Background

PAOLA-1/ENGOT-ov25 (NCT02477644) is the first phase III trial to evaluate the efficacy and safety of a PARP inhibitor with bev as first-line (1L) maintenance therapy for advanced OC, regardless of BRCA1/2 mutation (BRCAm) status.

Methods

PAOLA-1 is a randomized, double-blind, international phase III trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer. Pts had received standard PCh plus bev and were in clinical complete or partial response. Pts were randomized (2:1) to olaparib tablets (300 mg bid for up to 24 months [m]) plus bev (15 mg/kg, d1, q3w, for 15 m including when combined with PCh) or placebo (pbo) plus bev, stratified by 1L treatment outcome and tumour BRCAm status. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population (PFS; modified RECIST v1.1).

Results

537 pts were randomized to olaparib plus bev and 269 to pbo plus bev. Pt characteristics were well balanced. Median follow-up was 24.0 m in the olaparib arm and 22.7 m in the pbo arm. PFS was significantly increased in the olaparib arm. PFS2 is immature.Table:

LBA2_PR

Conclusions

Addition of olaparib to bev maintenance therapy following 1L PCh plus bev led to a statistically significant and clinically meaningful PFS benefit in pts with advanced OC. The PFS benefit in pts with a tBRCAm and in HRD-positive pts was substantial.

Clinical trial identification

NCT02477644.

Editorial acknowledgement

Medical writing assistance was provided by Laura Smart, MChem, from Mudskipper Business, Ltd, funded by ARCAGY Research, AstraZeneca, and MSD.

Legal entity responsible for the study

ARCAGY Research.

Funding

ARCAGY Research, AstraZeneca, Merck & Co., Inc. and Hoffmann-La Roche Ltd.

Disclosure

I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Pharma Mar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Pfizer. P. Pautier: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Genentech; Research grant / Funding (institution): PharmaMar. S. Pignata: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Pfizer; Honoraria (self): Incyte; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Honoraria (self): Clovis Oncology; Honoraria (self): Tesaro. D. Pérol: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Eli-Lilly; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): BMS. A. González-Martín: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Pfizer; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: MSD; Advisory / Consultancy: Genmad. P. Sevelda: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Amgen. K. Fujiwara: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Chugai Roche; Honoraria (self): Zeria; Honoraria (self): Taiho; Honoraria (self): Nihon Kayaku; Honoraria (self): Kyowahakko Kirin; Honoraria (self): Janssen; Honoraria (self): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Kaken. I.B. Vergote: Advisory / Consultancy: Advaxis, Inc.; Advisory / Consultancy: Eisai, Inc.; Advisory / Consultancy: MSD, Belgium; Advisory / Consultancy: Roche NV; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: F. Hoffman-La Roche Ltd; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Millennium Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: Clovis Oncology; Advisory / Consultancy: AstraZeneca NV; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Oncoinvent AS; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunogen Inc.; Advisory / Consultancy: Sotio; Research grant / Funding (institution): Oncoinvent AS; Research grant / Funding (self): Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Research grant / Funding (self): Stichting Tegen Kanker; Travel / Accommodation / Expenses: Takeda Oncology; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: BIOCAD. N. Colombo: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BIOCAD; Honoraria (self), Advisory / Consultancy: Takeda. J. Mäenpää: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Advisory / Consultancy: Glovis. F. Selle: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: MSD France; Honoraria (self): PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Non-remunerated activity/ies: Post-university teaching. J. Sehouli: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Merck; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisei; Advisory / Consultancy: Johnson & Johnson; Advisory / Consultancy: MSD; Advisory / Consultancy: Novocure; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bristol-Myers Squibb. D. Lorusso: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Clovis Oncology; Advisory / Consultancy: Immunogen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Officer / Board of Directors: GCIG. E.M. Guerra Alia: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: V Simposio Grupo Español de Investigación en Cáncer de Ovario (GEICO); Travel / Accommodation / Expenses: Baxter; Speaker Bureau / Expert testimony: Sociedad Española de Nutrición (SENPE)Parenteral y Enteral. C. Lefeuvre-Plesse: Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Pfizer. U. Canzler: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Lilly. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. F. Marmé: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Tesaro; Honoraria (self): Clovis Oncology; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Celgene; Honoraria (self): Genomic Health; Honoraria (self), Advisory / Consultancy: PharmaMar; Honoraria (self): Amgen; Advisory / Consultancy: Curvac Celgene; Advisory / Consultancy: Curevac; Advisory / Consultancy: Vaccibody. E. Pujade-Lauraine: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer. P. Harter: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Sotio; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self): Stryker; Honoraria (self): ASCO; Honoraria (self): Zai Lab; Honoraria (self): MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Immunogen; Advisory / Consultancy: MSD/Merck.

