Browsing Over 164 Presentations
59O - Preliminary results on mechanisms of resistance to ALK inhibitors: A prospective cohort from the MATCH-R study (ID 217)
- Gonzalo Recondo (Villejuif, FR)
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.
Presentation 1 (ID 246)
Incidental findings in sequencing programs: What is the issue? (ID 11)
- Thierry Frébourg (Rouen, FR)
Presentation of consensus findings (ID 12)
- Clare Turnbull (London, GB)
Panel discussion (ID 13)
- Clare Turnbull (London, GB)
Adoptive T cell therapy 2.0: Bringing cell therapy to common epithelial malignancies (ID 16)
- Christopher Klebanoff (New York, US)
Mutational processes, immune evasion and cancer evolution: The Achilles heel? (ID 14)
- Charles Swanton (London, GB)
Targeting DNA repair in gynecological cancers (ID 15)
- Thomas Helleday (Sheffield, GB)
9O - Novel mechanism of platinum resistance: Rapid selection of pre-existing BRCA1-proficient tumor cells during neoadjuvant chemotherapy (NACT) for ovarian cancer (OC) in BRCA1 germ-line mutation carriers (ID 119)
- Evgeny Imyanitov (Saint-Petersburg, RU)
Abstract
Background
Cancers arising in BRCA1 mutation carriers are highly sensitive to cisplatin due to somatic inactivation of the wild-type BRCA1 allele. Accordingly, BRCA1-driven OCs usually respond well to NACT and therefore almost always undergo complete cytoreduction. However, despite this seemingly effective treatment and continuation of platinum therapy in the adjuvant setting, almost all BRCA1-associated OCs inevitably relapse.
Methods
We compared BRCA1 LOH status in paired OC samples before and after NACT.
Results
BRCA1 LOH was detected in 19/28 chemonaive OCs. Surprisingly, heterozygous status was restored in 13/19 (68%) samples after median of 3 cycles of NACT. The analysis of linked SNPs demonstrated that the restoration of BRCA1 proficiency is not due to the second mutation in the BRCA1 gene, but due to selection of pre-existing BRCA1-proficient cells. Furthermore, the persistence of isolated BRCA1-heterozygous cells in the chemonaïve OCs was confirmed by FISH analysis. Absence of BRCA1 LOH in post-NACT samples could not be explained by errors in tumor microdissection, as residual cancer tissues still retained TP53 mutation. Relapsed OC tissues were analyzed in 4 patients, who experienced the restoration of BRCA1 heterozygosity during NACT; the return to the BRCA1-deficient state during platinum-free interval was observed in 3 of these cases.
Conclusions
1) Loss of the remaining BRCA1 allele is not the first molecular event in the pathogenesis of BRCA1-associated cancers: it is likely to occur only after TP53 gene inactivation. 2) BRCA1-driven chemonaive cancers still contain a fraction of BRCA1-proficient cells even if they demonstrate LOH in a gross tumor mass. Therefore, drugs targeting BRCA1 deficiency are unlikely to be curative if applied alone. 3) The ratio between BRCA1-deficient and -proficient cells undergoes rapid changes during platinum therapy and platinum-free intervals. 4) Continuation of platinum therapy in the adjuvant setting for the tumors with restored BRCA1 status does not have a biologic rationale. 5) Intratumoral interactions between BRCA1-deficient and -proficient cells deserve further investigation.
Legal entity responsible for the study
N.N. Petrov Institute of Oncology.
Funding
Russian Science Foundation (grant number 14-25-00111).
Disclosure
All authors have declared no conflicts of interest.
Emergent and emerging kinase targets (ID 18)
- Peter Parker (London, GB)