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PURPOSE This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O6-methylguanine–DNA methyltransferase (MGMT)–silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule. RESULTS Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported. CONCLUSION The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.

3141 Background: The approval of intratumoral (IT) immunotherapy for metastatic melanoma and the active development of numerous novel IT drugs have created a need for standardized evaluation of response to this unique treatment strategy. The Response Evaluation Criteria in Solid Tumors (RECIST) is not suitable for assessing responses separately for injected and noninjected tumors. Building on RECIST concepts, we propose an IT immunotherapy RECIST (itRECIST) to capture data and assess local and systemic responses in a standardized fashion for clinical trials involving IT immunotherapies. Methods: itRECIST will address the unique needs of IT immunotherapy trials but, where possible, aligns with RECIST 1.1 and iRECIST. It does not dictate which lesions to inject but provides guidelines for collecting data and assessing response as treatment evolves. Results: itRECIST enables overall response assessment, separate response assessments in injected and noninjected lesions, and continued assessment following modifications of therapy at initial progression. At baseline, lesions are classified into 4 categories: target injected, target noninjected, nontarget injected, and nontarget noninjected. After baseline, lesions can be reclassified from noninjected to injected if the investigator decides to change the lesions to inject, but target and nontarget designations never change. Overall response at each assessment is based on target lesion response (injected and noninjected), nontarget lesion response, and absence/appearance of new lesions. Noninjected lesion response is determined by comparing tumor burden with baseline and nadir values. Injected lesion assessment is based on visit-to-visit changes in the lesions injected during treatment and on a combined assessment once the patient is off treatment. A new response category is defined to capture progression that would be “confirmed” per iRECIST even though injected lesions are responding and therapy continues. Multiple examples have been created to aid in training and adoption. Conclusions: itRECIST is an important step toward a standardized method of response assessment for this promising and evolving therapeutic modality. The proposed guidelines can be adopted into trial protocols and routine clinical practice without the need for complex additional assessments by treating physicians. Until there is evidence to support wider use, itRECIST is intended only to support standardized collection of data and to facilitate exploratory analysis. Authors G.V.G. and A.D.K. contributed equally to this work.

590 Background: Biliary Tract Cancers (BTC) have poor prognosis and limited therapeutic options. There is mounting evidence for biomarker-directed therapy for BTC, with several potentially actionable molecular targets reported in up to ~50% of patients and significant biological differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gallbladder cancer (GBC). ESMO and ASCO recommends the use of tumour multigene next generation sequencing (NGS) for CCA. Methods: This was a monocentric study assessing real-life clinical actionability of molecular alterations identified with expanded NGS for patients (pts) affected by advanced BTCs treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from January 2016 to July 2022. NGS was performed either via the “Hotspot Cancer Panel, Ion Torrent”, the “Oncomine Comprehensive Assay Plus” or the FoundationOne CDx panel; FGFR2 testing was also performed via fluorescence in situ hybridisation. Molecular alterations were classified according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with targeted treatments administered and efficacy endpoints. Benefit from targeted treatment was evaluated by means of progression-free survival (PFS) ratio, as defined as the ratio of each patient’s PFS2 (i.e. PFS on molecularly informed therapy) to the PFS1 (PFS on his/her most recent previous treatment), with d for efficacy equal to 1. Results: Out of 340 pts with adequate tissue for NGS, 231 (68%) were affected by ICC, 61 (32%) by ECC and 48 (14%) by GBC. Actionable alterations as per ESCAT I-III were found in 33 % of pts (N= 113, including IDH1 mutation, FGFR2 fusions/rearrangement/mutations, MSI-H, BRAFV600E mutations, ERBB2 mutations/amplifications, BRCA1/2 mutations); 88% of these alterations were found in pts with ICC. Targeted therapy was actually started for 48 pts (14 %), with 9 pts treated with ivosidenib, 32 with FGFR2 inhibitors, 2 with PD-L1 inhibitor, 6 with BRAF+MEK inhibitor and 1 with an HER2 inhibitor). Overall response rate and disease control rate were 18% and 62%, respectively.Median PFS was 5.4 months(95% CI 3.0 - 6.4) overall and 10.12 months on BRAF+MEK inhibitors, 5.55 months on FGFR2 inhibitors, 2.92 months on ivosidenib and 6.23 months on PD-L1 inhibitors. Median PFS ratio was 1.1 (95%CI 0.7 - 1.4), with benefit rate of 51%. Of note, 5 (10%) received targeted therapy as > III line. Median overall survival of targeted therapy was 10 months. Conclusions: Expanded sequencing for BTCs is feasible in real-life and can improve treatment strategy. Analysis of PFS ratio and of treatment outcomes shows clinically meaningful benefit of targeted treatment in pretreated patients.

