any of the groups following the FDA label change policy (table). Conclusions: The U.S. FDA label restriction on first-line immunotherapy was associated with increased PD-L1 testing but was not associated with changes in treatment patterns or improved mortality among patients with mUC.[Table: see text]

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy.

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

Retroperitoneal lymph node dissection in patients with advanced non-seminomatous germ cell testicular tumors and incomplete radiological and serological response to chemotherapy: results

Objective: To evaluate the results of retroperitoneal lymph node dissection (RPLND) in patients with advanced non-seminomatous germ cell testicular tumors (NSGCT) and incomplete serological and radiological response to chemotherapy (CT).Materials and methods: The study included 96 patients with advanced NSGCT who underwent RPLND in N.N. Blokhin Russian Cancer Research Center in 1983-2020. The median age was 27 (15-57) years. All patients (n = 96, 100,0 %) received first-line cisplatin-based CT. Fifty-eight patients (60,4%) received second-line CT. After completion of CT, all patients presented with elevated levels of AFP and/or hCG and detectable tumor lesions (retroperitoneal metastases only in 77 cases (80,2 %), metastases in the retroperitoneal space and other sites in 19 cases (19,8%)). All patients underwent the follow-up surgery after CT completion: RPLND in 96 cases (100,0%) and resection of extra-retroperitoneal lesions in addition to RPLND in 8 cases (8,3%). In total, 29 (30,2%) of 96 patients received CT following surgery. The median follow-up was 39,4 (1-284) months.Results: Postoperative complications were reported in 10 (10,6%) patients, including grade 3-4 in 3 patients (3,1%). The mortality rate was 1,1%. The complete resection of retroperitoneal tumor lesions was performed in 80 cases (83,3 %), resection of all detectable tumor lesions in 69 cases (71,9%). None of the patients achieved complete response to postoperative CT. Pathological examination of retroperitoneal lesions revealed necrosis and fibrosis, teratomas, and malignant non-seminomatous tumors in 25 (26,0 %), 29 (30,2 %), and 42 (43,8 %) cases, respectively. The long-term overall survival (OS) and cancer-specific survival rates were 60,9 % and 61,7 %, respectively. The relapse-free survival rate in patients who underwent complete resection reached 65,2 %, the progression-free survival rate in patients who underwent incomplete resection was 35,9 %. A multivariate analysis revealed the following independent predictors of unfavorable OS: RPLND after second-line CT (odds ratio [OR] 4,667 (95% confidence interval [CI]: 1,987-10,961)), presence of a residual retroperitoneal mass of a malignant non-seminomatous tumor (OR 3,081 (95% CI: 1,178-8,055), and incomplete removal of residual lesions after CT (OR 4,445 (95% CI: 1,813-10,899)).Conclusion: Post-CT RPLND may be considered a viable option in the selected group of advanced NSGCT patients with an incomplete serological response to CT eligible for complete resection of all detectable tumor lesions.

AUREA study: Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC): A SOGUG study.

TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age &gt; 70 years, PS ECOG 0-2, creatinine Clearance &gt;30 and &lt;60 mL/min per Cockroft-Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky´s criteria, will be allowed, prior discussion with PI. Exclusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished &gt; 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.

The Synthetic Capsaicin‐analog Arvanil sensitizes Cisplatin‐Resistant Human Lung Cancer Cells to the pro‐apoptotic activity of Irinotecan

