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46 Background: Bone is frequently involved in metastatic hormone sensitive prostate cancer (mHSPC). Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) is a promising imaging technique for the assessment of bone response in prostate cancer. It is not known whether the addition of antiresorptive agents can improve disease response in bone in mHSPC patients undergoing next generation hormonal agents. Methods: In this multicenter phase II study patients with de novo or relapsed mHSPC and bone metastases at bone scan were randomly allocated with a 1:1 ratio to receive either androgen deprivation therapy (ADT) plus Enzalutamide (E arm) or the same combination with the addition of Zoledronic Acid (EZ arm). The study was designed to observe a significant increase in bone response rate in the experimental arm after 12 months of treatment, as assessed through WB-DW-MRI. WB-DW-MRI was performed centrally at baseline and after 6 and 12 months and images were evaluated by the same radiologist. Results: From February 2018 to June 2021, 126 mHSPC patients were randomized, 64 in EZ arm and 62 in E arm. A total of 111 patients, 54 from E arm and 57 from EZ arm, were eligible for WB-DW-MRI assessment (15 patients were excluded because of the absence of bone target lesions at MRI or specific contraindications to MRI). Bone response at 6 months was observed in 41 patients (76%) in E arm and 41 patients (72%) in EZ arm; the corresponding bone response at 12 months were 44 (82%) and 44 (77%), respectively (OR 0.77; 95%IC 0.30-1.93; p = 0.6). Complete response was the best overall bone response after 12 months in 9 patients (17%) from E arm and in 11 patients (19%) from EZ arm. In the same period, treatment was interrupted due to disease progression in 7 (13%) and 7 (12%) patients in E and EZ arm, respectively. Conclusions: The addition of Zoledronic Acid to Enzalutamide and ADT did not improve bone disease response in patients with mHSPC. WB-DW-MRI was able to detect bone responses in a great proportion of patients. Clinical trial information: NCT03336983 .

4596 Background: In advanced ACC, no significant progress has been made since introduction of mitotane and cisplatin-based therapy. EO2401 (EO) was designed to activate existing commensal memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in ACC, IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This Phase 1/2 trial (NCT04187404) investigated EO + nivolumab (N) (EO + N = EN) in pts with ACC. Cohort 1 lead-in established safety of EN. Cohort 2 includes pts with metastatic ACC, with (C2a), or without (C2b) prior systemic therapy. EN was given 4 times q2 w, followed by boosters q4 w until PD (iRECIST). Results: 33 pts with ACC started study treatment: C2a 26 pts (58% 1; 42% 2 prior lines), C2b 7 pts. Median age 47; 24% men; ECOG 0/52%, 1/42%, 2/6%; 61% ≥2 organs involved by metastases (61% liver, 76% lung). EN was well tolerated. The combination safety profile was consistent with the profile of N monotherapy except for higher local administration site reactions (any erythema/pain/induration in 35% of pts). Overall (n = 33), best RECIST response was PR 12%, SD 24%, PD 45%, NE 18%; median PFS was 1.9 mo (range 0.4-7.6+); median survival not reached, and survival rate at 6-mo 63% (median FU 4.9 mo, range 0.9-12.0). Strong CD8 T cell ELISPOT responses against the vaccine peptides (9/9 pts) and cross-reactivity against targeted TAAs (8/8 evaluable pts) was observed. Tetramer staining of specific CD8 cells for all 3 peptides was detected in 7/8 tested. When investigated, positive staining against BIRC5 was detected as early as 4 w after the first vaccination. In C2a, a group of pts (n = 10) with SD at the first CT (incl. 4 pts with PR) seemed to fare well; all investigated tumor samples in this group showed a low level of TMB, low MSI, and low PDL1 expression. In contrast, 10 pts had PD < 2mo and died < 6mo. There was no correlation between clinical benefit and a large panel of cytokines/chemokines. However, post-hoc analysis identified several clinical factors (prior mitotane, ECOG ≤ 1, ACC 1st diagnosis > 9 mo, max lesion ≤125 mm, ≤3 organs involved, lymphocytes ≤ grade 1) that excluded 90% of pts without benefit to EN. In the post-hoc selected group (n = 14) with median FU 6.9 mo (12 pts censored) the DCR was 64% (4 PR, 5 SD), 6-mo PFS was 42% and 6-mo survival rate 93%. Conclusions: EO2401 in combination with nivolumab was well tolerated and induced a specific immune response in all tested pts. In addition, efficacy was seen in a subpopulation of pts with ACC defined by clinical parameters in a post-hoc analysis. A randomized phase 2 study based on the findings of Cohort 2a is being planned. Clinical trial information: NCT04187404.