Background

Malignant pleural mesothelioma (MPM) is a rapidly progressive tumor with a poor prognosis. The benefit of first-line standard pemetrexed – platinum chemotherapy in MPM has been established. Currently, second-line chemotherapy is increasingly use, because many patients are fit at the progression of the disease. No standard second/further line chemotherapy exit for MPM after failure of first-line pemetrexed based chemotherapy. This study aimedat evaluating the clinical activity of weekly epirubicin as second/further line chemotherapy in elderly patients with MPM.

Methods

From July 2014 to March 2018, in Medical Oncology Department of Asst-rhodense Hospital, 22 patients (15 males and 7 females with a median age of 78 years, range 74-86) with MPM were eligible for analysis. Histology was epithelioid in 17 pts, sarcomatoid in 3 and biphasic in 2 patients. A Carboplatin-(AUC:4) pemetrexed doublet was administered in 14 pts and 8 pts received gemcitabine as single agent how first-line. Gemcitabine was given as second-line in 9 pts. Epirubicin was always administered with the same schedule at 20 mg/m2 day 1, 8, 15 every 28 until disease progression/intolerance.

Results

Overall response rate was as follows: 4 PR (18 %), 10 SD (45 %) and 8 PD (40%). Median time to progression was 5 months (range 3 – 11). No life threatening event occurred. No grade 3-4 toxicities were observed. Liver toxicity grade 1-2 in 2 pts (10%), thrombocytopenia grade 1 in 2 pts (9%), neutropenia grade 1-2 in 8 pts (40 %), fatigue grade 2 in 7 pts (32%), nausea grade 1 in 4 pts (20%).

Conclusions

Epirubicin has a modest clinical activity in pre-treated elderly patients with MPM in progression after one or two regimens, with an acceptable toxicity profile. It could be considered as a palliative treatment.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Non-small cell lung cancer (NSCLC) patients carrying epidermal growth factor receptor (EGFR) mutations are sensitive to tyrosine kinase inhibitors (TKIs); nonetheless, about 20% of patients show primary resistance to TKIs. We previously demonstrated the association between TP53 mutations and primary resistance to first-line TKIs in EGFR-mutated adenocarcinoma (ADC) patients. Here we analyze a validation case series of ADC patients treated with first-line TKIs to confirm our previous data, and we assess the association between TP53 status and the prognosis of ADC patients treated with third generation TKIs.

Methods

We considered 136 ADC EGFR-mutated patients treated with a TKI in the first-line setting. Also, we analyzed 42 patients who developed T790M mutation and were treated with a third generation TKI in second- or further line setting. EGFR and TP53 mutation analyses were performed by Sanger Sequencing or Next Generation Sequencing methodologies. TP53 mutations were evaluated in relation to disease control rate (DCR: complete response [CR], partial response [PR] or stable disease [SD]), objective response rate (ORR: CR, PR), progression-free survival (PFS) and overall survival (OS).

Results

Of 136 patients, we found 42 (31%) TP53 mutations: 12 mutations in exon 5 (28.6%), 6 in exon 6 (14.3%), 13 in exon 7 (30.9%), and 11 in exon 8 (26.2%). DCR and ORR were 31.8% and 32.5% in TP3-mutated patients with respect to 68.6% and 67.4% in TP53 wild-type (wt) patients, respectively. Exon 8 TP53-mutated patients had a worse PFS with respect to TP53 wt patients (HR 3.19 [1.62-6.27], p = 0.001), but not OS. Moreover, we assessed TP53 status in 42 patients who developed a T790M mutation and received a third generation TKI in second or additional lines of treatment. In 30 patients with evaluable clinical response, DCR and ORR were 62.5% and 25% in TP53 mutated patients, with respect to 77.2% and 54.5% in the TP53 wt patients, respectively. Data analyses of PFS and OS are ongoing.

