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Gilberto Lopes
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ES05 - Value in Lung Cancer, from Screening to Treatment (ID 203)
- Event: WCLC 2020
- Type: Educational Session
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 14:15 - 15:15, Scientific Program Auditorium
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ES05.06 - Molecular Testing, Targeted Agents and Immunotherapy in Lung Cancer: Are They Worth the Cost? (ID 4042)
14:15 - 15:15 | Presenting Author(s): Gilberto Lopes
- Abstract
- Presentation
Abstract not provided
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MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA08.04 - LIPI and Outcomes of Durvalumab as Consolidation Therapy after ChRT in Patients with Locally-Advanced NSCLC (ID 1969)
16:45 - 17:45 | Author(s): Gilberto Lopes
- Abstract
- Presentation
Introduction
The lung immune prognostic index (LIPI), which combines pretreatment derived neutrophils/[leukocytes minus neutrophils] ratio (dNLR) >3 and lactate dehydrogenase (LDH) > upper limit of normal (ULN), is associated with outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). We aimed to assess whether pretreatment LIPI correlates with durvalumab efficacy after concurrent chemoradiotherapy in the locally advanced setting.
Methods
Multicenter retrospective study of locally advanced NSCLC patients treated with durvalumab consolidation in 21 European/US centers from 12/2015 to 5/2020. Clinical and biological data were collected before durvalumab treatment. PD-L1 expression by immunohistochemistry was also collected at diagnosis. LIPI was calculated according to previous reports and three groups were characterized: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3 or LDH>ULN) and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS). Response was assessed according to the clinical routine of each center.
Results
A total of 267 patients were enrolled. One hundred eighty-five (69%) patients were male, 252 (94%) smokers, with median age of 67 [range 59-73] and 223 (98%) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. 260/266 (98%) were stage III, of which 96 were IIIA, 127 stage IIIB and 37 stage IIIC. 163 (63%) had non-squamous histology and 12/131 (27%) harbored driver alterations: 5 EGFR, 4 BRAF, 3 MET, 2 ALK; missing in 136 cases. PD-L1 was ≥1% in 191/233 (82%) patients both from Europe and US, missing in 34 cases. LIPI was evaluable in 143 patients: 90 were considered good (63%), 50 intermediate (35%) and 3 (2%) as poor LIPI group. dNLR >3 was found in 47/218 (22%) and LDH > ULN in 23/143 (16%) cases. Radiotherapy was delivered concurrent in 219 (82%) of cases. No differences in clinical characteristics were found between 3 LIPI groups, including the response to previous chemoradiotherapy.
With a median follow-up of 13.4 months [95% confidence interval (CI), 12-15], the median PFS was 20 months [95% CI, 12.7-not reached (NR)]. Median PFS was 7.5 months [95% CI, 3.1-NR] for poor group vs. 10.7 months [95% CI, 5.1-NR] for intermediate group vs. 19.1 months [95% CI, 11.6-NR] for good LIPI group (P=0.020). Median overall survival (OS) was NR [95% CI 47-NR] in the entire cohort and therefore considered not mature. The first objective response rate under durvalumab was 44% (111/251), being 36% (18/50) for the intermediate-poor group and 38% (33/87) for the good group with no significant differences (P=0.099). No differences in PFS and OS between groups were found regarding PD-L1 status (P=0.5 and P=0.4, respectively).
Conclusion
Pretreatment LIPI is associated with clinical outcomes in locally advanced patients treated with durvalumab as consolidation after chemoradiotherapy. This cohort is still ongoing to confirm our preliminary findings in a larger cohort.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.09 - Improved Outcomes With Ramucirumab & Docetaxel in Metastatic Non-Small Cell Lung Cancer After Failure of Immunotherapy (ID 2882)
00:00 - 00:00 | Author(s): Gilberto Lopes
- Abstract
Introduction
Currently, a combination of Chemotherapy & Immune Checkpoint Inhibitor (ICI) is considered standard first line treatment for metastatic NSCLC (mNSCLC) without driver mutations. Before the advent of ICI as first line agent, REVEL, a phase III trial showed improved survival & efficacy with Ramucirumab & Docetaxel (Ram+Doc) in patients who failed the platinum based first line therapy. There is limited data and few case reports supporting a remarkable response to Ram+Doc treatment in patients pretreated with ICI based therapy; however, the synergistic benefit hasn’t been comprehensively proven yet. Methods
We reviewed 39 patients with mNSCLC retrospectively who received Ram+Doc treatment between 1/1/2010 and 3/1/2020 at the University of Miami (UM), following disease progression on ICI. 4 patients with EGFR/ALK mutations were excluded from the analysis. 35 patients were investigated for progression free survival (PFS), overall survival (OS) and analyzed using Kaplan Meier method. Median survival and corresponding 95% confidence intervals (CI) were estimated.
