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Bladder cancer (BC) presenting with pelvic and retroperitoneal lymph nodes presents a therapeutic challenge. The impact of chemoradiotherapy on pelvic and retroperitoneal lymph node metastasis as a consolidation treatment has not been established. Between 2009 and 2020, 502 patients who were treated with first-line chemotherapy for BC in our center, were retrospectively identified. Patients who received chemoradiotherapy or radiotherapy with an equivalent radiation dose superior to 30 Gy were included in the RTCT group, and other patients were included in the control group (CT group). We performed an analysis of progression-free survival (PFS) and overall survival (OS) for these two cohorts using the Kaplan–Meier method. A total of 89 patients were included, 24 in the RTCT group and 65 in the CT group. Chemoradiotherapy improved both OS (p = 0.034) and PFS (p = 0.009) in comparison with chemotherapy alone: 26.3 months (95% IC 0.0–52.9) and 19.4 months (95% IC 5.0–33.7), respectively, in the RTCT group versus 17.2 months (95% IC 13.7–20.6) and 11.2 months (95% IC 8.6–13.8), respectively, in the CT group. Grade 3/4 toxicity was related to chemotherapy and to chemoradiotherapy at levels of 31% and 24%, respectively. For mBC with metastatic regional or retroperitoneal lymph nodes, chemoradiotherapy seems to confer benefits for both OS and PFS.

Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

Venous-thromboembolism (VTE) is increased in lung cancer patients (LCP) treated with immune-checkpoint inhibitors (ICIs) but risk factors are not identified and the Khorana Score (KS) is not validated. To assess VTE incidence and its clinical impact, to investigate potential clinical risk factors and KS performance in LCP. Retrospective analysis of LCP initiating ICIs treatment between June 2015 and November 2020 in a for-profit cancer center. 481 patients were included: 62% adenocarcinoma, 70% PDL1 + , 86% stage-IV-disease. Over a median follow-up of 9.8 months, 47 VTE were observed: 28 pulmonary embolisms, 15 deep venous thromboses (distal n = 9, proximal n = 6), 3 inferior vena cava thromboses, 1 other VTE, no superficial or digestive vein thrombosis. Median time from ICIs' initiation to VTE was 180 (11-1277) days. Overall survival was significantly lower in patients who experienced VTE (42.5 vs. 86.8 months, p = 0.006). In univariate analysis patients VTE was more frequent in metastatic patients (11.1% vs. 1.5%, p = 0.015) and lower in those treated with durvalumab (1.9% vs. 9.6%, p = 0.046). Logistic regression analysis showed that non-metastatic status (OR 0.13; 0.02-0.95, p = 0.04) and BMI (OR 1.07; 1.01-1.14, p = 0.028) were associated with VTE. The rate of VTE was the same in patients with a KS or ≥ 2 (10.2% vs. 9.3%, p = 0.87). ICIs-treated LCP are at high risk of thromboembolism. VTE has a negative impact on survival. KS does not perform well in LCP. It is important to identify which VTE prediction models are available to be used in adult ambulatory lung cancer patients.

