Ida Pavese

Eribulin Mesylate in Pretreated Breast Cancer Patients: A Multicenter Retrospective Observational Study

Background: Eribulin was recently approved in patients progressing after being treated with anthracyclines and taxanes and after two or more chemotherapy lines for advanced disease. Objectives: This multicenter observational retrospective study was performed in order to evaluate activity and tolerability of eribulin in real-world patient population. Methods: 133 advanced breast cancer patients pretreated with ≥ 2 chemotherapy lines for metastatic disease were retrospectively enrolled in the observational trial in 11 italian cancer centres. Results: A median of 5 cycles of eribulin (range, 1-15) were administered. Twenty-eight partial responses were observed, for an overall response rate of 21.1% (95%CI,14.1-28.0). A stable disease was recorded in 57 patients (42.8%), and a clinical benefit (response or stable disease lasting ≥ six months) was observed in 51 patients (38.3%, 95%CI, 30.1-46.6). The subgroup analysis showed that a significant improvement in term of partial response and clinical benefit was achieved when eribulin was administered in HER-2 negative tumors (p=0.01 and p=0.004, respectively) and when it is given as third-line (p=0.09 and p=0.02, respectively). Toxicity was manageable; fatigue is the most common side effect observed, usually of low-grade, and clearly cumulative-dose related. Conclusions: In this retrospective, observational analysis eribulin confirmed its efficacy and manageable tolerability even in real-world population and in heavily pretreated patients.

Rationale for Treatment and Study Design of TAILOR: A Randomized Phase III Trial of Second-line Erlotinib Versus Docetaxel in the Treatment of Patients Affected by Advanced Non-Small-Cell Lung Cancer With the Absence of Epidermal Growth Factor Receptor Mutations

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

Eribulin in cutaneous breast cancer metastasis treatment: clinical activity and symptom control

AIM This observational study evaluated the behavior and outcome of cutaneous breast cancer metastasis treated with eribulin. PATIENTS & METHODS From November 2012 to January 2013, oncologists completed a database with patient, tumor and treatment characteristics from 14 Italian cancer centers. Skin lesions were assessed by Response Evaluation Criteria In Solid Tumors and cutaneous symptoms by present/absent criteria. RESULTS A total of 23 metastatic breast cancer patients with skin metastasis who were treated with eribulin were analyzed. After treatment, 43% of patients exhibited a partial response, 35% stable disease and 22% progressive disease. Regarding only the skin response, 26% obtained a complete response, 22% a partial response, 39% stable disease and 13% progressive disease. We found an improvement in symptoms, infiltration and ulceration. With a median follow-up of 6 months, median progression-free survival was 4.3 months and median overall survival was 9.1 months. CONCLUSION The response rate of skin metastasis to eribulin treatment was coherent with systemic responses. The good clinical response in most patients reflected symptom improvement.

Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study

AIM To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer (CRC) in Italy. METHODS This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival (PFS). Secondary end-points included time to overall response (TOR), duration of response (DOR), time to treatment failure (TTF) and overall survival (OS). The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life (QoL) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit. RESULTS The intention-to-treat population included 197 patients (mean age: 62.3 ± 9.9 years, 56.4% males). At baseline, 16/34 evaluable subjects (47.1%) harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean follow-up of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression (PD, 45.4%) and AEs (25.4%). Median PFS was 9.7 mo (95%CI: 8.4-10.5) and the median values for secondary end-points were: TOR = 3.9 mo (95%CI: 2.6-4.7), DOR = 8.5 mo (95%CI: 7.3-10.3), TTF = 6.7 mo (95%CI: 6.0-7.7) and OS = 23.2 mo (95%CI: 20.1-27.2). Patients carrying at least one lesion had a lower overall response rate (66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant (P = 0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit (signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good. CONCLUSION The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.

600PTREATMENT (T) OF METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS) ≥75 YEARS (Y) OLD IN CLINICAL PRACTICE: A MULTICENTER ANALYSIS

ABSTRACT Aim: CRC pts have a median age of incidence > 65y although they are largely under-represented in phase III trials. This large population contains pts unfit for T, those suitable for monotherapy or for doublets and the impact of chemotherapy (CHT) outside clinical trial is unclear. Aim of the study was to retrospectively analyse T of elderly mCRC pts. Methods: Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for diferences between subgroups, Coxs proportional hazard model to assess the impact of known prognostic factors and T. Results: 751 pts with mCRC observed from January 2000 to January 2013 were collected. Median age was 79y (75-93); Variables HR (CI95%) P value Sex 1.21 (1.01-1.46) 0.04 Age 1.75 (1.45-2.12) ECOG PS 2.51 (1.94-3.25) CT 2.14 (1.68-2.73) S of metastasis 2.48 (1.88-3.29) S of primary tumor 1.66 (1.31-2.11) Site of metastasis 1.33 (1.09-1.63) 0.006 Conclusions: These data show that in clinical practice treatment of metastatic disease has a positive effect on elderly pts OS, confirmed at multivariate analysis. KRAS analysis deserve further evaluation. Update results will be presented. Disclosure: All authors have declared no conflicts of interest.

