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Rafael López
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MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Mireia Serra-Mitjans, Thomas A. D'Amico
- Coordinates: 9/08/2019, 10:30 - 12:00, Interlaken (1988)
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MA02.01 - Reccurrence Pattern After Adjuvant Customized Chemotherapy Based on BRCA Expression Level (SCAT Trial) (Now Available) (ID 2760)
10:30 - 12:00 | Author(s): Rafael López
- Abstract
- Presentation
Background
•Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement, (St II-IIIA). Customization is feasible in adjuvant setting (tissue availability) . Analysis of expressionin genes involved in DNA repair could be use to select CT regiment. •BRCA1 plays an important role in DNA repair pathways and functions as a differential regulator of response to cisplatin and antimicrotubuleagents. SCAT trial results found that for low BRCA1 levels subgroup Cis-Gemcitabine was superior to Cis-Docetaxel and in high BRCA1 levels subgroup Docetaxel single agent without platinum achieved similar survival to Cis-Doc. Analysis of recurrence pattern in different subgroups of the trials has been performed
Method
From Jun/2007 to May/2013 591 patients were screened and 500 p were included (108 in Control arm treated with Cisplatin-Docetaxel and 392 in Experimental arm treated with Cisplatin-Gemcitabine, Cisplatin-Docetaxel or Docetaxel alone according terciles BRCA1 expression level). With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence pattern are analysed in each arm and subgroup treatment and comparison are made for incidence of risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and site of metastases (liver, bone, brain)
Result
Cumulative recurrence 232/456 evaluable patients (p) (50.8%). Recurrence were seen in 182/354 patients treated in experimental arm and in 50/102 p treated in the control arm (RR 1.04; 0.83-1.30) (p=0.672). Majority of recurrences 159/232 (68.5%) were single site recurrence. Intrathoracic recurrences in 121/232 (52%) while extrathoracic metastatic disease 111/232 (47.8%). No significant differences were seen for single/multiple, intra/extrathoracic recurrences between experimental and control arm. More frequent distant metastatic sites were: bone (42 p), brain (38 p) and liver (11 p) In the experimental group between different treatments no significant differences were found for the overall metastatic rate or for the single/multiple, intrathoracic/extrathoracic recurrences. For specific metastatic sites related to experimental treatment a significant reduction of risk of brain metastases were found in the experimental group with high level BRCA1 treated with Docetaxel single agent (p=0.0016)
Conclusion
For NSCLC resected patients with lymph node involvement (Stages II-IIIA) risk of recurrence remains high with cumulative rate > 50%. There were no differences in the Relative Risk (1.04) of recurrence when control and experimental arm are compared. Majority of recurrences were single site (68.5%) and intrathoracic (52%) but distant metastases developed in 47.8% os p. More frequent metastatic site was bone, followed by brain and liver. Brain metastases risk were significant lower for patients with low BRCA1 expression treated with single agent Docetaxel
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.12-03 - Antitumor Activity of Single Agent Lurbinectedin in Patients with Relapsed SCLC Occurring ≥30 Days After Last Platinum Dose (ID 1710)
09:45 - 18:00 | Author(s): Rafael López
- Abstract
Background
Lurbinectedin (L) inhibits activated transcription and induces DNA double-strand breaks, leading to apoptosis.
Method
This multicenter, single agent, phase II Basket trial treated a cohort of 105 SCLC patients (pts) with ECOG PS 0-2 who had received one prior chemotherapy line. L 3.2 mg/m2 was administered as a 1-hour i.v. infusion on Day 1 q3wk. Primary endpoint, confirmed overall response rate (ORR) by RECIST v.1.1 according to investigator assessment, was met (ORR=35.2%; 95% CI, 26.2-45.2%). A sub-analysis excluding the 21 pts with disease relapse < 30 days after last platinum dose is reported here.
Result
Median age of 84 evaluated pts was 60 years (range, 41-83), 58.3% were male, ECOG PS 0-1/2 in 96/4%, liver metastasis in 36.9%, history of CNS involvement in 4.8%, prior platinum in 100%, median chemotherapy-free interval (CTFI)=3.9 months (1.1-16.1); prior immunotherapy in 8.3%. A median of 5.5 cycles (range, 1-24) was administered.
ORR, % (95% CI) (confirmed responses) (n=84)
40.5 (29.9-51.7)*
CTFI≥90d (n=60)
45.0 (32.1-58.4)
CTFI 30-89d (n=24)
29.2 (12.6-51.1)
Disease Control Rate at 6 months, % (n=84)
48.8
Median duration of response (months) (95% CI) (n=34)
5.3 (3.5-6.4)
CTFI≥90d (n=27)
6.2 (3.5-7.3)
CTFI 30-89d (n=7)
4.1 (2.6-5.3)
Median overall survival (months) (95% CI) (n=84)**
10.9 (7.8-14.9)
CTFI≥90d (n=60)**
11.9 (9.7-16.2)
CTFI 30-89d (n=24)**
(4.1-7.6)
*4 of 7 pts who failed prior immunotherapy had confirmed response
**Preliminary data
L was well tolerated. Neutropenia was the most common adverse event (AE) (G3:21.5% and G4:25%), whereas febrile neutropenia was reported in 2.4%. Most common non-hematological AEs included fatigue (G3: 7.1%), nausea and vomiting (all G1-2: 32.1% and 16.7%) and transaminase increase (G3:7.2%). There was no death due to treatment related AE.
Conclusion
L is an active agent for second-line treatment of SCLC. The highest ORR (45.0%) was reported for pts with CTFI≥90d. Notable antitumor activity (ORR=29.2%) was also observed in pts with CTFI 30-89d, for whom no therapy is currently approved. Hence, L is a valuable therapeutic option for SCLC pts with disease relapse after first-line platinum-based therapy.
Updated trial results will be presented at the conference.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-38 - Identification of a Novel Synthetic Lethal Vulnerability in Non-Small Cell Lung Cancer by Co-Targeting TMPRSS4 and DDR1 (ID 2191)
10:15 - 18:15 | Author(s): Rafael López
- Abstract
Background
Synthetic lethality has been defined as the inability of cells to proliferate when co-targeting two genes, with a synergistically superior inhibition than that found for each individual gene. Consistent co-expression of two genes involved in a similar function is a predictor of synthetic lethality, a strategy that is being applied to find out novel cancer vulnerabilities.
Method
Large-scale bioinformatics analyses across 5 public databases were used to identify genes consistently co-expressed with TMPRSS4, a novel therapeutic target that we have previously identified in NSCLC. Pyrosequencing was used to evaluate methylation levels in patients and cell lines. Functional in vitro experiments and animal models were used to assess synthetic lethality of TMPRSS4 and DDR1 in NSCLC.
Result
Consistent co-expression between TMPRSS4 and DDR1 was found in all NSCLC databases evaluated. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down cells, but not single knock-out cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and apoptosis. Moreover, double knock-down cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in mice injected with double knock-down-injected cells and lack of 18FDG-uptake by microPET analysis.
Conclusion
We have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4. This may help designing therapeutic strategies to impair NSCLC growth by co-targeting both genes.