11575 Background: To further explore the activity of T as second/further line treatment in retroperitoneal leiomyosarcoma (LMS) and well differentiated/dedifferentiated liposarcoma (LPS). The primary endpoint of the study was the growth modulation rate (GMR) defined as the ratio between the time to progression under T (TTP) and during previous chemotherapy treatment (TTP-1). The secondary end-points were objective response rate as per RECIST and PFS. Methods: This was a multicenter, single-arm Phase 2 study, conducted in 20 Italian centers. Patients with locally relapsed or metastatic disease, already treated with one or more previous systemic treatments with anthracyclines and/or ifosfamide, were enrolled. T was administered at a dose of 1.3-1.5 mg/mq with a top dose of 2.6 mg per cycle. T was administered as a 24h continuous infusion until progressive disease, major toxicity, patient’s intolerance or medical decision. As per protocol, patients were considered responders if the GMR was > 1.33, non-responders if < 0.75 and neither if 0.76-1.32. Eighty evaluable patients were needed to detect an odds of trabectedin response ≥ 2.5, corresponding to 71.4% of patients with a GMR > 1.33 (80% power, one-sided alpha 2.5%). Results: From August 2014 to February 2019, 104 patients were registered and 91 were evaluable for the primary endpoint (32 pts with LMS and 59 with LPS). Overall, the median number of cycles received was 6.0 (q1-q3 3.0-12.0), the main reason for treatment discontinuation was disease progression in 72% of patients, followed by medical decision (8%). The median TTP was 6.0 months (6.2 and 6.0 for LMS and LPS), while the median TTP-1 was 7.5 months (8.1 and 6.4 for LMS and LPS). Thirty three patients (52% 95%CI: 36-58, p = 0.674, odds of response = 1.1) had a GMR > 1.33 (LMS: 46%, 95%CI 26-67,odds = 0.85; LPS 56%, 95%CI 40-72, odds = 1.3).Overall, response rate (CR+PR) was 16% (24% for LMS and 12% for LPS). Overall, in LPS we observed 15/47 patients with GMR < 0.5 and 15/47 with GMR > 2. Among LMS patients, 9/26 had a GMR < 0.5 and 10/26 > 2. Between LPS six patients had a GMR > 5. Previous treatment had been based on anthracyclines and/or ifosfamide in 85% of patients (91% in LPS population). Conclusions: While the primary end point of the study was not met, we noticed a subgroup of patients with a markedly discrepant TTP with T in comparison to previous therapy (GMR < 0.5 or > 2, the latter including some pts with a long TTP with T). Efforts are ongoing to assess the pathologic counterparts of such discrepancies. T seems to be selectively active in poorly understood subgroups, with a pattern of activity distinct from other available agents. Clinical trial information: 2012-005428-14.

