Displaying One Session

Room Scene AB Educational session
Date
14.09.2018
Time
10:55 - 12:45
Location
Room Scene AB
Chairs
  • Nicholas McGranahan (London, GB)
Clonal evolution (ID 12) Educational session

Clonal evolution in lung cancers (ID 7)

Lecture Time
10:55 - 11:15
Speakers
  • Nicholas McGranahan (London, GB)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45
Clonal evolution (ID 12) Educational session

APOBEC (ID 8)

Lecture Time
11:15 - 11:35
Speakers
  • Reuben Harris (Minneapolis, US)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45
Clonal evolution (ID 12) Educational session

Mutational processes (ID 59)

Lecture Time
11:35 - 11:55
Speakers
  • Serena Nik-Zainal (Cambridge, GB)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45
Clonal evolution (ID 12) Educational session

PDX (ID 52)

Lecture Time
11:55 - 12:15
Speakers
  • Samuel Aparicio (Vancouver, CA)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45
Clonal evolution (ID 12) Educational session

Single cell/PDX (ID 9)

Lecture Time
12:15 - 12:35
Speakers
  • Sohrab Shah (Vancouver, CA)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45
Clonal evolution (ID 12) Educational session

59O - Preliminary results on mechanisms of resistance to ALK inhibitors: A prospective cohort from the MATCH-R study (ID 217)

Lecture Time
12:35 - 12:45
Speakers
  • Gonzalo Recondo (Villejuif, FR)
Location
Room Scene AB, Paris Marriott Rive Gauche, Paris, France
Date
14.09.2018
Time
10:55 - 12:45

Abstract

Background

ALK tyrosine kinase inhibitors (TKIs) have shown to be effective in the treatment of patients with ALK rearranged NSCLC. The clinical benefit is eventually limited by the acquisition of resistance to ALK TKIs by tumor cells. The study of the biological mechanisms implied in tumor progression can provide the rational for therapeutic strategies to overcome resistance.

Methods

In the MATCH-R prospective study, patients with unresectable or metastatic cancer were included upon acquired resistance to targeted therapies or immunotherapy, defined as progressive disease after partial or complete response or stable disease for 6 months. Upon progression tumor biopsy is performed and serial blood samples are collected. Targeted NGS, CGH, WES and RNAseq were performed on the tissue, and PDX models and patient derived cell lines were established to fully profile the underlying mechanisms of resistance.

Results

From June 29th 2015 and as of June 15th 2018, 309 patients were included of which 139 (45%) had advanced lung adenocarcinoma and n = 10 (7.2%) had tumors with ALK rearrangements. In 2 patients, multiple biopsies were taken upon progression to sequential treatments with ALK TKI. Evaluable tumor biopsies were taken upon progression to treatment with crizotinib (n = 3), ceritinib (n = 1), brigatinib (n = 2), lorlatinib (n = 5). PDX models/patient derived cell lines (n = 4) were developed from 2 patients. Mechanisms of resistance: Secondary mutations (n = 5), pathway bypass (n = 3), other non-genetic (n = 3). Novel compound mutations implied in resistance to lorlatinib were characterized by infecting BA/F3 cells with EML4-ALK V3 mutated lentiviral vectors, together with the characterization and reversion of a novel bypass mechanism. We also studied therapeutic strategies aiming at reverting resistance driven by EMT in patient derived cell lines treated with lorlatinib.

Conclusions

Mechanisms of resistance were identified in 9 out of 11 tumors from patients with ALK rearranged NSCLC. The development of patient derived cell lines provides further information on how to overcome the resistance to ALK inhibitors.

Clinical trial identification

NCT02517892.

Legal entity responsible for the study

 Gustave Roussy Cancer Campus.

Funding

Natixis, European Research Council (ERC), Foundation Nelia et Amadeo Barletta.

Disclosure

F. André: Research grants from Novartis. J-C. Soria: Full-time employee of MedImmune. B. Besse: Institutional grants for clinical and translational research from AstraZeneca, BMS, Boehringer-Ingelheim, Inivata, Lilly, Loxo, OncoMed, Onxeo, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier, and OSE Pharma. All other authors have declared no conflicts of interest.

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