Conclusions

EGFR-mutated NSCLC patients with concomitant TP53 mutations had a worse clinical response to first-, second-, and third generation TKIs, administrated in any line of treatment.

Legal entity responsible for the study

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The estimand framework requires a precise definition of the clinical question of interest (estimand) to account for “intercurrent” events, eg in RCC the appearance of second primary malignancies or the start of new therapy. Selection of the appropriate estimand will drive trial design and support discussions about relevant treatment effects, interpretation of study results, and the added value of drugs.

Methods

A cross-industry collaboration of statisticians and clinicians has worked on connecting estimand framework concepts to different applications. Data from previously reported phase 3, placebo-controlled studies S-TRAC (NCT00375674) and PROTECT (NCT01235962) will be used to illustrate the effect of different estimands on adjuvant treatment outcomes in RCC.

Results

Table shows the treatment outcomes for different estimands. Treatment outcomes were similar to the specified primary analysis irrespective of the clinical question asked; however, the studies were not powered to address each of these questions and not all reached statistical significance. The new framework clarifies that different analyses address different questions. The choice of the primary estimand impacts study design and may have regulatory implications. In RCC, considerations as to whether all second primary malignancies or non-disease related deaths should be considered disease-free survival events are required to further specify study objectives and to determine the events needed for the final analysis.Table:

980P

Conclusions

In S-TRAC and PROTECT, there are similar treatment effects irrespective of the estimand selected and the clinical question asked. However, this may not be the case in all trials and considerations should be given to the clinical question of interest during trial design. Dialogue between all stakeholders is required and physicians will play a key role in such discussions to select the appropriate estimand.

Clinical trial identification

NCT003756674 and NCT01235962.

Editorial acknowledgement

David Cope, PhD, of Engage Scientific Solutions and funded by Pfizer.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

D.J. George: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Exelixis; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Merck; Research grant / Funding (self): Genentech/Roche; Research grant / Funding (self): Novartis; Research grant / Funding (self): Astellas; Research grant / Funding (self): Celldex; Research grant / Funding (self): Acerta; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Innocrin Pharma; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb. M. Casey: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. E. Degtyarev: Full / Part-time employment: Novartis. M.J. Lechuga Frean: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. P. Aimone: Full / Part-time employment: Novartis. A. Ravaud: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Merck Sharp & Dohme. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline. All other authors have declared no conflicts of interest.

Background

Although the dramatic activity of EGFR TKIs for EGFR-mutant ANSCLC, nearly 20% of pts do progress rapidly. Poor prognosis was demonstrated to be associated with TH, which may be mirrored by the co-existance of concomitant mutant drivers, such as PTEN. The aim of this analysis was to investigate the correlation between the loss of function of PTEN (as a mirror of TH), and the activity/efficacy of EGFR-TKIs for advanced EGFR mutant ANSCLC pts.

Methods

FFPE-tumor blocks of EGFR-mutant ANSCLC pts undergone upfront TKIs from 2015 to 2017 were retrospectively collected (follow-up >18 mo. was required for maturity). The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry (IHC) and it was correlated with objective response rate (ORR), overall- and progression-free-survival (OS/PFS). Kaplan-Maier (KM) analysis was performed for independent factors at multivariate analysis.

