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Marcelo Graziano Custodio
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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: 3
- 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): Marcelo Graziano Custodio
- 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.
6f8b794f3246b0c1e1780bb4d4d5dc53 -
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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): Marcelo Graziano Custodio
- 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.
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P2.01-32 - Economic Evaluation of Diagnostic Platforms for T790M Detection in Post EGFR-TKI NSCLC in Brazil (ID 14328)
16:45 - 18:00 | Author(s): Marcelo Graziano Custodio
- Abstract
Background
50% of acquired resistance to first or second-generation EGFR-TKIs NSCLC treatment is attributed to T790M mutation. Clinical trials demonstrated superior efficacy of osimertinib versus chemotherapy in second line setting. Nevertheless, the required molecular testing to identify T790M mutation is a challenge considering difficulties related to tissue re-biopsies. Nowadays, availability of noninvasive ctDNA techniques permits safer and faster molecular diagnostic. In Brazil, there are some commercially available tests presenting different accuracy rates. Our objective was to compare current T790M ctDNA tests cost-effectiveness, under local perspective.
a9ded1e5ce5d75814730bb4caaf49419 Method
The population is NSCLC post first-line EGFR-TKI progression. Decision tree model started with cfDNA evaluation (RT-PCR based kit, Digital Droplet PCR, or NGS). Due to ctDNA methods intermediate sensitivity, tumor sample analysis is recommended if plasma result is negative. Strategies were a combination of cfDNA tests and RT-PCR based kit or NGS for tumors re-biopsies. Prevalence of T790M mutation, test accuracy, proportion of unknown or unfeasible samples were used to calculate each branch. Tissue re-biopsies complications and costs were also considered. The model was analyzed from a healthcare-payer perspective based on Brazilian private sector.
4c3880bb027f159e801041b1021e88e8 Result
Plasma ddPCR then tissue biopsy NGS (if plasma negative) was the most effective, with cost-effective ratio of US$ 3,855.43 per positive T790M detected. Its cost was higher than the second most effective strategy (plasma-NGS + tissue NGS). Incremental cost-effectiveness ratio between both was US$ 21,193.66 per additional positive case detected. All strategies using RT-PCR based kit for plasma and/or tissue were dominated.
8eea62084ca7e541d918e823422bd82e Conclusion
In terms of costs and effectiveness, the best algorithms to detect more T790M positive cases are combination of ctDNA (ddPCR or NGS) and NGS test for tumor re-biopsy. ddPCR use followed by NGS permits identification of 5% more T790M mutations than the dominated methods. This study is an effort to optimize expenditures and integrate diagnostics discussions in Brazilian health system.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-09 - Efficacy and Safety of Osimertinib After Prior EGFR TKI: Analysis of Patients Underrepresented in Randomized Clinical Trials (ID 14036)
16:45 - 18:00 | Author(s): Marcelo Graziano Custodio
- Abstract
Background
Osimertinib is a new standard of care in non-small cell lung cancer (NSCLC) after progression to an EGFR TKI in the presence of T790M mutation. Following results of the phase III study AURA 3, which led to the approval of osimertinib worldwide, we have conducted ASTRIS in Brazil.
a9ded1e5ce5d75814730bb4caaf49419 Method
This is a phase IV, international, multicentric, open trial, with the aim of confirming the efficacy and safety of osimertinib at a dose of 80 mg daily, orally. Eligible patients presented with diagnosis of T790M-positive NSCLC on progression after prior EGFR TKI. Herein, we present the Brazilian experience at ASTRIS, including subsets that were underrepresented in the phase III trial.