e21574 Background: From 25 to 50% of radically resected Merkel Cell Carcinomas (MCCs) develop local or distant recurrence with a 5 year Overall Survival (OS) of 35% and 13%, respectively. Due to the rarity of the disease, there are limited data about clinical/histological risk factors related to patients (pts) prognosis. Methods: We retrospectively evaluated a series of 57 MCCs pts treated with surgical curative intent at two Italian Centres from 2000 to 2020. For 43 of them, archival histological material was retrieved for further analysis. The following clinical and histological data were analyzed and related to time to relapse (TTR), OS and cancer specific survival (CSS): gender, age, Charlson Comorbidity Index value, immunodepression, surgical margins, re-excision and/or radiotherapy (RT) in case of positive margins, stage, perineural/lymphovascular infiltration, presence of inflammatory infiltrate (tumoral infiltrating lymphocyte (TILs) (> 1 positive cell per high-power field) and its composition CD3+, CD4+ T and CD8+ T cells), positivity for MCC-polyomavirus (MCCpV), Ki67 index and PDL1 expression CPS. Results: Pts were mainly female (52%), median age was 75 years (49-99), 70% were immunocompetent and 51% presented T1 stage. All pts received surgery as main treatment approach; in case of positive margins, pts received re-excision or RT, when feasible. During a median follow-up of 37 months (1- 188), 40% had a locoregional or distant recurrence. Median TTR of relapsed pts was 3 months (1-88); median OS and CSS in the whole population was 117 months (1-188) and not reached, respectively. At univariate analysis, only male gender was associated with a higher risk of relapse (HR 1.6; 1.07-2.55; p 0.02). Older age (HR 1.09; 1.04-1.14, p < 0.001), T stage ≥2 (HR 4.79, 1.99-11.53, p < 0.001) and positive margins after re-excision (HR 17.49, 1.09-279.74, p 0.043) were associated with shorter OS and negatively related to CSS. Re-excision and/or RT in cases of positive margins at diagnosis improved OS (HR 0.154, 95% CI 0.028-0.851, p = 0.032) and CSS (HR 0.15; 0.02-0.85, p 0.03). MCCpV positivity (HR 0.23, 0.08-0.62, p 0.004), TILs (HR 0.30, 0.11-0.80, p 0.017), a moderate or high content of CD3+ T cells (HR 0.33, 0.119-0.968, p 0.04), CD8+ T cells (HR 0.35, 0.12-0.99, p 0.04), and PDL1 CPS > 1 (HR 0.26, 0.08-0.82, p 0.02) resulted in longer OS. The impact of MCCpV positivity (HR 0.27; 0.08-0.88 p 0.03) and high TILs (HR 0.31, 0.09-0.99, p 0.04) was also confirmed for CSS. Conclusions: In primarily surgically treated MCCs, female gender, younger age, low T stage, positivity for MCCpV and tumoral immune cells infiltration were associated with better prognosis, as well as an aggressive management comprising re-excision and/or RT in case of positive margins.

107 Background: In patients (pts) with high-volume (HV) metastatic castration sensitive prostate cancer (mCSPC) the addition of six cycles of docetaxel (TXT) to androgen deprivation therapy (ADT) in the CHAARTED and STAMPEDE trials prolonged survival by 10-18 months (mo). Aim of our study was to evaluate the principal patterns of relapse after TXT and their clinical and prognostic significance. Methods: We conducted a multicentric (14 Italian Centers), prospective, observational study enrolling HV mCSPC patients treated with ADT plus early TXT. Clinical and pathological features were recorded. Time to castration resistance (TCR) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. The Chi-Square test, t-test or Wilcoxon-Mann-Whitney test were used to assess difference between the groups as appropriate. Results: We identified 166 de novo mCSPC pts, with a median age of 64 years (range 38-84). The most common metastatic sites at diagnosis were: bone (93%) and lymph nodes (81%); visceral disease (lung and liver) was present in 36% of cases. 87% of pts had good Eastern Cooperative Oncology Group Performance Status (0-1), the median baseline PSA was 359 ng/ml (range 2.64-5800) and 43% experienced cancer pain. 87% of 158 evaluable pts had a Grade Group (GG) ³4. The majority of pts (81%) completed six cycles of TXT. The median time to PSA nadir was 10.2 months (mo), PSA response > 50% was achieved in 96% of pts and the most common best response reported was partial response (58%). At the time of this analysis, 122 pts (67%) had biochemical or radiographic progressive disease (PD) to TXT and 67 of these (60%) developing new metastatic sites (NMS). No differences with respect of main clinical features was found between NMS pts and nonNMS, with the exception of GG (96% of NMS pts had GG 4-5 vs 74% of nonNMS; p = 0.002). In NMS group we found a higher rate of nodal PD (52% vs 22%, p = 0.001) and higher rate of bone PD (73% vs 47%, p = 0.005) compared to nonNMS. No differences in the rate of visceral PD. With a median follow-up of 27.9 mo, the median TCR was 14.3 mo (95%CI 12.8-16.7), without significant differences between NMS and nonNMS groups. About 90% of progressed pts received first-line treatment for mCRPC disease with similar outcomes. The median OS was 41.8 mo for the overall population, with not significant differences between NMS and nonNMS groups (22 mo and 25 mo). Overall, median OS from mCRPC diagnosis was 19.6 mo, similar in NMS and no-NMS pts (10 mo and 12 mo). Conclusions: In progressive mCSPC pts receiving early TXT, we observed more frequently the development of NMS with an elevated GG and a trophism for bone and lymph nodes. However, the NMS progression does not seem to have a prognostic role. An extended follow up and the prospective data will be provided.

