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Carolina Kawamura Haddad
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-128 - Low Positivity Rate in T790M Detection with ctDNA in NSCLC and Post EGFR-TKI Progression – Timing or Sensitivity? (ID 14293)
16:45 - 18:00 | Author(s): Carolina Kawamura Haddad
- Abstract
Background
The approval of Osimertinib in Brazil in 2016 for post EGFR-TKI progression T790M+ NSCLC treatment allowed offering to the patient the best available therapy, when, it is mandatory to identify the occurrence of T790M mutation before initiating the treatment. The prevalence of T790M mutation as resistance mechanism post EGFR-TKI treatment is estimated to be around 60%. Considering the limitations for tumor tissue biopsy in progressive disease setting, identifying molecular changes by using alternative tumor DNA sources, such as blood samples, serum, and plasma can become an interesting strategy in cases where a tissue specimen or acceptable quality biopsy is not available. However, the sensitivity of ctDNA analysis for T790M may be disappointingly low.
a9ded1e5ce5d75814730bb4caaf49419 Method
We performed a retrospective analysis of ctDNA samples database collected between June 2016 and December 2017 in Brazil. Blood samples of patients with post EGFR-TKI progression were submitted, at discretion of attending physicians, for EGFR mutation testing by cobas®.
4c3880bb027f159e801041b1021e88e8 Result
761 tests were included. The positivity rate was 43.9% for EGFRm and 10.4% for T790M. Considering EGFRm positive tests, the positivity rate for T790M among EGFRm positive was 23.7%. Data are shown in Table-1. This positive rate is lower than expected and may be explained by three factors: T790M ctDNA cobas® low sensitivity; test request before progression; or T790M prevalence lower in Brazilian population. Still, more detailed testing using tissue and/or more sensitive methods are needed before definitive conclusion. Tissue test should continue being recommended as gold standard in T790M detection on this patient setting.
Table 1- Frequency and mutations detected by ctDNA cobas® test in Brazil.
8eea62084ca7e541d918e823422bd82e ConclusionExon
18
19
20
21
19 + 20
21 + 20
Mutation
G719X
19Del
19Ins
T790M
L858R
L861Q
19Del + T790M
L858R
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T790M
Number
9
183
1
9
60
2
53
17
Positivity rate (%)
1.2
24.1
0.1
1.2
7.9
0.3
7.0
2.2
% of EGFRm
2.7
54.8
0.3
2.7
18.0
0.6
15.9
5.1
Our findings suggest that ctDNA approach in post EGFR-TKI progression may not be the best diagnostic strategy to identify resistance T790M mutation as first option. When patient cannot be submitted to tissue biopsy at progression, ctDNA test is an acceptable alternative.
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P2.01-31 - Updated EGFR Mutation Frequency in 1,689 NSCLC Brazilian Patients – A National-Wide Study (ID 14267)
16:45 - 18:00 | Author(s): Carolina Kawamura Haddad
- Abstract
Background
EGFR mutation status is crucial to improving therapeutic results in advanced NSCLC, due to the development of highly effective EGFR-TKIs. Recent local data suggest that EGFR mutation frequency is lower in Brazil ( 22%-33%) than in Asia and higher than in North America and Europe. We intended to describe the EGFR mutation frequency in a large national-wide Brazilian population.
a9ded1e5ce5d75814730bb4caaf49419 Method
This retrospective analysis evaluated a database composed of samples collected between January and August 2017, from all Brazilian regions. Tumor tissue samples of patients with advanced NSCLC were submitted, at discretion of attending physicians, for EGFR mutation testing. EGFR exons 18 to 21 were analyzed by cobas®, NGS, or other non-specified test. Unfortunately, smoking status data was not available and was not included in this analysis.