471 Background: In the phase 3 JAVELIN Bladder 100 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) vs BSC alone in pts with aUC that had not progressed with 1L platinum-based chemotherapy (CTx). The JAVELIN Bladder regimen is now standard of care with level 1 evidence in international treatment guidelines. The AVENANCE study (NCT04822350), is investigating the efficacy and safety of avelumab 1L maintenance in a real-world population of pts with aUC in France. Data from the full analysis set are reported for the first time. Methods: In this ongoing, noninterventional, ambispective study, eligible pts have locally advanced or metastatic UC that has not progressed with 1L platinum-based CTx and previous, ongoing, or planned avelumab 1L maintenance treatment. The primary endpoint is OS from start of avelumab; secondary endpoints include progression-free survival (PFS), duration of treatment (DOT), and safety. Results: 591 pts received avelumab. At data cutoff (July 31, 2022), median follow-up was 12.0 mo (95% CI, 10.9-12.9). Median age was 73.1 y (IQR, 67.0-78.1). At start of 1L CTx (excluding pts with missing data), disease stage was metastatic in 524 pts (90.5%; visceral metastases in 426 [81.5%]) and locally advanced in 54 (9.3%). ECOG PS was 0-1 in 407 pts (85.3%) and 2-3 in 69 (14.5%). Tumor histology was pure UC in 528 pts (91.8%) and UC with variant or pure variant in 47 (8.2%). 1L CTx was gemcitabine + carboplatin (GemCarbo), gemcitabine + cisplatin (GemCis), dose-dense methotrexate + vinblastine + adriamycin + cisplatin (DD-MVAC), and other in 353 (61.0%), 170 (29.4%), 28 (4.8%), and 28 (4.8%) pts, respectively. Median number of cycles was 5 (range, 1-10). Median DOT with avelumab was 5.8 mo (95% CI, 5.2-7.0); 241 pts (40.8%) remained on treatment at data cutoff. The most common reasons for treatment discontinuation were disease progression (74.1% [n=258]), death (11.5% [n=40]), and adverse events ([AEs] 10.3% [n=36]). Median OS from start of avelumab was 18.4 mo (95% CI, 15.4-not estimable [NE]), the 12-month OS rate was 64.8% (95% CI, 60.0%-69.1%), and median PFS was 5.7 mo (95% CI, 5.3-7.0). In pts who had received GemCarbo, GemCis, or DD-MVAC, median OS (95% CI) was 16.2 mo (13.4-NE), not reached (NR; 18.1-NE), and NR (15.2-NE), respectively. Subgroups analyses will be presented. 218 pts received subsequent 2L, including CTx, antibody-drug conjugates, immunotherapy, and other in 186 (85.3%), 22 (10.1%), 6 (2.8%), and 4 (1.8%) pts, respectively. Any-grade treatment-related AEs (TRAEs) occurred in 217 pts (36.7%), including serious TRAEs in 29 (4.9%). Conclusions: Real-world data for avelumab 1L maintenance in pts with aUC from AVENANCE support the findings of JAVELIN Bladder 100 and confirm the clinical activity and acceptable safety profile of avelumab in a heterogeneous population. Clinical trial information: NCT04822350 .

International audience; Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective studies suggested a decrease in Prostate Cancer incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in Prostate Cancer preclinical models, with increased apoptosis when added to DOCE. We aimed at exploring the role of MET in combination with DOCE in mCRPC.Patients and methods: Non-diabetic mCRPC patients were randomly assigned to receive DOCE 75 mg/m2 every 21 days + prednisone (5 mg. BID) with either MET 850 mg BID (D+M) or placebo (D+P) up to 10 cycles. Prostate-Specific Antigen (PSA) response ≥50% from baseline was the primary end point. Secondary end points included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL).Results: Out of 99 patients were randomized (D+M = 50; D+P = 49) in 10 French centers. The median follow-up was 86 (IQR 73-88) months. The PSA-response rate reached 66% in the D+M arm, but was not different from that observed in the D+P arm (63%, P = 0,94). In the D+M and D+P arms, the ORR was 28% and 24%, the median PFS was 7.8 and 6.0 months and the median OS was 27 and 20 months (ns), respectively. Diarrhea grade I to II was more frequent in the MET arm (66% vs. 43%). No impairment of QoL was observed.Conclusion: MET addition failed to improve the standard DOCE regimen in mCRPC. Further research targeting tumor cell metabolism should be performed.

Background: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum–etoposide) in treatment-naive patients with ES-SCLC. Methods: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum–etoposide; durvalumab plus tremelimumab plus platinum–etoposide; or platinum–etoposide alone. All drugs were administered intravenously. Platinum–etoposide consisted of etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL per min or cisplatin 75–80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum–etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum–etoposide group versus the platinum–etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. Findings: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum–etoposide group and 269 to the platinum–etoposide group. Durvalumab plus platinum–etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59–0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5–14·8) in the durvalumab plus platinum–etoposide group versus 10·3 months (9·3–11·2) in the platinum–etoposide group, with 34% (26·9–41·0) versus 25% (18·4–31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum–etoposide group and 166 (62%) of 266 in the platinum–etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. Interpretation: First-line durvalumab plus platinum–etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. Funding: AstraZeneca.