1 Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation. The primary endpoint of the study was RFS. Patients who refused randomization were eligible for the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. A total of 91 patients were enrolled in ADIUVO, 45 in the mitotane and 46 in the observation arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with mitotane and observation groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p = 0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p = 0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed that of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-yr RFS is 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care. Clinical trial information: NCT00777244.

8574 Background: Everolimus (EVE) improves progression-free survival (PFS) in patients (pts) with progressive non-functioning thoracic and digestive advanced neuroendocrine tumors (NET). The LUNA trial aimed to assess the efficacy and safety of long-acting pasireotide (PAS) and EVE alone or in combination in pts with progressive bronchial or thymic carcinoids. Core phase results for primary endpoint (PFS) and secondary endpoints at 9 and 12 months (mo) were previously published. Cumulative data results at the end of the extension phase are presented here. Methods: LUNA was a prospective, multicenter, randomized, open-label, 3-arm, phase II trial. Adult pts with carcinoids of lung/thymus were randomized (1:1:1) to receive either PAS (60 mg/mo i.m.) or EVE (10 mg/day orally) or PAS + EVE. The key secondary endpoints assessed in this extension phase, including all the patients who were still not progressing at 12 months, were PFS, duration of biochemical response (DBR), and biochemical PFS (BPFS). Results: Of the total 124 pts included in the core phase, 41 pts with a median age of 61 years entered the extension phase including PAS (12), EVE (14) and PAS + EVE (15). Lung was the primary site of cancer in 95.1% and 82.9% had non-functioning tumors. Surgery/local or regional therapy was the preferred prior treatment in 63.4% pts. Disease progression was the primary reason for discontinuation among 3 arms with 65.9% in overall extension phase; no pts in PAS arm discontinued due to adverse events (AEs). Mean relative dose intensity (RDI) was higher for PAS (95.6% alone and 90.4% in combination) when compared to EVE (76.6% alone and 72.4% in combination); 38.1% pts in the EVE arm and 43.9% pts in the combination arm with EVE had RDI 50% pts. Most common AEs of any grade regardless of the study drug in PAS +EVE arm were hyperglycemia (87.8%), diarrhea (80.5%), and weight loss (58.5%), while stomatitis was reported in 34.1%. Twelve deaths were reported during the study and up to 56 days from last study treatment dose. Duration of exposure and efficacy. Conclusions: Mature median PFS and BPFS data suggest a benefit of PAS+EVE combination. The safety and tolerability profile of PAS and EVE alone or in combination were consistent with prior experience of these treatments in the oncology setting, with no new safety signals being reported during the study. Post-hoc prognostic studies are ongoing. Clinical trial information: NCT01563354. [Table: see text]

