Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with mRCC prior to regulatory approval. Methods: Pts with mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events (AEs) using CTCAE v.4.0. Association between sex, age, BMI, metastatic sites, number and kind of previous therapies, ECOG PS and related toxicity were evaluated with a logistic regression model that identified only age ≥ 65 years (Odds Ratio= 1.54 (1.00-2.38; P = 0.05). Results: A total of 389 pts were enrolled between July 2015 and April 2016, 79% after 2 or more lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two (5.7%) pts discontinued treatment due to AEs. There were no treatment-related deaths. Treatment-related AEs (grade 1-4) were reported in 32% of pts. Median time to appearance of AEs was 1.4 months (range 0-11.4). Grade 3–4 AEs occurred in 27 (7%) pts. Of the 22 serious AEs who induced treatment discontinuation, 11 (50%) were considered irAEs including: grade 4 hyperglicemia (n = 1), grade 3 diarrhea (n = 1), grade 3 pulmonitis (n = 1), grade 3 bronchiolitis obliterans organising pneumonia (BOOP) (n = 1), grade 3 asthenia (n = 1), grade 3 hypertension (n = 1), grade 3 skin toxicity (n = 1), grade 3 tremor (n = 1), grade 2 eyelid ptosis (n = 1), grade 2 liver toxicity (n = 1), grade 2 hypothyroidism (n = 1). AEs were generally manageable with treatment as per protocol-specific guidelines. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7 - 6.2), the 12-months overall survival rate was 63%. Pts with toxicity (124 pts) had a significant (P = 0.01) longer survival (1 year OS 69%) in comparison to pts who did not experience AEs (1 year OS 59%). Conclusions: The appearance of AEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with Nivolumab. Legal entity responsible for the study: Italian Renal Cell Cancer Early Access Program Group. Funding: BMS. Disclosure: E. Verzoni: Honoraria/Consultancy: Novartis, Pfizer, Ipsen, BMS. C.N. Sternberg: Honoraria/Consultancy: Novartis, Pfizer, Ipsen, Eisai, BMS. G. Procopio: Honoraria/Consultancy: Ipsen, BMS, Pfizer, Novartis. All other authors have declared no conflicts of interest.

Background: The risk of developing renal cell carcinoma (RCC) increases with age, and given the constant gain in life expectancy of the general population, RCC is frequently observed in the elderly. More than 80% of cancer pts aged ≥ 70 years have at least one comorbidity requiring treatment, leaving them exposed to drug interactions. Due to high frequency of comorbidities, these pts are often under-represented in clinical trials. The purpose of this analysis is to evaluate the feasibility of treatment with nivolumab in the elderly (≥ 70 years) and very elderly (≥ 75 years) in the EAP in Italy, given a more realistic picture of real world setting. Methods: Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after at least one prior systemic treatment in the advanced or metastatic setting. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received ≥ 1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events. Results: Of 389 Italian pts with mRCC enrolled in the EAP in Italy 125 pts (32%) had ≥70 years and 70 (18%) had ≥75 years. With a median follow-up of 9.8 months (0.1-16.2) in the elderly population (≥70 years), the disease control rate (DCR) was 58% including 1 patient in complete response (CR), 32 pts in partial response (PR) and 40 patients in stable disease (SD). Regarding the very elderly population (≥75 years), with a median follow-up of 9.8 months (0.1 -14.9), the DCR was 60% including 1 patient with CR, 19 pts with PR and 22 with SD. As of May 2017, 6 and 12 months overall survival (OS) rate were 87.2% and 77.8% respectively in the elderly population. Regarding the very elderly, the 6 and 12 months OS rate was 83.6% and 77.7%, respectively. The safety profile was consistent to what already observed in the general population. Conclusions: These results suggest that elderly population can benefit from nivolumab treatment with safety results consistent to what previously reported, supporting the use of nivolumab in this subpopulation. Clinical trial identification: CA209-99M Legal entity responsible for the study: Sergio Bracarda coordinator Italian RCC EAP Group Funding: None Disclosure: All authors have declared no conflicts of interest.