9094 Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p < 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587. [Table: see text]

BackgroundOSE2101 (Tedopi®) is an anticancer vaccine with HLA-A2+ restricted modified epitopes targeting five tumor-associated antigens (TAAs) frequently expressed in lung cancer (CEA, HER2, MAGE2, MAGE3, P53). Step-1 results of the phase III, randomized, open-label ATALANTE-1 study comparing Tedopi® vs standard treatment (SoC) showed a favorable benefit/risk of Tedopi® over SoC (HR 0.71 for overall survival OS) in HLA-A2+ NSCLC patients in 2nd or 3rd line treatment after progression on immune checkpoint blockers (ICB).1 We analyze available tumor biopsies at initial diagnosis from some patients treated with Tedopi® to determine the expression of the 5 TAAs and to identify other tumor factors associated with long-term survival.MethodsTumor biopsies were available for 8 HLA-A2+ (blood test) stage IV NSCLC patients included in the trial. Primary (ResultsHLA-class I was expressed in all tumor samples. IHC analysis revealed that P53, CEA and HER2 were expressed in 6/7, 5/7 and 0/7 patients, respectively. P53, CEA, HER2, MAGE2, and MAGE3 were detected at RNA level in 5/5 tested patients (table 1). IMMUNOSCORE® IC CD8/PDL1 analysis showed High/High, High/Low and Low/Low scores for 1/7, 1/7 and 5/7 patients, respectively. The High/High IMMUNOSCORE® with a pronounced CD8+ T-cell tumor infiltration was observed in the patient with PR. High percentage of tumor cells expressing P53 (69%–97%) and overexpression of genes associated with activated macrophages (TREM2, MARCO, SLC11A1, CHIT1, SERPINB2) were observed in the PR and SD patients. High IFN-gamma and Expanded Immune Gene Signature scores were observed in long-term survivor patients with secondary resistance to ICB, even after progressive disease.Abstract 366 Table 1Summary of clinical and translational dataCEACarcinoembryonic antigen; HER2: Human Epidermal Growth Factor Receptor-2; ICB: Immune checkpoint blocker; IHC: Immunohistochemistry; ND: Not determined; OS: Overall Survival; Patient ID: Patient identification; PDL1: Programmed death-ligand 1; PFS: Progression-free survival; ssGSEA: Single-sample Gene Set Enrichment Analysis. Blue bars = Length of overall survival; Green bars = Gene Signature upregulation; Red bars = Gene Signature downregulationConclusionsThis study shows that all HLA-A2+ patients (blood test), expressed HLA class I in the tumors at initial diagnosis. Transcriptomic data in the patients that benefited from Tedopi® showed activated macrophage pathway, high IFN-gamma and Expanded Immune Gene Signatures scores. These data will be validated on larger number of patients treated with Tedopi® after the step 2 analysis.AcknowledgementsWe thank Julie Le Boulicaut, François Montestruc and Constant Josse (eXYSTAT, Malakoff, France) for the statistical analysis, and HalioDx for the IHC and NanoString analysis.Trial RegistrationEudraCT number2015-003183-36; NCT number: NCT02654587ReferenceGiaccone, et al. Activity of OSE-2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (ICI): step 1 results of phase III ATALANTE-1 randomised trial. ESMO meeting 2020, abstract #1260MO.Ethics ApprovalThe study protocol and its related documents (including the patient information and informed consent form) received approval from the Institutional Review Board (IRB), and the Competent Authority prior to study initiation.ConsentEach patient gave his/her written informed consent prior to study enrolment.

International audience; Non-clear cell renal cell carcinomas (nccRCC) represent a highly heterogeneous group of kidney tumors, consisting of the following subtypes: papillary carcinomas, chromophobe renal cell carcinoma, so-called unclassified carcinomas or aggressive uncommon carcinomas such as Bellini carcinoma, renal cell carcinoma (RCC) with ALK rearrangement or fumarate hydratase-deficient RCC. Although non-clear cell cancers account for only 15 to 30% of renal tumors, they are often misclassified and accurate diagnosis continues to be an issue in clinical practice. Current therapeutic strategy of metastatic nccRCC is based primarily on guidelines established for clear cell tumors, the most common subtype, however this approach remains poorly defined. To date, published clinical trials for all histological nccRCC subtypes have been collectively characterized into one group, in contrast to clear cell RCC, and given the small numbers of cases, the interpretation of study results continues to be challenging. This review summarizes the available literature for each nccRCC subtype and highlights the lack of supportive evidence from prospective clinical trials and retrospective studies. Future trials should evaluate treatment approaches which focus on a specific histological subtype and progress in treating nccRCC will be contingent on understanding the unique biology of their individual histologies.