e16087 Background: Several studies, the majority on melanoma and lung cancer, have addressed the value of gender with respect to immune check point inhibitors outcome as compared to standard therapy, showing conflicting results. Nevertheless, few focused on gender-related clinical outcome and toxicity in renal cell carcinoma (RCC) patients. Methods: This analysis evaluated the effect of gender on overall survival and adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 in an expanded access programme of nivolumab 3 mg/kg once every 2 weeks in second-line and beyond metastatic RCC. Only patients assuming at least one dose of nivolumab were analyzed. Results: Of 389 patients analyzed, 25.2% were female. On study entry, no differences were found in women as compared to men in terms of age, on average 64 years, p = 0.91; overweight/obesity, 45 versus (vs) 49%, p = 0.47; LDH , mean U/L 391 vs 32, p = 0.17); and neutrophils/lymphocytes ratio> 3 (62 vs 63%, p = 0.87). Disease presentation was similar according to gender, although women tended to present less lung (66% vs 76%, p = 0.06) and bone metastases (42% vs 52%, p = 0.07). Notably, there was no differences in the IDMC prognostic model by gender (p = 0.94). Any drug related AEs (38 vs 30%, p 0.15), grade 3-4 (6% vs 6%) and median number of drug doses 12 (53% vs50%, p = 0.58 ) did not differ between gender. After adjusting for known prognostic variables, multivariate analysis showed that women had similar overall survival as compared to men (hazard ratio 0.81, 95% confidence interval 0.56-1.17, p = 0.26). Conclusions: Women demonstrate similar overall survival than men in metastatic RCC treated with secondal line and beyond nivolumab, with no differences observed in serious AEs and dose administered.

4106 Background: Approved systemic therapies for advanced NETs have showed limited tumor shrinkage and no data of activity after progression to prior targeted agents (TA) is available. Lenvatinib, a potent VEGFR1-3 & FGFR1-4 inhibitor may increase efficacy and revert primary and acquired resistance to TA. We report the final results of the TALENT trial. Methods: Two independent cohorts were included: panNETs and giNETs. All pts had baseline documented progression disease (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless of prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT); and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was overall response rate (ORR) by central radiology review. Progression-free (PFS) and overall survival (OS) were assessed by investigator. With 55 pts per arm, our study was powered to identify an ORR ≥25% (90% power, 5% α-error). Results: We recruited 111 pts: 55 panNETs and 56 giNETs (78% from small intestine). Prior therapies were CHT 32%, SSAs 87%, everolimus 70% and sunitinib 30% for panNETs. ORR was 29%, 42.3% for panNETs and 16.3% for giNETs. With a median follow-up of 19 m, PFS and OS for panNETs were 15.5 m (95% CI 11.3-not reached (NR)) and 29.2 m (95% CI 23.2-NR); and 15.4 m (95% CI 11.5-19.4) and NR for giNETs, respectively. Pts who obtained a response by RECIST had a significantly better PFS compared with non-responders (NR vs 11.2 m in panNETs (p=0.004); 37.2 m vs 14.9 m in giNETs (p=0.005). In the subgroup analyses, all pts obtained the same benefit in PFS and ORR, including tumor grade, prior therapies, hormone release, primary location and tumor burden. The most frequent G3/4 adverse events were hypertension (22%), fatigue (11%) and diarrhea (11%). Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. Conclusions: To our knowledge, we report the highest ORR by central radiology assessment with a TA in this setting. Lenvatinib showed a promising PFS and OS in a pretreated population with benefit across subgroups. Further development in advanced NETs is warranted. Clinical trial information: NCT02678780.

e14130 Background: irAEs are autoimmune-toxic effects associated with ICIs used for treatment of advanced solid tumors. The correlation of these irAEs with survival is presently unknown. The objective of this meta-analysis is to assess the outcome of cancer patients treated with ICIs who develop irAEs. Methods: Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane library database from their inception to November 2018. Studies were selected if: 1) they reported correlation of irAEs (any) with outcome, 2) they included patients with solid tumors; 3) they included treatment with anti-PD-(L)1 or anti-CTLA-4 agents, 4) patients had no previous history of autoimmune disorders, 5) they were published in English language, and 6) they provided availability of adequate data to calculate hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs). Data were pooled using HRs for overall survival (OS) or progression-free survival (PFS) or ORs for overall response rate (ORR) of irAEs vs no irAEs according to fixed or random effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. Hazard ratio for PFS and ORs for ORR were secondary endpoints. Results: A total of 29 studies for a total of 4242 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death (HR = 0.52, p < .001). Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR = 0.51, p < .001). The combined odds of response was 4.87 (p < .001). Conclusions: In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T cell activation. Patients showing any form of irAEs can be informed about the positive prognostic effect, and physicians can detect patients with favorable outcome to ICIs.