BACKGROUNDPrevious studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer.PATIENTS AND METHODSThis study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments.RESULTSMCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found.CONCLUSIONSFor patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

e16611 Background: Many cancer patients (pts) receive chemotherapy at the end of life (EOL) with negative effects on quality of life and high economic burden. Palliative care services and hospice facilities became widely available in Italy during the last decade. We analyzed if this had an impact on chemotherapy use at EOL comparing current data with those obtained in a study carried out in year 2002, where we observed 33% of pts treated with chemotherapy in the last month of life (Giorgi et al. Proc ASCO 22: #6081, 2004). Methods: We performed a retrospective chart review of pts died in year 2010 and treated in three oncology divisions in which palliative care and hospice services have been available since 2004. Results were compared with those obtained in year 2002 when there was no palliative care program in the same oncology units. Results: Clinical records of 335 pts dead during 2010 were reviewed (F 156, M 179). The most frequent tumors were: breast 53 pts, NSCLC 53, colorectal 48, gastric 30, pancreas 16, prostate 13. Median age was 71 years (range 22-96). Seventy-one pts (21 %) received chemotherapy and 16 pts (5 %) targeted therapies in the last month of life (aggregate 26 %). In the last week of life 10 pts received chemotherapy and 8 pts targeted therapies (5 %). One hundred ninety-two pts (57%) entered a palliative care/hospice program managed by oncologists of the same unit: 126 pts home palliative care and 66 pts hospice care. Despite the expansion of standard second and third line chemotherapy and targeted therapy in the oncologist's therapeutic arsenal, we observed a 7 % reduction (21% relative reduction) of cancer-directed interventions in the last month of life. Conclusions: We observed a 21% relative reduction in anticancer treatment provided at the EOL between 2002 and 2010. We believe that most of this reduction can be ascribed to the implementation of palliative care services where oncologists ensure continuity of care. Maintaining a stable oncologist-patient relationship may foster better EOL decisions and utilization of health care resources.

BACKGROUND:A large proportion of colorectal cancer patients does not benefit from the use of anti-epidermal growth factor receptor (EGFR) treatment although in the absence of a mutation of the K-RAS gene. Preliminary observations suggested that HER-3, insulin-like growth factor-1 (IGF-1), nuclear factor-kB (NF-kB) and EGFR gene copy number (GCN) might identify patients not likely to benefit from anti-EGFR therapy. We tested the interaction between HER-3, IGF-1, NF-kB, EGFR GCN and K-RAS mutational analysis to verify the relative ability of these variables to identify a subgroup of patients more likely to benefit from EGFR-targeted treatment among those harbouring a K-RAS wild-type status. PATIENTS AND METHODS:We retrospectively collected tumours from 168 patients with metastatic colorectal cancer treated with irinotecan-cetuximab. K-RAS was assessed with direct sequencing, EGFR amplification was assessed by chromogenic in situ hybridisation (CISH) and HER-3, IGF-1 and NF-kB were assessed by immunohistochemistry. RESULTS:In patients with K-RAS wild-type tumours, the following molecular factors resulted independently associated with response rate: HER-3 [odds ratio (OR)=4.6, 95% confidence interval (CI) 1.8-13.6, P=0.02], IGF-1 (OR=4.2, 95% CI 2-10.2, P=0.003) and EGFR GCN (OR=4.1, 95% CI 1.9-26.2, P=0.04). These factors also independently correlated with overall survival as follows: HER-3 [hazard ratio (HR)=0.4, 95% CI 0.28-0.85, P=0.008], IGF-1 (HR=0.47, 95% CI 0.24-0.76, P<0.0001) and EGFR GCN (HR=0.59, 95% CI 0.22-0.89, P=0.04). DISCUSSION:We believe that our data may help further composing the molecular mosaic of EGFR-resistant tumours. The role of HER-3, IGF-1 and CISH EGFR GCN should be prospectively validated in clinical trials investigating anti-EGFR treatment strategies in colorectal cancer patients.

404 Background: Preclinical data suggested that in presence of HER3 altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. HER3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER3 expression and clinical outcome in KRAS wild-type advanced colorectal cancer receiving cetuximab and irinotecan.METHODSWe retrospectively analyzed immunoreactivity for HER3 in KRAS wild-type advanced colorectal cancer patients receiving irinotecan-cetuximab.RESULTSEighty-four advanced KRAS wild- type colorectal cancer patients were available for HER3 analysis. Forty patients (48%) showed HER3 negative colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER3 positive. In HER3 negative and HER3 positive tumors we observed a partial response in 17 (42%) and 8 (18%) patients respectively (p = 0.04). Progressive disease was obtained in 11 (35%) and 26 (53%) patients with respectively HER3 negative and positive tumor (p = 0.007). No differences were observed for stable disease. Median PFS was 6.3 months in patients showing HER3 negative tumors and 2.8 months for those who had HER3 overexpressing tumors (p < 0.0001). Median overall survival was 13.6 months in patients showing HER3 negative tumors and 10.5 months for those who had HER3-expressing tumors (p = 0.01).CONCLUSIONSHER3 proved to be a predictive factor for clinical outcome in KRAS wild-type colorectal cancer patients treated with cetuximab. Combined HER3 and KRAS analysis may represent an effective strategy for a better selection of responding colorectal tumors. Furthermore besides identifying colorectal cancer patients refractory to EGFR directed treatment, HER3 overexpression may also represent a potential biological indicator for the development of a new class of antineoplastic agents in this setting. No significant financial relationships to disclose.