Results

Forty-two EGFR-mutant ANSCLC pts were included [median age 65 yrs (42-86); M/F: 45/55%; current/former/never smoker: 13.5/35/51.5%; PS (ECOG) 0/1/2/3: 30/55/12.5/2.5%; GEF/AFA/ERL: 72.5/25/2.5%; del19/L858R/rare: 60/35/5%]. At multivariate analysis, PTEN loss (HR 6.02, 95% CI 2.48-14.5, p < 0.0001) and metastatic sites >2 (HR 2.38, 95% CI 1.01-5.62, p = 0.048) were significantly associated with shorter PFS. At KM analysis, pts with PTEN loss (13) had a median PFS of 2.0 mo. (95% CI 0-5.4) and a 1-year PFS of 7.7%, in comparison with pts without (27), median PFS 18.3 mo. (95% CI 16.5-20.1), 1-year PFS 69.6% (log-rank p < 0.0001). Coherently, at the multivariate analysis, PTEN loss (HR 5.11, 95% CI 2.06-12.6, p < 0.0001) and PS of 2-3 (HR 6.57, 95% CI 2.01-21.5, p < 0.002) were significantly associated with shorter OS. Pts with PTEN loss had a median OS of 4.5 mo. (95% CI 0.2-8.9) and a 1-year PFS of 15.4%, in comparison with pts without, median OS 26.9 mo. (95% CI 16.7-37.1), 1-year OS 81.5% (log-rank p < 0.0001).

Conclusions

A low-cost and reproducible IHC assay for PTEN-loss analysis represents a potential tool for identifying TH of EGFR-mutant ANSCLC pts. A powered clinical validation is currently ongoing.

Legal entity responsible for the study

Emilio Bria.

Funding

Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Disclosure

E. Bria: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background

The SENECA trial showed similar progression free survival (PFS) and overall survival (OS) in non-squamous non-small cell lung cancer (nsNSCLC) patients (pts) treated with second-line docetaxel/nintedanib, regardless relapsing-time from end of first-line chemotherapy and docetaxel schedule employed (weekly or q3wks) [presented at AIOM 2018]. Because of the lack of data about optimal therapeutic algorithms for nsNSCLC pts and the evidence of a strong biologic rationale for using both antiangiogenic drugs and immunotherapy (IT), aim of the present analysis is to investigate post progression survival of SENECA pts, exploring if third-line IT may be positively influenced from prior nintedanib use.

Methods

SENECA enrolled 212 nsNSCLC pts treated with docetaxel and oral nintedanib, with the possibility of maintenance in case of stabilization or response. This evaluation focus on those 64 pts receiving a third-line treatment and aims to compare who underwent IT with the remaining ones. PFS2 and OS2 (time from start of docetaxel/nintedanib to progression during third-line or death, respectively) are investigated. Comparisons between Kaplan Meier curves of the two groups are made with Log Rank test. Hazard Ratios (HR) with 95% Confidence Interval (95%CI) are also reported.

Results

Pts treated with third-line (39 with IT, 25 with other agents) correspond to 30.2% of the entire study population; they were 40 males and 24 females, mainly current or former-smokers, with ECOG-performance status 0 in 79.7% of cases and average age of 62.2 years. At the cut-off date (April 29th, 2019), after 39.5 months follow-up, no significant differences appear between pts who received IT after SENECA progression and the other ones in terms of PFS2 (10.78 vs 7.91 months; HR 0.602 [95% CI 0.342-1.058], p-value=0.0821), while there are in terms of OS2 (14.33 vs 11.32 months; HR 0.537 [95% CI 0.292-0.987], p-value=0.0161).

Conclusions

Despite the small sample size, this analysis shows a higher post progression survival for nsNSCLC pts treated with docetaxel/nintedanib and third-line IT, postulating a synergism between the two regimens. Being this topic extremely attractive for development of new therapeutic algorithms, this report could be the basis for further investigations.

Clinical trial identification

EudraCT: 2014-005016-42.

Legal entity responsible for the study

The authors.

Funding

Boehringer Ingelheim.

Disclosure

E. Capelletto: Advisory / Consultancy: Boehringer Ingelheim ; Advisory / Consultancy: AstraZeneca. A. Morabito: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS. F. Grossi: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Amgen. V. Scotti: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. D. Galetta: Honoraria (self): Boehringer Ingelheim ; Honoraria (self): Roche; Honoraria (self): MSD. S. Novello: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Celgene; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AbbVie. All other authors have declared no conflicts of interest.