332 Background: Pts with advanced G1/G2 NETs have limited treatment options with overall response rates (ORR) with targeted agents (TA) < 10%. Benefit on PFS after TA therapy has not been demonstrated. The mechanism of action of lenvatinib (VEGFR1-3 & FGFR1-4 inhibitor) may increase efficacy and revert primary and acquired resistance to TA. We report the updated results on PFS, safety and subgroups. Methods: This prospective phase II study had two cohorts: G1/G2 panNETs and giNETs. All pts had baseline documented disease progression (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT), and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was ORR by central radiology review. PFS was calculated by investigator assessment. Biochemical responses were defined as reduction from baseline > 50%. With 55 pts per arm our study was powered to identify an ORR ≥ 25% (90% power, 5% α-error). Results: We recruited 111 pts (55 panNETs/56 giNETs). Prior therapies were CHT 32%, SSAs 87%, everolimus (E) 70% and sunitinib (S) 30% for panNETs. ORR was 29%, 40% for panNETs and 18.5% for giNETs. With a median follow-up of 17 months (m), PFS for panNETs was 15.8 m (95% CI 11.4-NR) and 15.4 m (95% CI 11.5-19.5) for giNETs. Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. In the subgroups analyses, all pts obtained the same benefit in PFS and ORR, including grade and prior therapy with S (PFS: 16.4 m, ORR: 43.7%) or E (PFS: 15 m, ORR: 37.1%) (p = ns). A significant correlation of chromogranin A decrease and prolonged PFS in giNETs (17.6 m vs NR, p = 0.032) was observed. The most frequent G3-4 adverse events were hypertension (20.7%), asthenia (13.5%), diarrhea (7.2%) and abdominal pain (5.4%). Conclusions: Lenvatinib showed the highest reported ORR with a TA by central radiology assessment in panNETs and giNETs with promising PFS in a pretreated population. The benefit was observed across subgroups analyses, including pretreated pts with TA. Clinical trial information: NCT02678780.

5067Background: pAR gene aberrations in mCRPC patients (pts) may be associated with worse outcome on AA+P/D. Methods: This was an international, multi-institutional, open-label phase 2 study of AA ...

e12504Background: Aromatase-inhibitors (AIs) decrease the bone mineral density (BMD) and increase the risk of clinical fractures but the mechanism underlying the increased fracture risk (FR) is not...

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m2 on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m2 on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 × 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P = .10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P = .47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P = .08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug’s tolerability.

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m2 administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m2/d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

TPS9109Background: Despite high overall response rates (ORR) to EGFR TKIs, most pts with EGFR-mutated NSCLC develop acquired resistance; secondary activation of cMET as gene amplification, occurs i...

525 Background: Sunitinib (S) is a standard first line treatment of metastatic renal cell carcinoma (mRCC). Asthenia and fatigue are the most prevalent toxicities but the relevant causes are not fully elucidated. Since endocrine glands are highly vascularized, the potent antiangiogenic effect of S can potentially impair their function. With the exception of hypothyroidism, the endocrine-related side-effects of S have not been extensively explored. Methods: We performed a cross-sectional study in which pituitary, thyroid, parathyroid, adrenal and gonadal functions were assessed in 25 mRCC patients who received 9 months of S therapy. Since a high prevalence of hypogonadism was observed, we subsequently enrolled 16 mRCC male patients in a prospective cohort study in which serum testosterone (T) serum free T, serum FSH and LH were evaluated at baseline and after 6 weeks (1 cycle) of S therapy. In patients eligible for testosterone replacement after andrologic evaluation, a FACT-G questionnaire for quality of life (QoL) assessment was prospectively administered at baseline and after 3 months. Results: In the cross sectional study 15/22 S treated male patients (68%) had serum T below the normal range and 13 of them (87%) presented with low/normal levels of LH. In the prospective study mean T levels (95% CI) were 5.04 ng/ml (3.4 - 6.7) at baseline and 4.1 ng/ml (3 - 5.3) after 6 weeks (p 0.05). The corresponding free T were 91.4 pg/ml (66 – 116.8) and 80.2 pg/ml (65 – 95.3) (p 0.24), respectively. Hypogonadism was observed in 5 (31%) patients at baseline and 10 (63%) patients after 6 weeks of S therapy. In the 5 patients becoming hypogonadic after S therapy, LH was 11.4 mU/ml (3.2 - 19.5) at baseline and 11.5 mUI/ml (0 – 23.5) after 6 weeks. Four patients were addressed to testosterone replacement. QoL significantly improved in 3 of them, with the strongest advantage in the physical comfort area. Conclusions: S therapy induces hypogonadism in a high proportion of male patients with mRCC. Low or inappropriately normal LH levels are consistent with a pituitary origin of the endocrine disorder. Testosterone replacement may improve the QoL and treatment tolerance.