e16507 Background: The phase II BONSAI trial ( n = 25 ; NCT 03354884) met the primary endpoint demonstrating activity of cabozantinib in untreated metastatic collecting ducts carcinoma (mCDC), a rare and biologically poorly characterized disease. Here we report on molecular analyses of baseline tissue samples. Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 18 mCDC patients enrolled in BONSAI were sequenced by TruSeq RNA Exome kit (Illumina). The data were mapped and quantified using STAR and htseq, respectively. Globaltest and edgeR packages in R were used to assess the correlation between transcriptional profiles and survival data. Nineteen samples underwent DNA Sequencing with the Oncomine Comprehensive Assay Plus (ThermoFisher Scientific). The reads were aligned to the human genome reference (hg19) and analyzed with Opencravat and IonReporter software. Germline variants were excluded based on 1000 Genomes, GnomAd and Exac databases, and Clinical annotation of somatic variants was performed using ClinVar. Results: The global expression levels of thirty-one genes have been found significantly associated with overall survival (OS). The natural grouping of the 18 tumor samples based on the 31-gene signature identified a main group of 11 cases, showing global higher expression levels in 22 out of the 31 genes. This group displayed overall a significant higher OS rate in comparison to the remaining 7 patients, carrying opposite expression trend and mostly undergoing to disease progression. The identified signature was enriched in biological processes like cell junction, cytoskeleton organization and methylation. FOS oncogene was among the 9 genes negatively associated to OS, showing common higher expression in the poorer survival rate group. Furthermore, a 22-gene signature was found significantly associated with progression-free survival (PFS), involving mainly genes associated to cell cycle regulation or recognized as components of Golgi apparatus. Only three genes were globally up-regulated in the group of 9 patients characterized by shorter PFS. Finally, heterogeneous pattern of somatic mutations was identified in 19 tumor samples, with at least 8 genes recurrently affected in more than three patients. Notably, mutated genes were mostly involved in DNA repair and chromatin modification processes. Conclusions: Our findings for the first time define specific molecular signatures that differentiate therapy-specific outcomes in first-line mCDC, warranting further investigation of their involvement in the tumor biology. Clinical trial information: NCT 03354884.

