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Juan Jose Garcia Mosquera
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)
09:45 - 18:00 | Author(s): Juan Jose Garcia Mosquera
- Abstract
Background
BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.
Method
Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.
Result
BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.
Conclusion
It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)
10:15 - 18:15 | Author(s): Juan Jose Garcia Mosquera
- Abstract
Background
Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.
Method
We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.
Result
Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).
Table 1 Total 19 Gender
Women, n (%)
7 (36,8%)
Age
Median (range)
63,4 (51-82)
Cancer type, n (rate)
NSCLC Adenoca
NSCLC Squamous
SCLC
Mesothelioma
13 (68,4 %)
4 (21%)
1 (5,3%)
1 (5,3%)
Line of therapy, n (rate)
Adjuvant
First line
Second or further line
1 (5,2 %)
8 (42,1%)
10 (52,6%)
Tumor Response, n (rate)
CR
PR
SD
PD
NE
2 (10,5%)
8 (42,1%)
5 (26,3%)
3 (15,8%)
1 (5,2%)
table 2 Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%) Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%) Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%) Atezolizumab, 33 0 0 0 Durvalumab, 4 2 (50%) 0 0 Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%) Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)
Conclusion
In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.
