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

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.

Background

REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point.

Methods

HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided).

Results

Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM).

No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.02).

Conclusions

In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.

Legal entity responsible for the study

Giuseppe Lombardi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The cancer treatments bring with it body image challenges, causing low self-esteem and contributing to worsen the quality of life. Chemotherapy (CT)-induced hair loss (HL) is one of the most emotionally distressing side effects of several breast cancer (BC) treatments. The DigniCap system (DCS), using the scalp cooling system, has been shown to reduce CT-induced alopecia (A) in a multicenter prospective trial. The purpose of this prospective observational study was to describe our experience.

Methods

Two DCS device are available at the Brindisi Oncology Dpt. From February 2016 and January 2019, 158 consecutive early stage BC pts who received anthracycline and/or taxane-based treatment were enrolled, post local Ethics Committees approval. A nurse and a psychologist were dedicated for these pts. Success of scalp cooling was defined according to the Dean’s scale: G0=no HL; G1 < 25% HL; G2=25–50% HL; G3=50–75% HL; G4 >75% HL.

Results

A total of 158 women were included in the following treatment cohorts: n = 70 (44.30%) received 4 courses of EC (epirubicin at 90 mg/m2 and cyclophosphamide (c) at 600 mg/m2 intravenously (IV) on day 1, with 21 days between cycles) followed by 12 courses of paclitaxel (P) 80 mg/m2 IV once a week (w); n = 56 (35.4%) received only 4 courses of EC, n = 28 pts (17.7%) P (80 mg/m2 IV once a w) and concurrent trastuzumab (2 mg/Kg IV; loading dose 4 mg/kg) for 12 consecutive doses and n = 4 (2.6%) pts received 4 courses of TC (docetaxel at 75 at 90 mg/m2 and c at 600 mg/m2 IV on day 1, every three w. Median age was 49 years (range 31-74). Overall success was observed in 115 pts (72.8%). Full preservation of the hair (G0) was observed in 37 pts (23.4%), G1 in 47 pts (29.7%) and G2 in 31 pts (19.6%). Most frequent scalp cooling-related symptoms were coldness (n = 129, 81.6%), neck pain (n = 83, 52.2%) and headache (n = 113, 71.5%). Overall, 14.6% (n = 23) of pts discontinued DCS because of unsatisfactory hair preservation (n = 11, 7.0%) and cold discomfort (n = 12; 8.4%). Furthermore we observed a hair growth when DCS was continued for pts with A G3 – G4.

Conclusions

Our results confirmed and reinforced previous evidences, showing that DCS is a good chance to prevent A during CT with anthracycline and/or taxane-based regimen and supported the wider use to all women with early stage BC.

Legal entity responsible for the study

Saverio Cinieri.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Genotyping on cfDNA offers potential advantages in clinical practice for pt selection and serial monitoring of treatment (Tx) efficacy. Clinical relevance of sequential RASmut in cfDNA at different time points during 1L of pt with RASwt solid biopsies (SB) was evaluated.

Methods

Prospective, multi-center study in mCRC pt with RASwt according to SB and treated following standard practice. Liquid biopsies (LB) were collected before starting 1L, at 20 (± 2) weeks (w) and at disease progression (PD). Beaming PCR was used for cfDNA analysis; 3 mutant allele fraction (MAF) cutoffs were considered: 1%, 0.1% & 0.02%.

Results

Median progression-free survival (PFS) was 11.7 months (m) (9.9-13.0) (n = 102). There were no differences in the overall response rate (ORR) according to baseline LB at any cut off, being at MAF 0.02%: 78.7% (68.2- 87.1) in RASwt pt (n = 80) vs 61.5% (31.6 - 86.1) in RASmut pt (n = 13) (OR: 2.32; p = 0.180). MAF was not correlated with total cfDNA levels (p = 0.957). The % of mut cfDNA pt varied along time, with the smallest % at 20 w (Table). There were no emergent mutations at 20 w. Ten pt wt according to baseline LB presented mutations at PD. ORR was 76.9% (63.2 - 87.5) in pt always wt (n = 52) vs 76.2% (52.8 - 91.8) in pt with mut cfDNA at any time point (n = 21) (p = 1.0). There were also no differences in PFS between these 2 groups of pt: 13.0 m (10.9 - 15.4) vs 11.4 m (7.1 – 13.7) at MAF 0.02% (p = 0.095).Table:

