1. Unità Clinica di Diagnostica Istopatologica e Molecolare
NSCLC ALK-traslocato
Valutazione e problematiche patologiche
Massimo C.P. Barberis
Unità Clinica di Diagnostica Istopatologica e Molecolare

2. Translating Genomic Profiling Data into Therapeutic Strategies
(Lung Adenocarcinoma)
RET: Cabozantinib : RR=40%
HER2 mutation
HER2 mutation:
>50% RR to Afatinib;
~20% to Dacomitinib
ROS1:
70% RR to
Crizotinib
BRAF (V600E):
>60% RR to
BRAF + MEK inhibitor combo
ALK: 65%RR to Crizotinib:
~70% RR to 2° Gen TKI Ceritinib in resistant cancers
Differentially mutated genes and patterns identified by MutSigCV in Transversion-High and Transversion-Low samples. Data from TCGA samples were combined with published data17 to increase the sample size in each group.
METex14:
RR >50% to Crizotinib
EGFR: RR>70%
to 1°-2° Gen TKIs;
~60% RR to 3° Gen TKIs
in resistant cancers
KRAS:
35% RR to MEK inhibitors +
Chemotherapy

3. NSCLC : ALK rearrangement prevalence 3-5% ROS1 < 2%
ALK and ROS1 detection epitomize the rapid advances being achieved in the basic science, diagnosis, and treatment of lung cancer.
Three drugs (crizotinib, ceritinib, and alectinib) have become available for the treatment of ALK-rearranged
lung tumors, and one drug (crizotinib) is now available for ROS1-rearranged tumors.
NSCLC : ALK rearrangement prevalence 3-5%
ROS < 2%
Clinical role of the different fusion partners is unknown

4. 70-80% 40-50 yrs never smokers adenocarcinoma
ALK Patients characteristics
70-80% yrs never smokers adenocarcinoma
NSCLC yrs
EGFR mut yrs
ALK rearranged tumors have been found in patients older than 70 yrs and younger than 40 yrs

5. ALK rearrangement in NSCLC
Presented By Alice Shaw at 2017 ASCO Annual Meeting

6. Presented By Alice Shaw at 2017 ASCO Annual Meeting
Study rationale
Presented By Alice Shaw at 2017 ASCO Annual Meeting

7. Primary endpoint: PFS, investigator-assessed
Presented By Alice Shaw at 2017 ASCO Annual Meeting

8. PFS by baseline CNS metastases status*
Presented By Alice Shaw at 2017 ASCO Annual Meeting

9. Secondary endpoint: <br />Time to CNS progression (by IRC, ITT)
Presented By Alice Shaw at 2017 ASCO Annual Meeting

10. Presented By Alice Shaw at 2017 ASCO Annual Meeting
Conclusions
Presented By Alice Shaw at 2017 ASCO Annual Meeting

11. What is the most cost-effective screening method?
Targeted-therapy for patients with advanced NSCLC (adenocarcinomas or tumors with
an adenocarcinoma component) is encouraging
Molecular testing is crucial for therapy
The approval of the IHC test ( clone D5F3) gives access to specific drugs in an easier way
Which patients should be screened for ALK and ROS1 gene rearrangements?
What is the most cost-effective screening method?

12. Screening for ALK and ROS1 rearrangement should be done for all patients with
advanced NSCLC ( adenocarcinoma or cancer with an adenocarcinoma component)
Screening should be considered in patients with younger age, never/light smoking history, or
negative results on testing for EGFR and KRAS mutations
Currently, two assays are approved: the ALK FISH Break Apart assay and the ALK (D5F3) IHC
(Ventana).
In the future?

13. NGS represents a practical and reliable ALK and ROS1 testing approach for use with routine lung cancer tissue specimens, enabling patients to receive optimal therapies. This novel methodology can also assess genomic-related mechanism of resistance to ALK-targeted therapies and guide the appropriate selection of the next generation of inhibitors.

15. NSCLC –biopsy -
H&E
IHC
FISH
Molecular Testing

16. a b c
EBUS-TBNA
DiffQuick stain (R.O.S.E.)
H&E from cyto-block
Anti TTF-1 from cytoblock

17. Criteria of acquired resistance to TKIs in NSCLC (
Criteria of acquired resistance to TKIs in NSCLC (. Modified Criteria of acquired resistance to TKIs in NSCLC from Jackman et al.6)
Jackman D, Pao W, Riely GJ et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28;