Background With the recent introduction of novel treatment options, real-world data from patients with metastatic castration-resistant prostate cancer (mCRPC) are required to better understand the impact on routine clinical practice. This study primarily aimed to describe the time to treatment failure (TTF) of mCRPC patients treated with abiraterone acetate plus prednisone or the corticosteroid of choice (AAP) in the pre-chemotherapy setting. Other relevant outcomes, clinical and treatment characteristics of these patients were also evaluated. Methods This retrospective, observational study collected data from chemotherapy-naïve mCRPC patients treated with AAP from four European countries. Kaplan-Meier curves were used to estimate TTF, progression-free survival (PFS), and time to first skeletal-related event. The impact of baseline characteristics on TTF and PFS was explored using univariate and multivariate Cox proportional hazard models. Log-rank test was used to assess the potential role of duration of response to ADT in predicting response to AAP treatment. Results Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150; UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years (interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR: 22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer ECOG PS scores at AAP initiation (p

Introduction This single-arm phase II trial aimed to evaluate a stop-and-go strategy with cisplatin-based chemotherapy and bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC). Methods Patients were initially treated with three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 1) followed by bevacizumab maintenance and after progression, re-introduction of three cycles of pemetrexed, cisplatin plus bevacizumab (sequence 2) and pemetrexed plus bevacizumab maintenance. The primary endpoint was the proportion of patients with advanced non-squamous NSCLC receiving the complete sequence 2 without platinum dose reduction (hypothesis ≥75%). Results 120 patients with performance status ≤1 were included. Of 113 patients evaluable for efficacy, 65 (57.5%) entered in sequence 2 and 56 (86%) received the three planned cycles including 37 (56.9%, 95% CI 45.1 to 73.6) without platinum dose reduction. The median progression-free survival 1 (PFS1; inclusion to progression 1) was 5.6 months (95% CI 5.0 to 6.3) and median PFS2 (progression 1 to progression 2) was 6.8 months (95% CI 5.8 to 8.8). The median disease control duration (PFS1+PFS2; n=65) was 12.4 months (95% CI 11.2 to 14.9). The median overall survival was 17.7 months (95% CI 13.1 to 21.6) and 20.5 months (95% CI 16.9 to 26.9) for patients reaching the sequence 2 (n=65). Conclusion Although the stringent primary endpoint was not met, this stop-and-go strategy with platinum-based chemotherapy plus bevacizumab continuation beyond progression compares favourably with standard schedule, deserving to be further studied in advanced non-squamous NSCLC.

Introduction: Tedopi is a neoepitope vaccine restricted to HLA-A2 positive patients targeting five tumor-associated antigens frequently expressed in lung cancer cells. Potential enhanced efficacy of cancer vaccines after ICI treatment remains unexploited and its biological basis is poorly understood. The integrity of the antigen presentation pathway is crucial in vaccine activity and genetic alterations such as beta-2-microglobulin inactivating mutation may explain lack of efficacy. Tedopi is currently being tested in the phase III ATALANTE-1 trial compared with chemotherapy in advanced NSCLC patients (pts.) who relapse after ICI. We report early signs of safety and efficacy with Tedopi in the first step of the open-label study. Methods: 18 pts have been enrolled in the experimental arm and received at least one dose of Tedopi. These pts have been assessed every 6 weeks for radiological response according to RECIST 1.1 criteria as well as toxicity according to CTCAE criteria. Tedopi dose was 5 mg injected subcutaneously every 3 weeks for 6 doses, then every 2 months completing 1 year of treatment and thereafter every 3 months until progression or toxicity. Description of three patients with significant clinical benefit with third-line treatment with Tedopi is presented. Results: Patients’ clinical characteristics are reported in table 1. Treatment duration with Tedopi ranges from 4.9 to more than 12 months, including one patient with brain metastases. One patient achieved a partial response and two patients achieved stable disease by RECIST 1.1 criteria. Safety profile was manageable and no patient withdrawn for toxicity. Conclusions: Tedopi after failure to previous ICI therapy as third-line treatment has shown long-term clinical benefit and good safety profile. Baseline genomic molecular profile assessment, as well as, immunophenotype searching evidence of vaccination are ongoing. Citation Format: Santiago Viteri, François-Roger Vanel, Werner Hilgers, Jordi Remon, Guillermo Viteri-Ramirez, Elisabeth Quoix. Early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 946.