Progression-free survival (PFS) with maintenance treatment with bevacizumab (B) in patients with responding mCRC after first-line chemotherapy (CT) plus B.

612 Background: Maintenance treatment with B is considered an option for mCRC pts in responding pts after a first line CT + B, but few data are available on its real benefit on PFS. METHODS We collected data from a cohort of mCRC pts consecutively treated in five oncologic centers of Lazio. One-hundred-ninety-nine mCRC pts treated with first line CT + B achieving a response [partial (PR) or complete (CR)] or a stable disease (SD) were considered eligible, 117 pts had received B maintenance (BM) whereas 82 did not (noBM). The two groups were homogeneous for main characteristics. First-line therapy in the BM vs noBM group included FOLFIRI regimen (96 vs 59 pts), FOLFOX (18 vs 22 pts) and FUFA (3 vs 1 pts). K-ras status was analyzed in 115 pts with an higher percentage of wild-type (wt) in the BM group (65 vs 50 pts, p= 0.04). A CR or PR have been achieved in 65% of pts in the BM group and 61% of noBM group, while a SD was observed in 35% and 39% of pts respectively for the BM and noBM group. The median number of BM cycles administered was 7 (range 3-25). Effectiveness measures included the PFS duration. A multivariate Cox proportional hazard model was developed using stepwise regression (forward selection) Results: At a median follow-up of 18 months (1-109), the median PFS was 13 months (C.I.95%: 11-15) vs 8 months (C.I.95%: 7-10; p<0.0001, and the 1-year PFS 53% vs 28% for BM and noBM respectively. Pts with CR/PR had a mPFS of 15 months (CI 95% 12-19) vs 10 months (CI 95% 10-12) p=0.004 and a 1-year PFS of 62.6% vs 33.7% for the BM vs noBM group respectively. No difference in the 1-year PFS was observed in pts showing SD to chemotherapy and bevacizumab. The mPFS in these patients was 12 (CI 95% 10-13) vs 8 months (CI 95% 7-10, p=0.11) for the BM and noBM group respectively. The multivariate analysis did not show any difference in PFS comparing age, sex, number and site of metastasis, ECOG PS and k ras status. A significant difference in PFS was observed for response to first-line CT (CR/PR vs SD, p=0.002) and for BM vs noBM (p=0.003). CONCLUSIONS The maintenance strategy with B shows a longer PFS in pts responding to the first line chemotherapy + B whereas for pts who achieving an SD no difference was observed.

Abstract B77: KRAS mutational status impact progression-free survival of patients treated with platinum-based chemotherapy in NSCLC.

Background: KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatment. However, such evidence is only drawn from retrospective series giving controversial results. Moreover, it is possible that the various KRAS mutations differently affects prognosis, carcinogenesis and drug response as demonstrated in preclinical setting. Aim of this study is to prospectively assess the prognostic value of KRAS mutations in NSCLC patients treated with a first line platinum containing regimen. This is a properly planned ancillary study within the TAILOR trial (NCT00637910) which is mainly focused on the second line. Methods: Tissue and blood samples were collected at diagnosis in the whole cohort of registered patients. KRAS status was centrally determined with standard direct sequencing and KRAS genotype was assessed by real time PCR. The primary hypothesis is a difference in PFS according to KRAS mutational status; the impact of the three more frequent KRAS substitutions (G12C, G12V, and G12D) was also explored. The analysis was planned at occurrence of 200 events (HR≥1.49, power 80%, 2-tailed alpha 10%), in a Cox model adjusting for Performance Status and radical surgery. Results: Out of 565 patients registered, 341 (60.5%) were evaluable for KRAS and 85(25%) were mutated. At a median follow-up of 17 months KRAS mutated patients showed a statistically significant worse PFS (HR 1.42 95%CI 1.06–1.94; p=0.02). No differences among doublets were observed in KRAS mutated patients. The most frequent KRAS mutations were: G12C (36.4%), G12V (21.1%), G12D (16.4%), others (25.9%). Prognostic differences among variants are observed. Final genotype analyses are ongoing. Conclusions: This is the first prospective, pre-planned and adequately sized evaluation of KRAS in NSCLC. Patients mutated for KRAS seem to have a higher risk of progressing. These results suggest that KRAS mutation epidemiology in this setting highly differs from that of colon cancer. Clinical data suggest that tailored strategies for these patients are warranted and our preclinical studies will help in clarifying the molecular mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B77.