6051 Background: In platinum-resistant recurrent-metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients (pts), survival improvements have been achieved with immune checkpoint inhibitors (ICI), however this benefit is limited to a relatively small subgroup of pts. Predictive biomarkers are still under investigation and their contribution to the clinic has been limited. An immune-related cluster (Cl6) has been defined by means of a metanalysis in locally advanced HNSCC. Methods: Gene expression profiling was performed on two cohorts of platinum resistant R/M HNSCC pts treated with ICI alone: i) 20 patients as training set, divided in long-term (OS >18 months; n=12) and short-term (OS < 6 months; n=8) survivors matched according to site of recurrence (distant metastases only, or locoregional recurrence with/out metastases); ii) 80 patients enrolled in a phase II trial (EudraCT number: 2017-000562-30; NIVACTOR study) as testing set. The molecular subtyping stratification (De Cecco, Oncotarget 2015) was applied. Subsequently, a score was determined between each sample and the centroids for the 6 clusters previously identified. The threshold point was imputed in the training set as the closest value to the observed prevalence. A Cox multivariable analysis including TMB, CPS and TPS PD-L1 status, age, tumoral subsite and performance status (PS) was performed. Results: Among all the clusters, Cl6 turned out to be significant and applied to training set it provided evidence to discriminate pts’ survivals (AUC=0.86, 95%CI=0.7-1.0; p=2E-05). The stratification based on Cl-6 along with the cut-off point defined in the training set were challenged in the testing set: samples were divided in 28 (35%) having high Cl-6 scores and 52 (65%) with low scores, reaching HR=0.46 (95% CI= 0.27-0.76; p=0.0024). Multivariate analysis showed that only Cl6 (high vs low, HR=0.44; p=0.00443) and PS (1,2 vs 0, HR 1.85; p=0.02686) resulted to be significant on pts’ OS. Conclusions: By analysing two series of pts receiving immunotherapy alone, we identified an immune-related gene expression signature, able to discriminate the prognosis of platinum-resistant R/M HNSCC pts. The multivariate analysis confirmed the immune-related Cl6 as factor linked to outcome in pts treated with immunotherapy, as well as it confirmed the importance of PS. An analysis of the signature on pts receiving first line treatment with immunotherapy is currently ongoing. [Table: see text]

11570 Background: In recent years evidence of long term stabilization and spontaneous regression of primary sporadic DT resulted in a paradigm shift towards more conservative approaches. We present herein the results of an observational study aimed at prospectively assess the behavior of primary sporadic DT initially managed by active surveillance and its relation to CTNNB1 mutational status. Methods: This is an Italian prospective, multicenter, observational study (NCT 02547831) to evaluate primary sporadic DT behavior in patients (pts) >16 years with primary naive or incompletely resected and measurable disease, at any site, with CTNNB1 mutational status available. Pts were assessed by contrast enhanced MRI or CT scan at baseline, at 3, 6, 9, 12 months, then every 6 months until the third year. Tumor changes were assessed by RECIST. In case of dimensional or symptomatic progression active treatment could be proposed on an individualized basis CTNNB1 mutational status was obtained in all patients by Sanger and deep sequencing was performed in wild-type cases. Primary end-point was progression-free survival (PFS) at 3 yrs. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated using survival analysis methods, including Kaplan-Meier plots, log-rank test for survival curves comparison, and Cox proportional-hazard multivariable regression (age, size, anatomic site and CTNNB1 mutational status). Results: From April 2013 to February 2018 108 pts were included (82% female, 18% male); median age was 39 (interquartile range, IQR 34-48) and median size 50 mm (IQR, 40-80 mm). Tumor location was: 4/108 (4%) = head&neck, 25/108 (23%) = trunk, 59/108 (55%) = abdominal wall, 3/108 (3%) = intra-abdominal, 17/108 (16%) = extremities. CTNNB1 mutations were as follow: T41A 54/108 (50%), S45F 13/108 (12%), WT 20/108 (19%), other mutations 21/108 (19%). At a m-FU of 32.3 months, the 3-year PFS was 54.5% (95% CI, 44.9%-66.1%). 42/108 (39%) pts showed a RECIST progression, with equal distribution among the different anatomic sites. None of the variables analyzed were associated to PFS. Spontaneous regression was initially observed in 27/108 (25%) patients, while it followed dimensional progression in another 33/108 (30%). 35/108 (32%) pts received active treatment, 18/42 (43%) after RECIST progression and 17/66 (26%) after symptomatic progressions. TFS at 36 months was 65.9% (95% CI, 57.3%-75.9%). S45F mutation, larger tumor size and extremity location were associated to a shorter TFS. No dimensional or symptomatic progression were observed after 36 months of FU. Conclusions: Active surveillance was marked by spontaneous regressions in 60/108 (55%) pts. An active treatment was needed in 32%. If no events occur after 3 yrs of FU, more relaxed FU schedules can be considered given the low risk of subsequent progression. Attention should be paid to patients with DT located to the extremity and/or carrying a S45F mutation. Clinical trial information: NCT 02547831.