TPS9121 Background: New treatment strategies are needed for advanced NSCLC patients who progress on treatment with immune checkpoint inhibitors (ICI). Tedopi (OSE2101) is a neoepitope vaccine restricted to HLA-A2 positive patients (45%) targeting five tumor-associated antigens frequently expressed in lung cancer cells, ACE, HER2, MAGE2, MAGE3 and P53. Previously, in a phase II trial (Barve et al. JCO 2008), Tedopi showed a median overall survival (OS) of 17.3 months with a manageable safety profile in advanced NSCLC patients. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard of care (SoC) treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy. Methods: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements; progressive disease to platinum-based chemotherapy (ChT) with sequential or concurrent ICI; HLA-A2 positivity (blood test); ECOG PS 0-1; with treated and asymptomatic brain metastases,, are randomized 2:1 to receive 5mg Tedopi subcutaneously Q3W for 6 cycles, then Q8W for the reminder of the year and finally Q12W, or SoC treatment with: docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W (in non-squamous and pemetrexed-naïve patients). Treatment continues until progression, intolerable toxicity or consent withdrawal, in both arms. Patients are stratified by histology, best response to first line, and line rank of ICI. Tumor assessment is performed every 6 weeks (RECIST 1.1). Primary endpoint is OS. Secondary end points are PFS, ORR, DCR, and duration of response, quality of life and safety. This is a superiority study with a hazard ratio of 0.7, two-sided alpha 5% and power 80%, after 278 events are observed. An independent analysis (1year OS rate) is planned in the first 84 patients treated with Tedopi. Last trial review by the DMC in June 18 suggested that the trial continues as planned. Translational research will be performed evaluating pharmacodynamic markers of efficacy such as immunogenicity response against Tedopi vaccine neoantigens, as well as parameters in liquid and tissue biopsies. End January 19, 87 patients (51 Tedopi, 36 Soc) have been enrolled. Clinical trial information: NCT02654587.

5004 Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective cohort studies suggest a decrease in PC incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in PC preclinical models, with increase apoptosis when added to DOCE. The addition of MET could enhance DOCE efficacy in mCRPC patients (pts). Methods: TAXOMET is a phase II prospective multicentric randomized controlled trial. Non-diabetic mCRPC pts were assigned 1:1 to receive DOCE 75mg/m2 every 21 days + prednisone (P) 5 mg twice a day and either MET 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. The primary end point was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data. Results: From January 2013 to December 2015, 99 pts were randomized (50 pts in arm A and 49 pts in arm B) in 10 french centers, and 95 pts were evaluable. No difference was observed between arm A and arm B in PSA-response rate (72% in both arms), ORR (28% in both arms), clinical or biological mPFS (7.3 months vs 5.8 months p = 0.848) and mOS (24.2 months (95CI: 17.2 – 33.7) vs 19.7 months (95CI: 14.8 – 36.8), p = 0.53), respectively. There was no difference between arms in adverse events, except a trend for diarrhea to be more common with MET (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period. Conclusions: This is the first prospective randomized controlled trial to evaluate the combination of MET with DOCE+P in mCRPC. The addition of MET has no meaningful clinical benefit in this setting. Clinical trial information: NCT01796028.

Background: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients. Patients and methods: Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay >1 week. MTD was the DL with DLT in 2/2 or ≤2/6 patients during cycle 1–2. Results: Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1–2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations >3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. Conclusion: Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.