4c3880bb027f159e801041b1021e88e8 Result
Eighty-eight patients were enrolled in Brazil between August 2015 and March 2017. The median age was 64 years (34-89), and most were females (66%). Fifty-four patients (61%) had received prior therapy with erlotinib, forty-two (48%) with gefitinib, and 3 (3%) with afatinib. Nineteen patients (22%) were exposed to a EGFR TKI more than 6 months before enrolment. Importantly, 11 patients (12.5%) presented with a PS of 2, 23 (26%) presented with brain metastases, and 3 with leptomeningeal disease. Exon 19 deletions were the most common primary mutation in EGFR, present in 55 cases (62.5%), followed by L858R in 24 cases (27%). Tumor samples were acquired from the primary tumor in 14 cases (45%) and in a metastatic site in 16 (52%); all other cases had T790M detected at plasma. After a median follow-up of 9.3 months, 26 progression events and 23 deaths were documented. The response rate was 58.2% (95%CI 46.6-69.2), and median progression-free survival was 9.4 months (95%CI 8.2-not reached). The 12-month overall survival was 69.7% (95%CI 56.5-79.6). Thirty patients (34%) presented an adverse event, 14 of which led to dose modification and 5 to treatment discontinuation. The most common adverse events were infection in 14 cases (15%), gastrointestinal and hematologic (4 cases each). Nineteen patients (22%) had a serious adverse event, mostly infections (14 cases).
8eea62084ca7e541d918e823422bd82e Conclusion
The profile of patients enrolled in Brazilian institutions highlights the presence of cases with poor PS, which was excluded in the AURA 3 trial. Despite these features, the efficacy and safety of osimertinib was confirmed, suggesting that results could be extrapolated to a broad range of subsets. This study also underscores the role of liquid biopsy in the detection of T790M, in detriment to tumor re-biopsy.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- 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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P3.01-12 - EGFR Mutation and Targeted Therapies: Difficulties and Disparities in Access to NSCLC Treatment in Brazil. (ID 14236)
12:00 - 13:30 | Author(s): Marcelo Graziano Custodio
- Abstract
Background
Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype, commonly presenting as advanced disease at diagnosis. Epidermal growth factor mutation (EGFRm) occurs in 10-15% of Western population with advanced NSCLC and its management includes the use of mutation-driver EGFR tyrosine kinase inhibitors (EGFR-TKIs). In Brazil, patients with EGFRm NSCLC may face barriers to access EGFR test and directed-therapy; otherwise, there is a lack of national clinical data addressing this issue. This study intended to evaluate the access to molecular EGFR testing, initial treatment, and its respective response in this patients setting in public and private institutions in Brazil.
a9ded1e5ce5d75814730bb4caaf49419 Method
In this retrospective cohort, patients with newly diagnosed advanced NSCLC between January and December 2014 were consecutively included. Data were collected from medical records of 10 Brazilian cancer institutions, and recorded in electronic clinical report form. Demographic data, medical history, tumor staging, pathological characteristics, treatments and outcomes were collected and analyzed. For each patient, maximum follow-up was 36 months.
4c3880bb027f159e801041b1021e88e8 Result
402 patients from 8 different Brazilian states were enrolled, and 391 were included in the analysis, being 236 men (60.4%). Median age was 64 years, 80% have been treated in the public and 20% in private health system; 74.9% (n = 293) were former or current smokers. The most frequent histological subtypes of NSCLC were adenocarcinoma (ADC) with 267 cases (68.3%) and squamous cell carcinoma (SqCC) with 87 cases (22.3%). Among smokers, 66.6% were diagnosed with ADC and 24.6% with SqCC; among never smokers (n = 63), 84.1% had ADC and 9.5% SqCC. Clinical staging (CS) at diagnosis was IV in 251 cases (81.6%) and locally advanced (stage IIIB) in 62 cases (18.4%). From patients diagnosed with ADC, only 52.1% (n = 139) have been tested for EGFR mutation and, of these, 21.6% (n = 30) had an EGFR activating mutation. Only 43.3% (n = 13) of those with EGFRm (n=30) received an EGFR-TKI as initial therapy, while the remaining were treated with cytotoxic chemotherapy. Based on the number of patients with EGFRm, the rate of access of EGFR-TKIs in first-line treatment was 75% in private care, compared to 31.8% in public care. Only 8 of 13 mutated patients (61.5%) treated with EGFR-TKI were evaluable for response, and the disease control rate was 62.5%.
8eea62084ca7e541d918e823422bd82e Conclusion
The frequency of EGFRm in locally advanced or metastatic ADC in Brazil was comparable to previous studies. Access to EGFR test and EGFR-targeted therapies are restricted specially in public health system. In Brazil, public policies to assure a broader access to these technologies must be implemented.
6f8b794f3246b0c1e1780bb4d4d5dc53