5506 Background: Intensive follow-up in cancer patients, which absorbs a lot of health system resources and can be a source of increased stress for patients, are often proposed on the assumption that an early recognition of relapse will translate in better outcomes. In endometrial cancer few randomized controlled trials were conducted to assess the role of a reduced number of the scheduled visits and of different settings of the follow-up, but did not investigate the contribution of routine serum, cytological or imaging follow-up investigations in improving overall survival or quality of life. The TOTEM study was planned to compare an intensive (INT) vs minimalist (MIN) 5- year follow-up regimen in endometrial cancer patients in terms of overall survival (OS). Methods: Patients surgically treated for endometrial cancer, in complete clinical remission confirmed by imaging, FIGO stage I-IV, were stratified by center and in low (LoR) or high (HiR) risk of recurrence and then randomized to INT or MIN hospital-based follow-up regimens. The main study hypothesis was to demonstrate an improvement from 75% to 80% (expected hazard ratio, HR = 0.78) of the 5-year OS with the INT regimen. Secondary objectives were to compare relapse free survival (RFS), health-related quality of life (HRQL) assessed at baseline, at 6 and 12 months and then yearly (with the SF-12 Physical and Mental Health Summary Scale) and costs. Results: 1884 patients were randomized in 42 centers between 2008 and 2018, and 1847 patients were available for the final analysis (60% LoR). Compliance with the follow-up scheduled visits was 75.3%, similar between INT (74.7%) and MIN (75.9%) arms, whereas the mean number of recorded exams (laboratory or imaging) was markedly higher in the INT than in the MIN arms (9.7 vs 2.9, p < 0.0001). After a median follow-up of 66 months, the overall 5-year OS was 91.3%, 90.6% in the INT and 91.9% in the MIN arms, respectively (HR = 1.12, 95%CI 0.85-1.48, p = 0.429). Comparing the INT vs MIN arms, the 5-year OS were 94.1% and 96.8% (HR = 1.48, 0.92-2.37, p = 0.104) in the LoR and 85.3% and 84.7% (HR = 0.96, 0.68-1.36, p = 0.814) in the HiR group. No relevant differences emerged in RFS between INT and MIN regimens, (HR = 1.13, 0.87-1.48, p = 0.365). At the time of the relapse most women were asymptomatic (146/228, 64.0%), with a tendency of higher proportions in the INT than in the MIN arm, both in the LoR group (78.8% vs 61.1%, p = 0.070) and in the HiR one (64% vs 60%, p = 0.754). HRQL was available only for a subgroup of patients (50% at baseline) and did not differ between arms. Conclusions: Intensive follow-up in endometrial cancer treated patients showed a weak and uncertain advantage in detecting earlier asymptomatic relapses but did not improve OS, even in HiR patients, nor influenced HRQL. Frequent routine use of imaging and laboratory exams in these patients should be discouraged. Clinical trial information: NCT00916708.

Purpose Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696). Patients and Methods Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) ≥ 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m2 weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m2 added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral α .05, 355 events were needed and 400 patients planned. Results Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS ≥ 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity. Conclusion The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.

Purpose Doublet chemotherapy is more effective than single-agent as first-line treatment of advanced non–small-cell lung cancer (NSCLC). As second-line treatment, several randomized trials have been performed comparing single-agent with doublet chemotherapy, but each trial had an insufficient power to detect potentially relevant differences in survival. Methods We performed meta-analysis of individual patient data from randomized trials, both published and unpublished, comparing single-agent with doublet chemotherapy as second-line treatment of advanced NSCLC. Primary end point was overall survival (OS). All statistical analyses were stratified by trial. Results Eight eligible trials were identified. Data of two trials were not available, and data of six trials (847 patients) were collected. Median age was 61 years. Performance status was 0 or 1 in 90%; 80% of patients had received previous platin-based chemotherapy. OS was not significantly different between arms (P = .32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% CI, 0.79 to 1.08). Response rate was 15.1% with doublet and 7.3% with single-agent (P = .0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for single agent (P = .0009; HR, 0.79; 95% CI, 0.68 to 0.91). There was no significant heterogeneity among trials for the three efficacy outcomes. Patients treated with doublet chemotherapy had significantly more grade 3 to 4 hematologic (41% v 25%; P < .0001) and grade 3 to 4 nonhematologic toxicity (28% v 22%; P = .034). Conclusion Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent.

Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Δ4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

Background Financial toxicity in cancer patients has been initially reported in the United States and subsequently in other countries, including Italy, despite a health care system grounded on universal coverage. Considering that the way healthcare and welfare systems are shaped does impact on financial problems faced by cancer patients, we are developing an instrument for evaluating occurrence, gravity, and consequences of financial toxicity in Italy, and hopefully for fighting it. Methods Concept elicitation, item generation and qualitative analyses represented the initial tasks of the project. Literature review, focus groups with 34 cancer patients or caregivers in three regions located in North, Central, and South Italy, and semi-structured interviews with 97 oncologists were conducted for concept elicitation. A recursive process was used to identify themes in the data to inform the instrument until saturation was reached. Importance analysis questionnaires were administered to a further 44 cancer patients to evaluate and revise the draft item pool. A multi-disciplinary committee (including oncologists, psychologists, statisticians, patient association’s representatives, nurses, social science researchers and economists) oversaw the project. Results Overall, 156 concepts were distributed among 10 themes (bureaucracy, medical care, domestic economy, emotion, family, job, health workers, welfare state, free time, transportation). After controlling for redundancy, 55 candidate items were generated and 30 items, with at least one per each theme, remained after importance analysis. Out of the 30 items, 23 (77%) refer to material conditions, 4 (13%) to psychological response, and 3 (10%) to coping behaviors. Conclusions The first results of the proFFiT project show that most of the items selected by patients are related to material conditions that cause, or derive from, financial hardship. The final questionnaire will be ready by the end of 2019. Supported by Fondazione AIRC IG grant 2017-20402. Clinical trial identification NCT03473379. Legal entity responsible for the study Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Pascale IRCCS, Naples, Italy. Funding Fondazione AIRC IG grant 2017-20402. Disclosure S. Riva: Honoraria (self): CSL-Behring; Honoraria (self): GlaxoSmithLine Foundation. M. Di Maio: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Janssen. F. Efficace: Honoraria (self): BMS; Honoraria (self): Incyte; Honoraria (self): Orsenix; Honoraria (self): Amgen. V. Montesarchio: Honoraria (self): BMS; Honoraria (self): Italfarmaco; Spouse / Financial dependant: Bayer. F. Perrone: Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Celgene; Honoraria (self): Incyte; Honoraria (self): Janssen-Cilag; Honoraria (self): Pierre Fabre; Honoraria (self): Sandoz. All other authors have declared no conflicts of interest.

5516 Background: The standard of treatment of stage I MOGCTs is surgery followed by BEP (bleomycin + etoposide + cisplatin) chemotherapy, except for stage IA dysgerminoma (D) and IAG1 immature teratoma (IT). Surveillance has emerged as a possible option to avoid adjuvant chemotherapy in IB-C1 D, IA-C G2 – G3 IT, and in stage IA mixed and yolk sac tumors (YST), after comprehensive surgical staging (CSS) with negative postoperative markers. The aim of this study was to analyze oncological outcome of stage I MOGCT patients included in the MITO9 study. Methods: MITO9 was a prospective observational study analyzing data collected between 2013 and 2018. 41 patients with stage I conservatively treated MOGCTs were included. Three groups were identified: group A. IA D and IAG1 IT candidate to surveillance according to guidelines; group B. stages IB-C1 D, stage IA-C G2-G3 IT, stage IA mixed and YST were consulted about the option of close surveillance vs adjuvant chemotherapy in case of CSS; group C. all other patients receiving BEP. Results: Median age was 25.6 years (range 14-40). Median follow up was 36,4 months. Group A included 12 patients, 5 IA G1 IT and 7 IA D. Group B included 24 patients. Of these, 2 out of 5 patients (40%) were positive at restaging and were excluded from surveillance protocol. Seven of the 22 remaining patients (31.8%) received chemotherapy, while 15 (68.1%) were enrolled in the surveillance protocol. Out of these 15 patients, 4 were stage IC D (one IC1, one IC2 and two IC3), 2 were mixed stage IA with YST tumor, 9 were G3 IT (four IA, three IC2, one IC3 and one IB). The 7 patients receiving chemotherapy were: 1 dysgerminoma IC2, 2 YST IA, 3 IT G3 (one IA and one IC2) and 1 mixed IA tumour. Group C included 5 patients, three IC YST and two mixed IC2 with YST. Survival of these patients was 100%, while disease free survival was 97.5%. Only one patient in C Group, a stage IA G3 IT treated with adjuvant BEP, relapsed as mature teratoma. None of the patients in the surveillance protocol experienced relapse. Conclusions: These data suggest that close surveillance could be an alternative option to avoid adjuvant chemotherapy in properly staged IB-C1 D, stage IA G2 – G3 IT, stage IA mixed and YST. These findings deserve further confirmation in an international cooperative setting.