531PD

Conclusions

RAS mutational status assessed in cfDNA before starting 1L or sequentially during P+CT Tx in pt with RASwt SB was not a significant predictor of PFS and ORR in none of the cutoffs considered, although in RASmut pt clinical results tended to increase as MAF decreased. The highest proportion of mutated pt was observed at PD, which may be linked to the emergence of resistance. Mutated cfDNA by itself did not predict a lack of clinical benefit to CT and P in our study.

Editorial acknowledgement

Marta Muñoz-Tudurí (TFS, S.L.).

Legal entity responsible for the study

Amgen S.A.

Funding

Amgen S.A.

Disclosure

M. Valladares-Ayerbes: Honoraria (self): Amgen, Merck, Roche, Servier, Bayer, Bristol-Myers; Advisory / Consultancy: Merck, Sanofi, Amgen; Speaker Bureau / Expert testimony: Roche, Servier, Bayer; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Merck, Servier, Amgen, Roche. J.M. Viéitez: Travel / Accommodation / Expenses, attendance at conferences: Amgen, Roche, Servier; Research grant / Funding (self): Roche, Amgen. J.J. Cruz-Hernández: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Farma; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche Farma, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche Farma. M. Llanos: Advisory / Consultancy, collaboration in lectures: Servier, Roche, Ipsen, Merck, Bristol, Sanofi, Eisai; Advisory / Consultancy: Amgen. A. Lloansí Vila: Shareholder / Stockholder / Stock options, employee and stakeholder of Amgen S.A: Amgen. All other authors have declared no conflicts of interest.

Background

We have recently shown that breast cancer tissue cultures with higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB) were inhibited by antiprogestins. This highlights the relevance of determining the PRA/PRB ratio to identify patients that may benefit from this therapy. The aim of this study was to evaluate the concordance between the PR isoform ratio determined by western blots (WB) in core biopsies and in surgical samples from the same breast cancer patients (n=48) from the Hospital “Magdalena V Martínez” from General Pacheco, Buenos Aires. The protocol has been approved by Institutional Review Boards.

Methods

We determined the PRA/PRB ratio by WB using nuclear extracts from frozen tissues (biopsy and surgery) and the percentage of cells expressing PR measured by immunohistochemistry (IHC) was obtained from the clinical records (surgical samples). The analysis of the concordance between the core biopsy and surgical categorization was performed using the Cohen's Kappa coefficient. To categorize samples according to the PRA/PRB ratio, we considered samples enriched in PRA (PRA-H) those with PRA/PRB ≥ 1.2, those enriched in PRB, (PRB-H) with PRA/PRB ≤ 0.83, and equimolar (EQUI) samples, those with ratios in between 1.2 and 0.83.

Results

A 93% of coincidence was observed between WB and IHC data. The discordant samples had low PR levels determined by IHC (<20%) and proved negative in WB. When these 3 groups of PR+ samples, together with PR negative samples, were analyzed comparing the core biopsy and the surgical categorization, a 77% of concordance and a Kappa coefficient of 0.637 (N=48, p< 0.01) was obtained. However, when PR+ cases in which an agreement with the IHC and the WB data was observed, this value rose to 0.724 (N=18, p<0.01).

Conclusions

This study indicates that the PR isoform categorization from core biopsy specimens reflects the PRA/PRB ratio in the tumor in cases in which PR status observed by IHC and WB from biopsy cores are coincident suggesting the possible use of this tool to potentially predict antiprogestin response in case of neoadjuvant treatment.

