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Michelangelo Fiorentino
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Lunch & Poster Display session (ID 58)
- Event: ELCC 2019
- Type: Poster Display session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/11/2019, 12:30 - 13:00, Hall 1
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146P - Clinical significance of ROS1 5’ deletions detected by FISH and response to crizotinib (ID 399)
12:30 - 13:00 | Author(s): Michelangelo Fiorentino
- Abstract
Background
ROS1-rearranged non-small cell lung cancer (NSCLC) patients (pts) are eligible for crizotinib therapy. Diagnosis is based on break-apart fluorescence in situ hybridization (FISH), as for ALKrearrangements, and include 5’ deletions. We report assessment of ROS15’ deletion by FISH and next-generation sequencing (NGS) and outcome of crizotinib treatment.
a9ded1e5ce5d75814730bb4caaf49419 Methods
We included all consecutive NSCLC pts treated at our Institution with: i) diagnosis of 5’ ROS1 gene fusion by break-apart FISH (≥15% of tumor cells with any 5’ deletion pattern); ii) availability in the samples of at least 50 ng of extracted RNA with at least 50% tumor cell enrichment; iii) treatment with crizotinib for at least 4 weeks following the diagnosis of ROS1fusion; iv) availability of clinical and radiological response data after therapy. FISH assay was performed using the Zytolight SPEC ROS1 Dual Color Break Apart Probe (ZytoVision, Germany). NGS was performed on Ion Torrent Personal Genome Machine (Thermo Fisher Scientific). The RNA panel identified rearrangements in 23 genes including ROS1 rearrangements with EZR, CD74 and SCD4.
20c51b5f4e9aeb5334c90ff072e6f928 Results
Eight patients were included. No patient had brain metastasis at diagnosis. Five pts were never-smoker, 2 light former smoker and 1 (case #1) a current heavy smoker (50 pack-year). Crizotinib therapy lasted for a mean of 11.0 months (range 2-31). The median overall survival was not reached at a median follow-up of 11.1 months (15.7 months for censored only). In 4 of the 8 cases (cases #2, 3, 7, 8; 50%), NGS confirmed a ROS1 fusion: 3 of them with the partner EZR and 1 with SCD4. All of these pts showed an objective response to crizotinib, 2 of them being complete responses according to RECIST v1.1 criteria. All these pts were alive at the time of last follow-up. In the other 4 pts (cases # 1, 4 ,5 ,6), NGS analysis did not detect ROS1 fusions. Of these, objective response to crizotinib was observed in only 2 pts, including one (case #5) with a concomitant EML4-ALKrearrangement, confirmed by FISH. The two other patients experienced rapid progressive disease.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
FISH-detected ROS15’ deletion is associated with a high response probability to crizotinib, similarly to classical ROS1 gene rearrangement. However, confirmation with at least one other method, e.g. NGS, is recommended, in order to exclude possible false positive results.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
The authors.
213f68309caaa4ccc14d5f99789640ad Funding
This work was in part supported by the Pallotti fund to Michelangelo Fiorentino.
682889d0a1d3b50267a69346a750433d Disclosure
All authors have declared no conflicts of interest.
cffcb1a185b2d7d5c44e9dc785b6bb25 -
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148P - KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic non-squamous NSCLC (ID 368)
12:30 - 13:00 | Author(s): Michelangelo Fiorentino
- Abstract
Background
Programmed cell death -1 (PD-1) PD-ligand 1 (PD-L1) inhibitors represent a novel therapeutic option for advanced chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients, leading to a significant improvement in median and long-term survival. However, about 50% patients do not benefit from therapy and experience rapid disease progression. PD-L1 expression and tumor mutational burden (TBM) have been proposed as biomarker of benefit to anti-PD-1/PD-L1 therapy. However, PD-L1 is not an ideal biomarker and TMB calculation is hardly obtainable for all patients. Here, we planned to test specific NSCLC genetic alterations as potential predictive factors of response to immunotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Methods
Tumor DNA was obtained from advanced NSCLC patients treated with anti PD-1 monoclonal antibody nivolumab (N = 44) or pembrolizumab (N = 3). The mutational status of 22 genes was assessed by targeted next-generation sequencing using Oncomine™ Solid Tumour DNA assay (Thermo Fisher).
20c51b5f4e9aeb5334c90ff072e6f928 Results
The most frequently mutated genes were TP53 (49%), KRAS (43%), ERBB2 (13%), SMAD4 (13%), DDR2 (13%), STK11(9%), ERBB4 (6%), EGFR (6%), BRAF (6%) and MET (6%). We observed that KRASmut patients have a better response to PD-1 inhibitors, showing a longer progression-free survival (PFS) and overall survival (OS) than KRASwt patients. Additionally, we observed that patients with ERBB-family, including EGFR, ERBB2 and ERBB4, mutations all failed to respond to PD-1 blockers, independently from KRAS status.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
These results suggest that the analysis of the mutational status of KRAS and ERBB-family genes is a potential molecular biomarker of response to PD-1 inhibitors that could be used in clinical practice.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
The authors.
213f68309caaa4ccc14d5f99789640ad Funding
Associazione Italiana per la Ricerca sul Cancro (AIRC).
682889d0a1d3b50267a69346a750433d Disclosure
M. Tiseo: Advisory boards, speakers’ fee: BMS, MSD. A. Ardizzoni: Grants, personal fees: BMS; Grants: Celgene; Personal fees: MSD, Eli Lilly, Boehringer Ingelheim, Pfizer, outside the submitted work. All other authors have declared no conflicts of interest.
cffcb1a185b2d7d5c44e9dc785b6bb25