e17028 Background: Recurrent disseminated cervical cancer is a discouraging clinical entity with 1-year survival rates between 10-15%, and development of novel, effective treatments remains an unmet medical need. We investigated the preclinical efficacy of IMMU-132 (sacituzumab govitecan), an antibody-drug conjugate (ADC) comprised of a humanized anti-trophoblast-cell-surface-antigen (Trop-2) antibody (hRS7), conjugated with a hydrolysable linker to the active metabolite of irinotecan (SN-38), against Trop-2 positive primary cervical cancer cell lines and mouse xenografts. Methods: Trop-2 expression was evaluated in 151 cervical tumors and 5 primary tumor cell lines by immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and flow cytometry. Cervical cancer cell viability against IMMU-132, non-targeting control ADC, and naked antibody (hRS7 IgG) was evaluated using flow-cytometry-based assays after 48-72 hours of incubation at a concentration of 0.05, 0.5, 1, 2, 4, and 10 nM of each agent. In vivo antitumor activity was tested in xenograft models with 3+ Trop-2 expression. Results: Out of 151 cervical tumors, 123 were squamous cell carcinoma (SCC), 26 were adenosquamous/adenocarcinoma, 1 was neuroendocrine carcinoma, and 1 was clear cell carcinoma. Strong diffuse staining was seen in 61% (75/123) of SCCs, and 92% (24/26) of adenocarcinoma/adenosquamous cancers. The neuroendocrine carcinoma was also strongly positive, while there was no staining in the clear cell carcinoma. Four out of five (80%) primary cervical cancer cell lines evaluated overexpressed Trop-2 as determined by RT-PCR and flow cytometry. Trop-2 positive cell lines showed high sensitivity to IMMU-132 in vitro, with IC50-values in the range of 0.18 to 0.26 nM ( P= 0.02). In contrast, a Trop-2 negative cervical cell line was highly resistant to the ADC with similar IC50 for IMMU-132 and control ADC. In xenografts, twice-weekly intravenous administration of IMMU-132 for three weeks demonstrated significant tumor growth inhibition compared to controls ( P≤0.001). Overall survival was significantly increased in mice treated with IMMU-132 ( P= 0.014) when compared to naked antibody and ADC-control groups. Conclusions: Sacituzumab govitecan may represent a novel class of active drugs for cervical cancers overexpressing Trop-2. Clinical trials are warranted.