261 Background: AA is approved for mCRPC, coadministered with prednisone (P) (5 mg BID) to prevent adverse events (AEs) associated with mineralocorticoid excess (ME). Lower GC doses had not previously been formally evaluated in combination with AA. Methods: This was an open-label, multicenter, phase 2 trial (NCT01867710) of asymptomatic chemotherapy-naïve mCRPC pts randomized 1:1:1:1 to AA (1000 mg QD) plus P 5 mg BID or P 5 mg QD or P 2.5 mg BID or dexamethasone (DEX) 0.5 mg QD. Pts who had previously received GC or ketoconazole were excluded. The primary end point was no ME (% of pts experiencing neither hypokalemia nor hypertension during the first 24 weeks of treatment).Secondary end points included additional safety, as well as response rate in the first 24 weeks, defined as a decline in prostate-specific antigen (PSA) ≥ 50% confirmed after 4 weeks. Results: 164 pts were randomized; 133 (81.6%) completed 24 weeks’ treatment. Median age: 70 years. Table 1 shows the rates of ME, hypertension, hypokalemia and PSA response. Changes in HbA1c values were minimal and observed in 16 (10.7%) pts. Conclusions: These data suggest that P 5 mg BID, which is approved in combination with AA, and DEX 0.5 mg QD, are effective in preventing ME-associated AEs, and that P 2.5 mg BID and P 5 mg QD can be safely used with appropriate monitoring. The suggestion of a higher PSA response rate with DEX 0.5 mg QD arm warrants further validation. Clinical trial information: NCT01867710. [Table: see text]

175 Background: Abiraterone acetate (AA) deeply inhibits androgen synthesis but leads to an ACTH driven increase in mineralocorticoid hormones requiring glucocorticoid supplementation that may impair its antineoplastic efficacy. New strategies for the management of the AA induced mineral corticoid excess syndrome (MCES) are warranted. Methods: We analyzed in vitro the interaction in terms of proliferative activity of AA plus/minus prednisone with the steroid aldosterone receptor antagonists: eplerenone, spironolactone, a non-steroidal aldosterone receptor antagonist (PF-03882845) and the epithelial sodium channel antagonist amiloride. LNCaP were grown in a medium with charcoal-treated serum and concentration-response curves for each studied drug were performed. Besides, the activity of amiloride plus hydrochlorothiazide was assessed in the clinical management of AA induced MCES in 5 consecutive patients with castrate resistant prostate cancer. The recovery of AA induced MCES symptoms and signs was the primary end point. Results: Prednisone, spironolactone and eplerenone induced an increase in the LNCAP proliferation rate and antagonized the AA-induced reduction of the cell proliferation in a concentration-dependent manner, while PF-03882845 did not. Amiloride at high concentrations induced cell death. When combined with AA +/- prednisone, amiloride at low concentration did not interfere with AA anti-proliferative activity however an additive inhibitory effect was observed at higher concentrations. The association of amiloride with hydrochlorothiazide led to a complete disappearance of all clinical and biochemical signs of abiraterone induced MCES in the 5 treated patients. Conclusions: Amiloride and PF-03882845 do not negatively interfere with the AA inhibition of proliferative activity of prostate cancer cells in vitro. The association of amiloride plus hydrochlorothiazide is efficacious in the management AA induced MCES.