4c3880bb027f159e801041b1021e88e8 Result
1,689 tests were included. Table-1 demonstrates EGFR mutation rates according to test used. Mean age (±SD) was 64.5 (±11.3) for female and 66.0 (±11.1) for male population. From all detected mutations, exon 19 deletion was the most frequent (49.2%), followed by L858R (25.6%), exon 20 insertion (8.4%), T790M (4,7%), and G719X (3.0%). Patients with multiple EGFR variants (more than one EGFR mutation) corresponded to 10.3% of cases. Among different Brazilian geographic macro-regions, EGFRm rate was 33.3% in North (36 tests only), 25.1% in Northeast (307 tests), 30.9% in Central-West (175 tests), 25.8% in Southeast (841 tests), and 20.6% in the South (330 tests) region.
Table1 – EGFR mutation rate divided by gender and EGFR mutation detection method.
8eea62084ca7e541d918e823422bd82e Conclusioncobas®
NGS
Other
Overall
Female
58/183
(31.7%)
223/586
(38.1%)
25/159
(15.7%)
306/928
(33.0%)
Male
25/167
(15.0%)
89/447
(19.9%)
9/147
(6.1%)
123/761
(16.2%)
Overall
83/350
(23.7%)
312/1,033
(30.2%)
34/306
(11.1%)
429/1689
(25.4%)
Our findings confirm that EGFR mutation rate among Brazilian is higher than observed in Western countries, women have a higher EGFR mutation rate than men, and detection rate using NGS is higher than cobas®. Frequency of EGFR mutation was lower in South region, what could be explained by a higher smoking rate (not evaluated in this study) and a larger Caucasian population.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.13 - Targeted Therapy (Not CME Accredited Session) (ID 979)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.13-33 - Lung Adenocarcinoma Harboring RET Fusion and Dramatic Response to Combination of Vandetanib (VAN) and Everolimus (EVE): A Case Report from Brazil (ID 14111)
12:00 - 13:30 | Presenting Author(s): Carolina Kawamura Haddad
- Abstract
Background
The identification of oncogene addicted NSCLC and the development of target therapies lead to improvement in survival rates and quality of life. In addition to other drugable targets such as EGFR mutation and ALK translocation, RET fusion has been shown to be an oncogenic driver in 1 to 2% of patients with NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Here we report a 23-year old never-smoker male patient (Pt) diagnosed with lung adenocarcinoma, metastatic to lymph nodes, bones and lungs. Tumor biopsy was performed during broncoscopy. Tissue molecular testing was negative for EGFR (cobas) and ALK (FISH), and PDL-1 tumor proportional score (22C3) was 5%. Pt presented rapid disease progression after one cycle of cisplatin and pemetrexed, with pleural effusion and respiratory distress. Since initial tissue biopsy paraffin had been exhausted, next generation sequencing in cell-free tumor circulating DNA in plasma was performed (Guardant360). CCDC6-RET fusion and TP53 mutation (T256I) were identified.
4c3880bb027f159e801041b1021e88e8 Result
Based on promising activity of the combination of VAN with EVE previously reported, and the lack of clinical trials in this setting in Brazil, Pt started oral target therapy with VAN 300 mg and EVE 10 mg daily. He had unequivocal clinical improvement over the following weeks, with discontinuation of pain medications and relief of respiratory symptoms. After 30 days on treatment, restaging CT scans demonstrated a dramatic response. Adverse events were grade (G) 1 cutaneous rash, G1 stomatitis and G1 diarrhoea. Pt also presented G1 pneumonitis that resolved rapidly with EVE temporary discontinuation. He remained without disease progression at 4+ months. After 5 months, he presented pneumonitis recurrence with respiratory failure.
VAN is a multi-targeted tyrosine kinase inhibitor of EGFR, VEGFR and RET, with limited activity in RET-rearranged NSCLC phase 2 trial. However, the concurrent inhibition of RET and the mammalian target of rapamycin (mTOR) has shown promising activity for RET-rearranged tumors in preclinical models. Among the 6 evaluable NSCLC patients with RET fusions treated with VAN and EVE in phase I trial, 5 achieved partial responses (83%) and 1 stable disease (16%). In particular, it has been suggested that CCDC6-RET subtype shows higher sensitivity to VAN.
8eea62084ca7e541d918e823422bd82e Conclusion
This case report corroborates the promising activity of combination of VAN and EVE in RET-rearranged NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53