The recognition of biologically distinct tumor subsets is fundamental to understanding tumorigenesis. This study investigated the mutational status of the serine/threonine kinase BRAF and the cyclin E regulator FBXW7 (CDC4, FBW7, AGO, SEL10) related to two distinct pancreatic carcinoma subsets: the medullary KRAS2-wild-type and the cyclin E overexpressing tumors, respectively. Among KRAS2-wild-type carcinomas, 33% (3 of 9) contained BRAF V599E mutations; one of which was identified in the pancreatic cancer cell line COLO357. Among 74 KRAS2-mutant carcinomas, no BRAF mutations were identified. Among the KRAS2/BRAF wild-type carcinomas, no mutations within pathway members MEK1, MEK2, ERK1, ERK2, RAP1B, or BAD were found. Using pancreatic cancer microarrays and immunohistochemistry, we determined that 6% (4 of 46 and 5 of 100 in two independent panels) of pancreatic adenocarcinomas overexpress cyclin E. We identified two potential mechanisms for this overexpression including the amplification/gain of CCNE1 gene copies in the Panc-1 and Su86.86 cell lines and a novel somatic homozygous mutation (H460R, in one of 11 pancreatic cancer xenografts having allelic loss) in FBXW7, which was accompanied by cyclin E overexpression by immunohistochemistry. Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets.

Our understanding of the biology of pancreatic carcinoma has greatly benefited from studies of the genetic alterations in this tumor type. The p16-CDK4-cyclinD-Rb pathway, the p53 tumor suppressor pathway, and the DPC4/Smad4 pathway are genetically inactivated in the majority of sporadic pancreatic carcinomas, whereas oncogenic K-ras signaling is almost ubiquitously activated. These genetic data have provided the basis to shape a first genetic progression model of this tumor type. Furthermore, a number of well defined genetic syndromes which are associated with an inherited risk for pancreatic carcinoma have been identified recently.

Loss of heterozygosity (LOH) of chromosome arm 18q is frequent in gastrointestinal cancers. Over 90% of pancreatic carcinomas have 18q LOH. Bi-allelic inactivation of the MADH4/DPC4/SMAD4 gene at 18q21.1 is seen in about half of pancreatic carcinomas with 18q LOH. In the remaining tumors with 18q LOH, MADH4 is not mutated and its expression is unaffected, and no alterations in MADH2/SMAD2, a MADH4-related gene at 18q12.3, have been found. A controversial candidate tumor-suppressor gene at 18q21.2 is DCC (deleted in colorectal carcinoma), which encodes a netrin-1 receptor component with functions in cell migration and apoptosis. Reduced or absent DCC expression has been observed in many cancers, but few somatic mutations that would clearly inactivate DCC function have been reported. We studied a panel of 115 pancreatic and 14 biliary cancers for homozygous deletions of DCC exons and flanking 18q regions. Seven homozygous deletions were seen in the region that includes the DCC gene. In two tumors, the deletions inactivate DCC but not MADH4. A physical and transcript map of the deleted regions was constructed, and DCC was the only known gene affected by all seven deletions. These data are the strongest mutational evidence presented yet in support of the hypothesis that DCC or another gene in the region distal to MADH4 is inactivated, playing a causal role in cancer development.

Alterations of the candidate tumor suppressor gene FHIT have been reported in multiple tumor types, including pancreatic carcinoma. The mechanism of FHIT genomic inactivation is unusual, most frequently occurring by homozygous deletion, whereas only rare cases have missense mutations. Altered (shortened) transcripts and reduced protein expression are reported, but a genetic basis for these is often inapparent. We studied FHIT genomic alterations of pancreatic carcinomas. Loss of heterozygosity (LOH) was found in 41% of 93 carcinomas without microsatellite instability (RER(-)), but no mutations were found by genomic sequencing. Homozygous deletions inside the FRA3B fragile site were found in four RER(-) tumors, but only two affected the FHIT coding region. In contrast, FHIT alterations were found in the three RER(+) pancreatic carcinomas screened; two had FHIT homozygous deletions affecting exon 5 and the third had a heterozygous missense mutation (H76N). The excess occurrence of homozygous deletions at this site in RER(+) pancreatic cancers is statistically significant (P < 0.01). Since homozygous deletions have not previously been reported in RER(+) carcinomas at any genomic site, an extremely high rate of site-specific deletion must exist within the FRA3B-related FHIT gene. Consequently, the paucity of documented inactivating point mutations cannot be used to judge the presence or absence of putative FHIT-related selective pressures that act during tumorigenesis of RER(-) neoplasia. Nonetheless, the identification of a heterozygous mutation as the sole sequence abnormality might raise doubt as to whether strong selective pressures are afforded by FHIT genomic inactivation in this tumor type. Genes Chromosomes Cancer 27:239-243, 2000.