Background

Mature oocyte vitrification and storage is currently used to help patients preserving their ability to have offspring either for fertility preservation (FP) before gonadotoxic treatment such as chemotherapy or for elective purposes. Our meta-analysis investigated whether letrozole co-administration during controlled ovarian stimulation (COS) for FP is effective and safe.

Methods

A literature search using PubMed was conducted up to March 8^th, 2019 to retrieve information from studies that compared the performance of COS with or without letrozole co-administration for FP. Mean or median values and 95% confidence intervals (CIs) or standard deviations (SDs) were collected for efficacy (number of collected oocytes, number of mature oocytes, maturation rate) and safety (peak estradiol levels [E2], total gonadotropin dose, number of stimulation days) endpoints. Statistical analysis was conducted with random-effects model.

Results

A total of 10 articles were eligible including 1930 patients undergoing COS with or without letrozole. Studies compared COS with and without letrozole in cancer or infertile cohorts (N = 9) and infertile cohort only (N = 1). The total number of oocytes and mature oocytes collected were similar between letrozole and no letrozole groups while the peak estradiol was significantly higher in the standard COS without letrozole (Table).Table:

1829P

Conclusions

Letrozole co-administration during COS resulted to be as effective as standard COS but with significantly decreased peak estradiol levels, suggesting its increased safety especially for hormone-sensitive cancer patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Diffuse Large B cell lymphoma (DLBCL) is usually diagnosed between the 5th-6th decade of life. Its incidence increases with age. Chemotherapy (CT) with R-CHOP is the standard treatment for any age. However, in the clinical practice, alternative treatments with less toxicities are offered to elderly patients. This group of patients is usually not well represented in clinical trials. Our aim is to asses the benefit of standard treatment in this population, as well as discontinuation of treatment and its impact on overall survival (OS). As secondary endpoint, we have analyzed the survival rate in the subgroup of patients older than 75 years of age treated with CT.

Methods

A retrospective review was performed in patients ≥65 years who were diagnosed with DLBCL during the years 2013-2015 in the Hospital of Leon. Patients with histological confirmation of the primary diagnosis and who received treatment were included.

Results

65 patients were analyzed. The average age was 75 years. 64% were male and 30% had stage 4 disease at the time of diagnosis. The CT schemes were: R-CHOP (N = 28), R-CEOP (N = 11) and R-miniCHOP (N = 8). 10 patients had grade 4 AEs. One death ocurred after receiving the first cicle. 70% completed at least 4 cicles of CT. Median OS was 51 months versus (vs) 11 months in favor of R-CHOP group (HR = 0,59, p = 0,112 IC 95%=0,30-1,13). Results were not statistically significant likely because of the small sample size. 45% of patients had a complete response, 20% had a partial response and 10% had no response to treatment.The main cause of death was disease progression. Median OS was 15 months in both groups, in patients older than 75 treated with CT vs < 75 years of age. No statistically significant difference was seen, regardless of the treatment they received.

Conclusions

In clinical practice, age is an important variable to account for when deciding on the management approach for heamatological malignancies such as DLBCL. Although our results show a non-statistically significant benefit in OS of R-CHOP vs other schemes, this could be due to the small sample size. Given the prevalence of elderly population in our country, and the proved benefit of standard chemotherapy in the approach of DLBCL, more studies are needed.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Highly myelosuppressive chemotherapy (HMC) is the standard treatment for several types of sarcoma. Severe neutropenia is a common adverse event, which can lead to febrile neutropenia (FN) and major infections requiring hospitalization, with up to 15% mortality rate. Several trials showed an equal efficacy of filgrastim (F) and Peg-filgrastim (Peg-F) for preventing FN in many cancer types, but limited evidence is available in adult sarcoma patients (pts). We retrospectively compared the incidence of FN and hospitalization due to neutropenic infections in sarcoma pts treated with HMC with the support of either F or Peg-F.