6145 Background: The transition from curative to palliative care is a difficult phase in the illness trajectory of many oncologic patients (pts). Change of the health care professionals involved in EoL assistance may result in a sense of abandonment for pts and families. Methods: A semistructured telephone interview was conducted by two psychologists on relatives of pts who died between 01/2008 and 06/2009 (time from death ranged between 6 and 24 months). Research questions focused on the last month of life and included oncologist's involvement, sense of abandonment if the patient-oncologist relationship was lost, satisfaction with the quality of care (measured with a five-point scale: poor, fair, good, very good, excellent; and converted to a 0-to-100 scale) and oncologist's involvement in bereavement activities. A final open-ended question addressed suggestions for improvement. Results: Fifty-eight patient's relatives were contacted, 50 accepted the interview (32 spouses, 14 children, 3 in-laws, 1 nephew). Twenty-two pts had died at home, 28 in hospital. In 39 (78%) cases the oncologist-patient relationship was maintained in the last month of life, and this continuity was highly appreciated by the family. For the 11 pts (26%) who lost contact with their oncologist, a sense of abandonment was reported only in one case; in all other cases there was a closure of the patient-physician relationship that prevented feelings of abandonment. While the mean score of overall satisfaction relative to the quality of care in the last month of life was 61, this score dropped to 34 for pts who were no longer followed by their oncologist. Only in 13 (26 %) cases there was a post-mortem communication between the family and the oncologist, always on the family's initiative. Every relative interviewed expected at least a phone call from the oncologist. Conclusions: Continuity of care at the EoL is a priority issue for the families of cancer pts. The daily routine of palliative care and hospice facilities should involve the oncologist to improve the experience of care. Patients' families expect a commitment by the oncologist in bereavement activities. No significant financial relationships to disclose.

4126 Background: Previous reports have suggested that mucinous colorectal adenocarcinomas have a poorer prognosis than nonmucinous colorectal adenocarcinomas. This retrospective analysis was conducted to explore whether mucinous carcinoma (MC) is associated with a worse prognosis than nonmucinous carcinoma (NMC) for patients with Dukes B2 and C radically resected colon cancer. Methods: We investigated 1,006 unselected patients who underwent curative surgery for sporadic colon cancer and followed up at six Oncology Department between 1998 and 2006. Univariate and multivariate analyses were performed to determine prognostic factors of survival. Results: MC accounted for 17.9% (n=180) of all colon carcinomas. Patient characteristics were as follows. MC: M/F 104/76; median age, 68 (range, 28–97); pT1/2/3/4, 1/4/153/22; Dukes B2/C 98/82; invasion 26 (14%); ≥12 examined lymph nodes, 115 (64%); adjuvant chemotherapy, 110 (61%). NMC: M/F 445/381; median age, 68 (range, 29–95); pT1/2/3/4, 9/51/715/51; Dukes B2/C 384/442; invasion 199 (24%); ≥12 examined lymph nodes, 499 (60%); adjuvant chemotherapy, 545 (66%). MC were more frequently located in the proximal colon (54.4% versus 34.6% for NMC; p<0.001). No difference between MC and NMC in disease-free survival (hazard ratio, HR 1.01; 95% CI, 0.76–1.36; p=0.92) and overall survival (HR 1.05; 95% CI, 0.74–1.49; p=0.78) was found. After stratification by stage of disease, MC and NMC had no statistically significant difference in 5-year disease-free survival (Dukes B2: 79.1% and 78.1%, respectively, p=0.86; Dukes C: 53.8% and 56.2%, respectively, p=0.58) and overall survival (Dukes B2: 84.2% and 85.5%, respectively, p=0.80; Dukes C: 68.0% and 67.3% p=0.52). Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage at diagnosis (p<0.0001), grading (p<0.0001), and number of lymph node examined (p=0.0002) in the specimen. Conclusions: In this preliminary analysis, patients with mucinous histology who underwent surgery with curative intent for stage Dukes B2 and C colon cancer had similar prognosis compared to NMC. No significant financial relationships to disclose.