e15770 Background: Metastatic pancreatic cancer (mPAC) has a poor prognosis, with few therapeutic options and an overall survival (OS) at 5 years < 5%. O6-methylguanine-DNA methyltransferase ( MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Its promoter methylation results in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). Of note, both reductions in MGMT expression and MGMT promoter methylation are described in a variety of gastrointestinal malignancies, including colorectal cancer (CRC). Here we present data on MGMT methylation tested in mPAC pts treated at our center. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI). Furthermore, the exploratory analysis of MGMT status was performed via methyl specific PCR (EZ DNA Methylation-Gold™ KIT) to assess promoter methylation, and immunohistochemistry (IHC) was done to assess protein expression. Results: Archived FFPE tissue sections obtained from 60 pts treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to December 2018 were analyzed. 47 samples (78%) had adequate tissue for extended analyses. As expected, 44 (93%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 pts (6%), respectively. MGMT promoter methylation was identified in 14 pts (29%), with low/negative MGMT protein expression in 7 (14%). Interestingly, amongst MGMT methylated pts, there were 3 (21%) BRCA1/2 somatic mutant and 1 (7%) MSI, suggesting possible genomic instability. Conclusions: MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 29% of patients with mPAC. This data warrant further prospective confirmation, but there is definitely a growing interest in the role of MGMT methylation as a predictive and prognostic biomarker in mPAC.

3509 Background: Overall response rate (ORR) to temozolomide (TMZ) is ∼10% in refractory mCRC pts with MGMT methylation detected by qualitative assays, e.g. methylation-specific PCR (MSP). ORR to irinotecan/FOLFIRI in second-line trials was 4-16%. The efficacy of TMZ may be improved by its combinatorial use in earlier lines and molecular selection beyond MSP. Lack of MGMT expression by immunohistochemistry (IHC) and high MGMT % methylation by MethylBEAMing (MB) are prognostic for higher ORR/PFS in TMZ-treated pts. Methods: This multicenter, randomized phase 2 trial investigated PFS superiority of second-line CAPTEM (Arm A: capecitabine 750 mg/sqm bid days1-14/TMZ 75 mg/sqm bid days10-14q28 days) over FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts: ECOG PS 0-1, measurable disease, failure of 1st-line oxaliplatin-based tx (or relapse within 6 mos from oxaliplatin-based adjuvant tx). Randomization was stratified by time from the start of oxaliplatin-based therapy to PD ( < /≥9 months); prior bevacizumab (yes/no). A one-sided log-rank test with a sample size of 82 pts (41 per arm) achieved 90% power at a 5% significance level to detect mPFS increase from 2 to 4 mos. Secondary endpoints: safety, QoL, OS, ORR. Exploratory endpoints: predictive value of MGMT IHC/MB. Results: From Nov 2014 to Feb 2019, 82 pts (arm A/B: 41/41) were enrolled in 18 Italian sites. Baseline characteristics (arm A/B): males 44/56%, median age 70/67, ECOG PS 0 54/51%, right-sidedness 37/39%, 1 metastatic site 44/34%, prior bevacizumab 68/66%, 1st-line PFS 9,4/10,2 months. At a median follow up of 26.6 mos, 70 PFS/46 OS events were collected. The mPFS was 3.6 vs 4.1 mos in arm A vs B (HR = 1.26;95%CI 0.78-2.02;p = 0.34) and mOS was 9.1 vs 14.2 mos (HR =1.08;95%CI 0.60-1.94;p = 0.79). ORR and DCR (arm A/B): 12/10% and 51/51%. Grade 3-4 adverse events: 15/44% (diarrhea 0/12%, stomatitis 0/7%, anemia 2/10%, neutropenia 2/22%, thrombocytopenia 7/0%). Neither MGMT IHC nor MB status were prognostic. MGMT IHC positive subgroup, arm A (n = 12) vs arm B (n = 22): mPFS, 2.0 vs 4.1 mos (HR = 2.06;95%CI 0.96-4.45;p = 0.06), mOS, 6.4 vs 10.6 mos (p = 0.78), ORR (0% vs 14%) and DCR (25% vs 55%;OR = 0.28;95%CI 0.06-1.31;p = 0.11). In MGMT IHC negative subgroup, no PFS/OS/ORR/DCR differences were noted between the two arms. P interaction IHCxArm: 0.171 for PFS, 0.917 for OS, 0.06 for DCR. Similar accuracy was achieved by MB. Conclusions: The use of TMZ should be explored by phase 3 trials enrolling MGMT IHC-negative +/- high MGMT % methylated mCRC. Clinical trial information: NCT02414009.