Background

The combination of sunitinib (SU) and nivolumab (NI) showed to be safe in the previous phase I of IMMUNOSARC study. We present the results of the phase II of the combination of SU-NI in the advanced STS (pts) cohort.

Methods

Pretreated progressing pts, ECOG 0-1, with UPS, synovial (SS), clear cell (CCS), angio(AS)/epithelioid hemangioendothelioma (EH), solitary fibrous tumor (SFT), epithelioid sarcoma (ES), extraskeletal myxoid chondrosarcoma (ECM) or alveolar soft part sarcoma (ASPS) were eligible. SU 37.5 mg/d as induction was given days 1-14 and then reduced to 25mg/d continuously. NI was administered at 3 mg/Kg every 2 weeks from week 3. SU-NI was maintained up to progression or intolerance. Primary end-point was progression-free survival rate (PFSR) at 6 months (m) by RECIST. Secondary end-points: overall survival (OS), objective response rate (ORR) by RECIST and CHOI and toxicity.

Results

From Nov 2017 to Dec 2018, 50 eligible pts were included in 8 centres: (M/F 30/20), median age 45y (19-77). Diagnosis was: SS in 9 (18%), CCS in 7 (14%), SFT in 7 (14%), UPS in 6 (12%), ES in 6 (12%), AS in 5 (10%), ECM in 4 (8%), ASPS in 3 (6%) and other in 3 (6%). With a median FU of 6.1 m (0-13), 23 pts (46%) progressed based on RECIST with a median PFS of 5.9 m (95% IC 2.7-9.1) and 9 pts (18%) died, with median OS not reached yet. PFSR at 3 and 6 m based on local evaluation were 69% and 50% respectively and OS at 3 and 6 m were 86% and 77%. Based on central radiological review (RECIST, 43 evaluable pts), there were 1 CR (2.3%), 3 PR (7%), 26 SD (60%, 12 pts showing shrinkage) and 13 PD (30%). By CHOI (31 evaluable), there were 19 PR (61.3%), 8 SD (25.8%) and 4 PD (13%). Most relevant G3/4 toxicities were: AST increase 6 (11.8%), ALT increase 5 (9.8%), neutropenia 5 (9.8%), fatigue 3 (5,9%), thrombocytopenia 2 (3.9%), diarrhea 2 (3.9%), renal function impairment 2 (3.9%), without toxic deaths.

Conclusions

The trial met its primary endpoint. SU-NI is an active combination for the treatment of advanced selected STS patients, with 50% of patients free of progression at 6m. Further exploration of immunomodulatory strategies is warranted in selected sarcoma subtypes.

Clinical trial identification

NCT03277924.

Legal entity responsible for the study

Grupo Español de Investigación en Sarcomas (GEIS).

Funding

Pfizer and BMS.

Disclosure

J. Martin Broto: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Amgen; Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Eisai; Research grant / Funding (self): GlaxoSmithKline . N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. G.E. Grignani: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Novartis. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis; Research grant / Funding (institution): Eisai. C. Valverde: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bluprint; Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Decyphera; Research grant / Funding (institution): Incyte. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. S. Stacchiotti: Research grant / Funding (institution): Pfizer . E. Palmerini: Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Bristol-Myers Squibb (BMS); Research grant / Funding (institution): Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Takeda. D.S. Moura: Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Novartis. L. D’Ambrosio: Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: PSI. J.A. Lopez Martin: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties: PharmaMar; Advisory / Consultancy: Chobani; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

Abemaciclib, a selective CDK4 & 6 inhibitor, demonstrated single-agent activity in NSCLC and melanoma (Patnaik et al., 2016). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma (Sahebjam et al., 2016).

Methods

Study JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ breast cancer, NSCLC, or melanoma. Here, we report NSCLC and melanoma cohorts. Pts with ≥1 new or not previously irradiated BM ≥ 10mm or a progressive BM previously irradiated were eligible. Abemaciclib was orally administered BID on a continuous dosing schedule. Primary endpoint was objective intracranial response rate (OIRR; [confirmed CR+PR]) based on Response Assessment in Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, OS, and safety.