Methods

We reviewed data of pts consecutively treated in our institution from Sep 2014 to Mar 2019. Inclusion criteria were: age >18 years; diagnosis of soft tissue sarcoma; at least 1 cycle of HMC supported by prophylactic F or Peg-F. Included HMC regimens were: doxorubicin ≥60 mg/m² (D) + ifosfamide ≥9 g/m² (IFO) +/- vincristine; high-dose IFO (≥12 g/m); IFO ≥9 g/m² + etoposide. Neutropenia prophylaxis included F (5-7 doses) or Peg-F (1 dose) according to physician‘s choice. χ²-Test was used to compare the outcomes; p ≤ 0.05 was considered significant.

Results

79 pts were found eligible, receiving 330 cycles of HMC. F and peg-F were used as prophylaxis in 66.6% (n = 220) and 33.3% (n = 110) of cases, respectively. The rate of FN was higher in the Peg-F group compared to the F group (11.8% vs 6.8, p = 0.12), while the rate of cycles complicated by a hospitalization was 9% and 3.2% (p = 0.02), respectively. 8/16 hospitalizations were due to pneumonia. One death during hospitalization occurred in the Peg-F group. 70% of hospitalizations occurred in metastatic pts, whereas 30% occurred during adjuvant treatments.

Conclusions

The use of peg-F was associated with a significantly higher rate of neutropenic infections requiring hospitalization compared with F in adult sarcoma pts receiving HMC. FN rate was numerically higher in pts receiving peg-F, not reaching statistical significance. These data suggest that F prophylaxis may be preferred in this setting to peg-F. Overall, prophylaxis with both agents provided a relatively low rate of hospitalizations and FN, compared with the myelosuppressive potential of the regimens.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Perivascular epithelioid cell tumors (PEComa) are exceedingly rare mesenchymal neoplasms arising in a variety of anatomic sites. mTOR inhibitors are active in these neoplasms. However, no other effective treatments are available in those patients progressing to them. The PI3K–Akt–mTOR signaling pathway modulates neoplastic growth through signaling activation of ER and the EGF receptor family of receptor tyrosine kinases. ER drives PI3K/AKT activation in response to mTORC1 inhibition. This provides a rationale for combining anti-estrogens and mTORC1 inhibitors.

Methods

We retrospectively identified patients with advanced PEComa treated with mTOR inhibitors since January 2002 at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan – Italy. In a subgroup of them, exemestane was added at the time of progression.

Results

Twenty-eight patients with advanced PEComa treated with mTOR inhibitors were identified. Twenty–six were evaluable for response. Twelve out 26 (46%) had a PR and seven (27%) a SD, with a median PFS of 7 months. At the time of progression to sirolimus, 5 patients received a combination of sirolimus and exemestane and one of sirolimus, exemestane and GnRH. Three patients out 6 had a PR, 2 out 6 had a SD, and 1 out 6 had a PD, with a median PFS of 6 months. In this subgroup of patients treated with the combination, previous PFS to mTOR inhibitors was 6.6 months.

Conclusions

In this small retrospective series, the combination of mTOR inhibitors and exemestane obtained a reversion of resistance to mTOR inhibitors in one half of patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sanfilippo: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Advanchen Laboratories; Research grant / Funding (institution): Amgen Dompe; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Epizyme Inc; Research grant / Funding (institution): Galxo; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer. C. Fabbroni: Research grant / Funding (institution): Advanchen Laboratories; Research grant / Funding (institution): Amgen Dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Epizyme Inc; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): PharmaMar. E. Fumagalli: Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): karyopharm Pharmaceuticals; Research grant / Funding (institution): Pfizer. R. Bertulli: Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo ; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): PharmaMar. S. Stacchiotti: Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Advenche Laboratories; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Pfizer. P.G. Casali: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Deciphera; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Blueprint Midicines; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Amgen dompe’; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): KaryopharmPharmaceuticals; Research grant / Funding (institution): PharmaMar. All other authors have declared no conflicts of interest.

Background

Myoepithelial tumors of soft tissues (MT) and Extraskeletal Myxoid Chondrosarcoma (EMC) are closely related pathological entities whose overlapping features, in terms of morphology and immunoprofile, make differential diagnosis challenging. Different fusion genes have been described in MT. Instead, the rearrangement of NR4A3 is conventionally considered an exquisite feature of EMC. Nevertheless, whether there is a biological overlap between MT and EMC is still controversial. In order to shed light on this issue we compared the transcriptional profiles of the two entities.