Pancreatic ductal adenocarcinoma is a complex genetic disease. As might be expected for a malignancy that is rather homogeneous in clinical presentation and behavior, a distinct subset of genes are found to be genetically inactivated in a majority of the tumors. A yet larger subset of genes experiences genetic inactivation at much lower frequencies. The latter subset could solely reflect a somewhat trivial genetic heterogeneity of the tumor, but more likely will represent the initial insights into pathways whose more widespread importance will be shown in future work. Familial pancreatic cancer susceptibility underlies a significant fraction of the overall incidence. Genetic testing is feasible for many of the causative genes, although the clinical utility remains unsettled. The precursor lesion for pancreatic cancer shares some of the genetic lesions of the more advanced invasive stage, and follows a stepwise progression model both histologically and genetically. Genes Chromosomes Cancer 26:1‐12, 1999. r 1999 Wiley-Liss, Inc.

Chromosomal arm 1p has long been suspected, on the basis of loss of heterozygosity (LOH) and other data, to harbor a tumor suppressor gene important in pancreatic carcinomas and other tumors. We constructed a high-resolution map of LOH at I p in a panel of pancreatic adenocarcinomas. Using 44 markers, we identified LOH on I p in 49% of 43 cancers. Breakpoints in 1p were identified in 15 of the carcinomas and could be used to ascertain consensus patterns. We found a major consensus region of LOH at 1p35 between loci D1S233 and D1S247. This region participates in the majority of LOH events on 1 p in pancreatic cancer. These data provide a roadmap for further regional mapping, homozygous deletion searches, comparison to LOH patterns seen in other tumor types, and prioritization of studies using candidate genes.

9077Background: Pemetrexed (Pem) + Cisplatine (Cis) + Bevacizumab (Bev) followed with maintenance therapy (Bev and/or Pem) is a therapeutic standard in advanced non-squamous NSCLC. Methods: A singl...

Background Primary leiomyosarcoma of the seminal vesicle is exceedingly rare. Case Presentation We report a case of a 59-year-old man with tumour detected by rectal symptoms and ultrasonography. Computed tomography and magnetic resonance imaging suggested an origin in the right seminal vesicle. Transperineal biopsy of the tumour revealed leiomyosarcoma. A radical vesiculo-prostactectomy with bilateral pelvic lymphadenectomy was performed. Pathological examination showed a grade 2 leiomyosarcoma of the seminal vesicle. The patient received adjuvant radiotherapy. He developed distant metastases 29 months after diagnosis, and received chemotherapy. Metastatic disease was controlled by second-line gemcitabine-docetaxel combination. Fifty-one months after diagnosis of the primary tumour, and 22 months after the first metastases, the patient is alive with excellent performance status, and multiple asymptomatic stable lung and liver lesions. Conclusions We report the eighth case of primary leiomyosarcoma of the seminal vesicle and the first one with a so long follow-up.