Results

28 (NSCLC) and 23 (MEL) pts were enrolled and 23 (NSCLC) and 22 (MEL) were evaluable. Pts had a median of 2 prior systemic therapies in the metastatic setting. 35% (NSCLC) and 46% (MEL) of pts had prior whole brain radiotherapy. 35% (NSCLC) and 27% (MEL) pts had stereotactic radiotherapy. Median time from radiation to study enrollment was 4.8 (NSCLC) to 5.6 (MEL) months. No confirmed intracranial response was observed (OIRR 0% for both cohorts). 21.7% (NSCLC) and 13.6% (MEL) of pts showed a decrease in the sum of their intracranial target lesions. ICBR (CR+PR+SD persisting for > 6 months) was 26.1% (NSCLC) and 9.1% (MEL). Median PFS was 1.5 months (95% CI, 1.4-2.8) for NSCLC and 1.2 months (95% CI, 1.0-1.6) for MEL. Median OS was 7.1 months (95% CI, 3.7-9.4) for NSCLC and 2.9 months (95% CI, 1.2-4.3) for MEL. Based on efficacy results, enrollment closed at end of stage 1. Safety and tolerability were similar as previously reported for abemaciclib.

Conclusions

There was limited intracranial clinical activity for abemaciclib monotherapy in NSCLC and MEL pts in this study; OIRR and short median PFS suggest that no further studies for abemaciclib monotherapy are warranted in this pt population.

Clinical trial identification

NCT02308020.

Editorial acknowledgement

Medical writing assistance was provided by Kristi Gruver, employee of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

E. Le Rhun: Advisory / Consultancy, Research grant / Funding (institution), Oscar Lambert Center, Lille, FR: Mundipharma; Research grant / Funding (institution), University Hospital, Lille, FR: Amgen; Advisory / Consultancy, personal fees: Novartis; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. G. Jerusalem: Advisory / Consultancy, Non-remunerated activity/ies, per patient investigator fee: Eli Lilly and Company; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Novartis; Research grant / Funding (self), Non-remunerated activity/ies, personal fees: Roche; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Pfizer; Advisory / Consultancy, personal fees: Celgene; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: Amgen; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: BMS; Advisory / Consultancy, personal fees: Puma Technology; Advisory / Consultancy, Non-remunerated activity/ies, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Daiichi Sankyo; Advisory / Consultancy, personal fees: Abbvie. D. Subramaniam: Advisory / Consultancy, personal fees: AstraZeneca; Advisory / Consultancy, personal fees: Takeda Oncology; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech. Y. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment, employee and stock options: Eli Lilly and Company. P.F. Conte: Research grant / Funding (self): Novartis; Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Travel / Accommodation / Expenses, travel grant: Celgene; Travel / Accommodation / Expenses, travel grant: Tesaro. All other authors have declared no conflicts of interest.

Background

NETTER-1 demonstrated that Radioligand Therapy (RLT) with LUTATHERA^® significantly prolongs PFS in progressive midgut neuroendocrine tumor patients compared to 60 mg octreotide (Oct). In oncology, treatment efficacy has often been associated with early reduction of tumor size. As RLT differs from traditional treatments, we sought to verify whether objective tumor shrinkage predicts duration of PFS by assessing the relations between changes in lesion size and treatment efficacy, evaluated by PFS among NETTER-1 patients.

Methods

Post-hoc analyses were performed on the NETTER-1 population on local tumor imaging assessments on the full analyses set (n = 231) with data cut-off date on June 30^th, 2016. The best response (change from baseline in sum of target lesion diameters) during 3 intervals after treatment onset was used as a covariate in a Cox regression, thus differentiating whether the time corresponds to an event or a censoring. One interval corresponded to 150 days, i.e. a month prior to 4^th injection; 180 days matched the 4^th injection and the last interval was set to no limit.