Cisplatin-based combination therapy is the standard of care for the treatment of human lung cancer. Initially, cisplatin shows excellent therapeutic response but the tumor inevitably relapses (within a year) and this relapsed tumor is resistant to cisplatin. A few human lung cancers do not respond to cisplatin-based first-line chemotherapy. These patients are said to have platinum-refractory lung tumors. Patients with platinum resistant or refractory disease have very limited options, as the only standard chemotherapy with an FDA-approved drug, irinotecan has an objective response rate of approximately 3% and little or no survival benefit. Therefore, agents which improve the therapeutic response (of human lung cancers) towards irinotecan may be useful for the treatment of cisplatin-resistant human lung cancer. The nutritional compound capsaicin sensitized cisplatin-resistant H69-CPR human small cell lung cancer (SCLC) cells towards irinotecan-induced apoptosis. Arvanil is a synthetic capsaicin-analog which displays enhanced growth-suppressive activity in human SCLC. The present study aims to investigate the combinatorial apoptotic activity of arvanil and irinotecan in cisplatin-resistant lung cancer. Caspase-3 activity assays reveal that the combination of irinotecan and arvanil displayed greater apoptotic activity in H69-CPR human cisplatin-resistant SCLC cells than the drugs used alone. These experiments were repeated in a second cisplatin-resistant lung cancer cell line PC9-CDDP and similar results were obtained. Chou-Talalay isobologram analysis showed the interaction between irinotecan and arvanil is synergistic in H69-CPR and PC9-CDDP cells. The combination of arvanil/irinotecan showed a greater synergistic pro-apoptotic activity than the combination of capsaicin/irinotecan. in H69-CPR and PC9-CDDP cells. The pro-apoptotic activity of arvanil/irinotecan was mediated elevation of intracellular calcium and required the calpain pathway. Taken together, our findings pave the way for the discovery of novel combination therapies for the therapy of cisplatin-resistant human lung cancer.

Comprehensive genomic profiling (CGP) in patients with relapsed/refractory germ cell tumors (GCT).

388 Background: Understanding the genetic alterations in patients with relapsed/refractory GCT (rrGCT) could delineate the pathogenesis of cisplatin resistance. Our study uses CGP to characterize genomic alterations (GA) in refractory GCT and correlate with clinical outcomes. Methods: 432 patients with rrGCT were seen at Indiana University between Jan 2016 to Sep 2019 of whom 52 patients underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PDL1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients relapsed after first-line cisplatin-based combination chemotherapy. Median age at diagnosis was 33 (range 15-68). Primary site of GCT was testicular in 85% and mediastinum in 8%. 6 patients had pure seminoma and 46 had non-seminoma. Platinum refractory disease, defined as serologic or radiographic progression within 4 weeks of first-line chemotherapy comprised 23% of patients. The primary tumor was used for sequencing in 6 cases (12%) and non-primary tumor metastatic site (lymph node, lung, liver, brain, omentum) in 46 cases (88%). The most common GA in the entire cohort were FGF6 (27%), FGF23 (27%), KDM5A (27%), CCND2 (27%), KRAS (18%), TP53 (14%), KIT (8%), APC (8%), ZNF217 (6%), MUTYH (6%), AURKA (6%), NRAS (6%), EGFR (6%), CTNNB1 (6%), GNAS (6%). Most common alterations for testicular primary tumors were FGF6, FGF23, KDM5A, CCND2, KRAS, TP53, KIT. For non-testicular primary GCT, most common GA were APC, TP53, EGFR. Most common GA for non-seminoma were FGF6, FGF23, KDM5A, CCND2, KRAS, TP53, APC. Most common GA for pure seminoma was KIT. Potentially targetable genomic alterations were found in 17 patients (33%). 10 of 17 patients (59%) tested had PDL1 score ≥1% and 3 patients had PDL1 ≥50%. Median TMB was 3.5 mutations/MB. There were 4 patients (8%) with TMB ≥ 10 mutations/Mb and 2 patients (4%) with TMB ≥ 20 mutations/Mb. 1 of 48 patients (2%) evaluated for MSI had MSI-High status. Isochromosome 12p was detected in the majority of samples where it was tested. Outcomes with GA-directed therapy will be presented at the conference. Conclusions: CGP can reveal potential therapeutic targets in patients with rrGCT including EGFR, ERBB3, KIT, and MET. Consistent with reported clinical trials in rrGCT, biomarkers predicting response to immune checkpoint blockade are uncommon with most patients having low TMB, absence of MSI-H status, and low expression of PDL1.