e20632 Background: Elderly cancer patients (pts) population is expanding due to demographic changes. Currently 2.4 % of Italian population is older than 85, with this group accounting ∼8 % of all cancer pts in our geographic area. Since very elderly (85 years and over) cancer pts are generally excluded from clinical trials, few data are available about tolerability of chemotherapy in this population. Methods: We conducted a retrospective analysis of cancer pts aged 85 years and over receiving chemotherapy for advanced disease in the years 2005–2007 in three Oncology Unit of the Regione Marche, Italy. Results: We identified 50 patients (26 males, 24 females) with a mean age of 86.4 (range 85–95), ECOG PS 0 (4 pts) 1 (25 pts) 2 (13 pts) 3 (8 pts). Type of cancer (pts): NSCLC (13), colorectal (11), breast (5), prostate (4), gastric (3), NHL (3), bladder (2), head-neck (2), ovarian (2), vulvar (1), skin (1), pancreas (1), GIST (1), UPT (1). Main co-morbidities included hypertension (18 pts), COPD (8 pts) and heart disease (6 pts). The median number of cycles in first line chemotherapy were 6 (1–44); 20 pts received 2 or more lines of chemotherapy (range 2–5). Dose reductions were planned in all pts: in 26 dose reduction was 30 %, in 22 was 50%, in 2 > 50 %. Most used drugs were: vinorelbine os or iv (14 pts), capecitabine (9 pts), gemcitabine (7 pts). Target agents were used in 7 pts (5 erlotinib, 2 gefitinib, 2 rituximab, 1 sunitinib). Ten partial responses were observed; main toxicities were: grade 3–4 neutropenia (10 %), grade 3 diarrhea (5 %), and 1 pts had grade 3 hand-foot syndrome. No treatment related deaths were observed. Conclusions: Very elderly cancer pts (85 years and over) in good PS and few co-morbid conditions receiving dose reduced chemotherapy experienced acceptable toxic effects; a partial response was documented in 10 out of 50 pts. The expanding use of chemotherapy and target therapy in this clinical setting has profound influence on health care management and costs. Prospective studies specifically designed for this pts population could clarify the benefit, in terms of quality of life and survival, of an interventionist instead of a supportive care only approach. No significant financial relationships to disclose.

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T ) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes ( T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7–43.7 months) and 28.6 months (95% confidence interval: 25.6–30 months) in 56 T/T carriers and in 124 non- T/T carriers, respectively. The favorable association between T/T carriers’ status and survival was significant in the multivariate analysis ( P =0.018). Also, T/T carriers and non- T/T carriers were prevalent among patients with Karnofsky performance status 90–100 and 70–80, respectively ( P =0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.

We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5′-untranslated region (5′-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6+/6−) in the TS 3′-UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5′-UTR VNTR+G/C nucleotide change showed significant association with tumour response (P=0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.

BACKGROUND The prognostic significance of KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations in gastrointestinal stromal tumors (GISTs) is still controversial. PATIENTS AND METHODS In all, 104 patients were diagnosed with GISTs by KIT immunoreactivity; tumor DNA was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17 and in PDGFRalpha exons 12 and 18. Disease-free survival (DFS) was analyzed in 85 radically resected patients. RESULTS KIT mutations occurred in exon 11 (69), in exon 9 (11) and in exon 17 (1). PDGFRalpha mutations were detected in exon 18 (10) and in exon 12 (3). Ten GISTs were wild type. Exon 11 mutations were as follows: deletions in 42 cases and point mutations in 20 cases and insertions and duplications, respectively, in 2 and 5 cases. A better trend in DFS was evident for duplicated and point-mutated exon 11 KIT GISTs. There was a significant association between PDGFRalpha mutations, gastric location and lower mitotic index. Moreover, PDGFRalpha-mutated GISTs seemed to have a better outcome. CONCLUSIONS Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior.

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5–29.2%) and 49% (95% CI, 42.2–55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27–3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05–2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites ⩾2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.

PURPOSE:The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.MATERIALS AND METHODS:Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS).RESULTS:In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes.CONCLUSION:A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.