Methods

A series of EMC (12 cases) and MT (7 cases), retrieved from the pathology files, was selected for the study. The diagnosis was made according to the WHO classification. FISH analyses confirmed that all EMC harbored NR4A3 rearrangement (7 EWSR1-NR4A3 and 5 TAF15-NR4A3); 4 EWSR1 and 1 FUS rearrangement were detected in MT. No rearrangement was detected in 2 cases. RNA was extracted from FFPE specimens with tumor cellularity >70%. RNA-sequencing was carried out on an Illumina Hiseq1000 platform (average 70 million reads/sample). Diverse algorithms and bioinformatic suites were employed to identify fusion transcripts and functional annotation analysis.

Results

RNA-seq analysis confirmed the rearrangements detected by FISH and identified one PTCH1-GLI1 fusion in a MT. Principal component analysis and unsupervised hierarchical clustering indicated that MT and EMC feature a distinct transcriptional profile. Functional annotation of the genes differentially expressed highlighted Hedgehog (HH) and WNT signaling as significantly enriched pathways in MT compared to EMC, with canonical GLI1 and WNT target genes upregulated in MT. Ectopic expression in cell models of the PTCH1-GLI1 chimeric transcript identified in the MT sample correlated with the induction of GLI1 target genes.

Conclusions

This study corroborates the notion that MT and EMC represent two distinct biological entities, with MT featuring a distinctive activation of HH and WNT pathways. The PTCH1-GLI1 fusion represents one possible mechanism of HH pathway activation in MT.

Legal entity responsible for the study

The authors.

Funding

Fondazione AIRC per la Ricerca sul Cancro, CRO Intramural Grant, Italian Ministry of Health.

Disclosure

P.G. Casali: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Deciphera; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Nektar Therapeutics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Amgen Dompé; Research grant / Funding (institution): AROG Pharmaceuticals; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Epizyme Inc.; Research grant / Funding (institution): Glaxo; Research grant / Funding (institution): Karyopharm Pharmaceuticals; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): PharmaMar. A.P. Dei Tos: Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Background

In 2018 the role of clinical nurse specialist (CNS) was implemented in an ambulatory setting at our cancer research center in Italy. CNSs received specific training before taking on their new role. Although measuring the impact of CNSs is vital to support decision-making on the development and implementation of advanced nursing roles, the identification of indicators reflecting their impact on clinical practice remains one of the most challenging nursing research issues, mainly because of the complexity of the contributors who determine patient and organizational outcomes.

Methods

The study evaluated indicators measuring the implementation process and the impact of the CNS role one year after its introduction. Indicators for the former were: CNS interface mapping in disease pathways, participation rate of CNS in multidisciplinary team (MDT) meetings, and number of training hours/CNS on specific cancers. Indicators for the latter were: patient satisfaction with CNS (survey), compliance with priority criteria for waiting times for the first visit, total number of documented CNS-patient communications (i.e. first nursing interviews with new patients, phone interviews); and number of improvement projects to which CNSs contributed.

Results

One year after CNS introduction, pathway mapping was 100%; MDT meeting participation 95%; training hours 40.5/CNS vs. defined standard of 30 hours. 83.2% of interviewed patients were very satisfied with CNSs. An average of 27 patient interviews and 126 phone interviews per month were performed. Improvements to the instruments used for patient agenda management were made, positively impacting compliance (+13%) with waiting time criteria.

Conclusions

CNSs were successfully introduced into all identified disease pathways and played an active role within the MDTs. Although there are data in literature indicating optimal CNS staffing for specific cancers, there are no previous Italian experiences that can be used for comparative purposes. We need to better clarify how disease characteristics and the number of new patients influence CNS staffing in our specific organizational care context, which obviously differs from that of other countries. Measuring CNS activities and outcomes would also help to optimize CNS core activities.

Legal entity responsible for the study

Istituto Scientifico Romagnolo per lo Studio e per la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.