Results

For patients treated with Oct, Cox regression showed a HR of 0.914 [95% CI: 0.860 – 0.971], p = 0.0034. This suggests that the risk of disease progression decreases by 9% for each incremental percentage of shrinkage. Among the patients treated with Lu, Cox regression showed a HR of 1.006 [0.982 – 1.03] p = 0.6236, suggesting that LUTATHERA^® prolonged PFS even when tumor objective response was undetected during treatment cycles. As a sensitivity, a 180-day-limit and no-limit (i.e. using the best response up to time of censoring/event) were also applied. With the 180-day-limit, HRs were 0.952 [0.904 - 1.003], p = 0.0652 and 1.013 [0.991-1.037], p = 0.2523 for Oct and Lu, respectively; similarly the no-limit, HRs were 0.952 [0.922, 0.982] p = 0.0023 and 1 [0.984, 1.017] p = 0.9713.

Conclusions

Durable response of LUTATHERA^® treatment goes beyond objective tumor shrinkage. This study conveys crucial information on the patient’s management with respect to LUTATHERA^®: treatment benefit of 4 cycles should not be assessed only by objective tumor shrinkage.

Clinical trial identification

NETTER-1: NCT01578239.

Legal entity responsible for the study

Advanced Accelerator Applications.

Funding

Advanced Accelerator Applications.

Disclosure

M.E. Pavel: Advisory / Consultancy: Novartis. P. Broberg: Full / Part-time employment: Advanced Accelerator Applications. M. Caplin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Advanced Accelerator Applications. P. Ruszniewski: Speaker Bureau / Expert testimony: Advanced Accelerator Applications. P. Santoro: Full / Part-time employment: Advanced Accelerator Applications. L. Ravasi: Full / Part-time employment: Advanced Accelerator Applications. All other authors have declared no conflicts of interest.

Background

Current diagnostic approaches for pancreatic cancer (PC) mostly rely on cytologic examination of endoscopic ultrasound fine-needle aspiration (EUS-FNA) samples. However, in a subset of cases, PC diagnosis remains inconclusive due to low tumour cellularity. Molecular analysis of EUS-FNAs might be used as an auxiliary tool to strengthen diagnosis in samples with suboptimal cytology. This study aimed to evaluate the diagnostic utility of a single nucleotide variants (SNV) assay using molecular barcode technology performed on EUS-FNAs.

Methods

28 EUS-FNA samples of pancreatic masses (19 PC, 9 non-malignant lesions) were analyzed. FNAs were collected in RNAlater and stored at -80 C. Mutational status was evaluated using the Nanostring Vantage 3D™ DNA SNV Solid Tumor Panel, utilizing digital enumeration of unique barcoded probes to detect 104 SNV from 24 genes of clinical significance. 5ng of tumor-derived DNA was subjected to multiplexed preamplification and hybridization of variant-specific probes to unique fluorescent barcodes. A multiplex KRAS assay (G12/13) droplet digital PCR (ddPCR) was used to confirm SNVs.

Results

The SNV assay detected at least one variant in 18/19 (95%) PC samples. One PC case harbored 3 SNVs. Among the PC samples, KRAS variants (G12D, G12V, G12R, Q61H, Q61L) were detected in 17 (90%) cases, EGFR in 1 (5%), and PIK3CA in 1 (5%). All KRAS mutations were also detected by ddPCR. Diagnostic accuracy of cytology alone for PC was 68% (19/28). 32% of the FNAs were inconclusive; at least one SNV was detected in 5/6 inconclusive FNAs with a final diagnosis of PC. No SNV was identified in the remaining 3 inconclusive cases diagnosed as chronic pancreatitis. Combining cytology and SNV analysis for inconclusive cases increased the diagnostic accuracy to 96% (27/28).

Conclusions

Nanostring SNV assay combined with cytology can enhance the diagnostic power of EUS-FNA, especially in inconclusive cases, preventing repeat biopsies, unnecessary resections for benign disease or delay in PC patients care. Given the low DNA input, digital data output and rapid turn-around time, this novel technology may be instrumental for the preoperative molecular diagnosis of PC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.