To determine the maximum tolerated dose (MTD), recommended dose, dose limiting toxicities (DLT), safety and pharmacokinetics of irofulven combined with capecitabine in advanced solid tumor patients. Irofulven was given i.v. over 30 min on days 1 and 15 every 4 weeks; capecitabine was given orally twice daily, day 1 to 15. Dose levels (DL) were: irofulven (mg/kg)/capecitabine (mg/m2/day): DL1: 0.3/1,700; DL2: 0.4/1,700; DL3: 0.4/2,000; DL4: 0.5/2,000. Between May 2002 and March 2004, 37 patients were treated and 36 evaluable for MTD. DLT occurred in 1/6 evaluable patients in DL1 (grade 3 thrombocytopenia); 1/6 in DL3 (grade 3 thrombocytopenia); 2/7 in DL4 (grade 3 febrile neutropenia, grade 3 thrombocytopenia). DL4 was defined as the MTD and DL3 was established as the recommended dose (RD). DLTs occurred in 1 of 14 additional patients treated at DL3. No treatment-related deaths or grade 4 non-hematological toxicity occurred, and grade 3 toxicities were infrequent. Antitumor activity was observed; two partial responses were noted in thyroid carcinoma (DL1, DL4); one unconfirmed partial response was observed in a patient with nasopharyngeal carcinoma, (DL3); 12 patients had disease stabilization >3 months; of eight patients with hormone refractory prostate cancer (HRPC), one patient had PSA normalization and four short-term stabilizations of PSA occurred. Capecitabine and irofulven pharmacokinetics results did not suggest drug–drug interactions. Irofulven with capecitabine was adequately tolerated and evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and capecitabine 2,000 mg/m2/day.

The recognition of biologically distinct tumor subsets is fundamental to understanding tumorigenesis. This study investigated the mutational status of the serine/threonine kinase BRAF and the cyclin E regulator FBXW7 (CDC4, FBW7, AGO, SEL10) related to two distinct pancreatic carcinoma subsets: the medullary KRAS2-wild-type and the cyclin E overexpressing tumors, respectively. Among KRAS2-wild-type carcinomas, 33% (3 of 9) contained BRAF V599E mutations; one of which was identified in the pancreatic cancer cell line COLO357. Among 74 KRAS2-mutant carcinomas, no BRAF mutations were identified. Among the KRAS2/BRAF wild-type carcinomas, no mutations within pathway members MEK1, MEK2, ERK1, ERK2, RAP1B, or BAD were found. Using pancreatic cancer microarrays and immunohistochemistry, we determined that 6% (4 of 46 and 5 of 100 in two independent panels) of pancreatic adenocarcinomas overexpress cyclin E. We identified two potential mechanisms for this overexpression including the amplification/gain of CCNE1 gene copies in the Panc-1 and Su86.86 cell lines and a novel somatic homozygous mutation (H460R, in one of 11 pancreatic cancer xenografts having allelic loss) in FBXW7, which was accompanied by cyclin E overexpression by immunohistochemistry. Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets.

Marginal-zone B cells of the mucosa-associated lymphoid tissue (MALT) are the normal counterpart of the neoplastic cells in MALT lymphoma. In both cases these lymphocytes express surface immunoglobulins, but are negative when stained for B cell associated antigens like CD10 and CD23. Furthermore, the B cell gene rearrangement has been found in Helicobacter pylori associated chronic gastritis and in extranodal type of marginal-zone lymphoma. The aim of this study was to quantify the number of IgM-, CD10-, and CD23-positive lymphocytes in patients with type B gastritis and to compare the results with the antigen profile of mononuclear cells in patients with gastritis not associated with H. pylori. Additionally, the immunoglobulin heavy-chain (IgH) gene rearrangement in H. pylori positive and H. pylori negative gastritis was studied. From 23 patients with a positive urease test and/or histologically proven H. pylori infection and chronic gastritis and from 22 patients with H. pylori negative chronic gastritis mucosa biopsy specimens were taken. Single-cell suspensions were obtained following enzymatic digestion. For immunocytochemistry, an alkaline phosphatase-antialkaline phosphatase method was applied. IgH gene rearrangement in formalin-fixed, paraffin-embedded specimens was determined by polymerase chain reaction in 11 patients with chronic gastritis. An increase in mu-positive plasma cells and B lymphocytes was detected in patients with H. pylori positive gastritis as compared with patients with H. pylori negative gastritis (10.0 vs. 3.9%, p < 0.001, and 4.3 vs. 1.6%, p < 0.01, respectively). In both groups, the proportion of CD10- and CD23-positive lymphocytes was H. pylori negative chronic gastritis. Our finding of IgH gene rearrangement in some of the patients with H. pylori negative chronic gastritis indicates that additional factors may be critical for these genotypical changes and for the pathogenesis of gastric MALT lymphoma.