219 Background: We previously reported that QoL is not included among endpoints and QoL results are significantly underreported in a high proportion of recently published phase III trials in oncology. In this study our aim was to describe QoL prevalence and heterogeneity in QoL reporting in prostate cancer (PC) phase III trials. Methods: Whole database included all primary publications (P) of phase III trials evaluating anticancer drugs published between 2012 and 2016 by 11 major journals. For this analysis, we extracted the subset of PC trials. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis. Results: 35 P were identified (21 in castration-resistant [CRPC], 9 in advanced hormone sensitive [aHSPC], incl. both metastatic and biochemical relapsed, and 5 in earlier stages). In 13 (37.1%) QoL was not listed among study endpoints: 7/21 (33.3%) in CRPC, 3/9 (33.3%) in aHSPC, and 3/5 (60%) in earlier stages. Out of 22 primary P of trials including QoL among endpoints, QoL results were not reported in 9 (40.9%). Overall, no QoL data were available in 22/35 (62.9%) primary P (61.9% in CRPC, 44.4% in aHSPC and 100% in earlier disease). QoL data were not available in 15/25 (60%) trials with overall survival (OS) as primary endpoint, and in 7/10 (70%) trials with other primary endpoints. QoL data were not available in 7/16 (43.8%) trials with a positive result (25% in CRPC, 40% in aHSPC, 100% in earlier stages). In 18 trials with available QoL results (incl. secondary publications), most common QoL tools were FACT-P (11, 61.1%) and EORTC QLQ-C30 (6, 33.3%). Common methods of analysis were mean changes (6, 33.3%), mean scores over time (6, 33.3%), time to deterioration (6, 33.3%) and proportion of responders (3, 16.7%). QoL analysis was focused on the impact of toxicity in 10 cases (mostly in earlier stages), and on disease symptoms in 10 cases (mostly in CRPC). Conclusions: QoL is absent in a high proportion of recently published phase III trials in PC, although presence of QoL results is better in positive trials, especially in CRPC. Methodology of QoL analysis is heterogeneous in terms of type of instruments, analysis and presentation of results.

66 Background: In CLASSIC and MAGIC, MSI was a good prognostic factor, and adjuvant/perioperative chemotherapy had null/detrimental effect. Given the low prevalence of MSI in GCs and its association with other good prognostic variables, larger datasets are needed to draw more robust evidences on its specific prognostic/predictive impact. Methods: This was a multinational IPD meta-analysis of resectable GC pts enrolled in MAGIC, CLASSIC, ARTIST, ITACA-S. Data on pts’ demographics (age, sex, and race), primary site (stomach versus junctional), histotype (intestinal vs. other), T/N stage (7th TNM), treatment received (multimodal therapy vs. surgery alone) and MSI were pooled. Univariable and multivariable associations with disease-free survival (DFS)/overall survival (OS) were assessed. The predictive role of MSI according to treatment received was assessed overall and in the 2 RCTs with a surgery alone arm (MAGIC+CLASSIC). Results: We pooled 1,552 pts with available MSI status: 121 (7,8%) were MSI, 572 Caucasian/980 Asian. In MSI versus MSS subgroups, 5-y DFS was 71.8% (95% CI: 63.8-80.7%) versus 52.3% (49.6-55.0%) (HR = 0.50, 95% CI 0.35-0.72; p < 0.001); 5-y OS 77.4% (69.9-85.8%) versus 59.2% (56.6-62.0%) (HR = 0.50, 95% CI 0.34-0-74; p < 0.001). In multivariable analyses, MSI was independently associated with DFS (HR = 0.48 [0.33-0.70]; p < 0.001) and OS (HR = 0.48 [0.29-0.81]; p = 0.005), as T/N/race/treatment. Conclusions: In resectable primary GC, MSI is an independent good prognostic marker that should be adopted as stratification factor in future RCTs. Chemotherapy omission and/or immune checkpoint blockade should be prospectively investigated in MSI-high GCs according to the clinically-defined risk of relapse. [Table: see text]