Results
35 patients with mNSCLC who received Ram+Doc therapy as second line or beyond were studied. The patient cohort aging 45-76 had a median age of 65, with 17 females (48.6%) and 18 males (51.4%). Ethnically, 12 patients were white (34.3%), 19 Hispanics (54.3%) and 1 African American (2.8%). 28 were smokers (80%) and 7 non-smokers (27.3%). Histologically, 33 patients had Adenocarcinoma and 2 Squamous Cell Cancer. All patients had at least 3 metastatic sites; bone being the most common, followed by liver and brain, respectively. All 35 patients received ICI as first line or second line therapy, which was followed by Ram+Doc upon disease progression. Median progression free survival (mPFS) among patients who received Ram+Doc therapy after failure of ICI was 6.6 months and median overall survival (mOS) was 20.9 months.
Conclusion
Our study demonstrated improved median PFS of 6.6 months, p<0.0001 (95%CI= 5.5 to 14.9), and median OS of 20.9 months, p<0.0001 (95%CI= 13.4 to -), in comparison to REVEL study where mPFS was 4.5 months (95%CI= 4.2 to 5.4) and mOS was 10.5 months (95%CI= 9.5 to 11.2). Since 95% CIs of UM and REVEL for both PFS and OS were not overlapping, we considered median PFS and median OS in our study (UM) to be statistically different from those in REVEL.
In summation, treatment with Ram+Doc, when used subsequent to failure of ICI therapy, exhibited a statistically significant improvement in mOS and mPFS. It’s hypothesized that combining an anti-angiogenic agent with a cytotoxic agent after ICI therapy increases synergism, leading to improved efficacy and outcome. The improvement in PFS is striking, given the statistical significance; however, due to a smaller cohort, further analysis in a large prospective trial would be crucial to strengthen our results.
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P36 - Pathology - Prognosis (ID 106)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P36.01 - KEAP1 and NRF2 Mutations in Hispanic and Non-Hispanic Patients with NSCLC: Clinicopathologic Characteristics and Prognosis. (ID 3712)
00:00 - 00:00 | Author(s): Gilberto Lopes
- Abstract
Introduction
The KEAP1 is the third most mutated gene in NSCLC, activated in over 20% of both squamous and nonsquamous lung cancers. The KEAP1-NRF2 pathway regulates cellular detoxification and has been associated with poor prognosis, metastases, and treatment resistance in lung cancer. Notably, KEAP1 mutations have been also associated with lack of benefit to chemoimmunotherapy even in patients with good tumor predictive markers such as high PDL1 status. The incidence of KEAP1-NRF2 mutations and potential impact on treatment response for Hispanic patients with lung cancer has not been well characterized.
Methods
A total of 617 patients, 426 Non-Hispanic Whites (NWH) and 181 Hispanics, with a diagnosis of lung cancer and next generation sequencing information available in the University of Miami central genomic database were included. Incidence of KEAP1/NRF2 mutations, clinico-pathologic characteristics, common co-occurring mutations, and treatment response were analyzed. Progression Free Survival (PFS) was defined as the time from therapy initiation to radiologic progression. Overall survival (OS) was defined as time from diagnosis of metastatic disease to death or last contact.
Results
KEAP1/NRF2 gene mutation rate was 8.4% in our lung cancer cohort (52/617). Incidence of KEAP1/NRF2 mutations in Hispanics vs. NHW was (11%, 20/181) vs. (6.6%, 28/426), p= 0.066. Median age was 70 years (range 48-90). Patients presented with advanced (80%) and locally advanced disease (16%). There were 21 women, 30 light smokers (<1pack/day), 18 heavy smokers (>1pack/day) and 4 never smokers. Most patients had adenocarcinoma histology (82.7%), while 15.4% displayed squamous cell carcinoma. Most common co-occurring mutations were KRAS (36/52), TP53 (23/52), and STK11 (17/52). Of twenty-one patients with available PDL1 testing, the majority were PDL1 negative (16/21), and a positive PDL1 expression >1% was seen in 5 patients. There were 12 patients with intermediate and 8 patients with high tumor mutation burden. Median PFS for patients treated with platinum-based chemotherapy (n=21), chemoimmunotherapy (n=8) and immunotherapy (n=4) was 4.6, 2.9 and 2.0 months, respectively. Median OS for patients with KEAP1/NRF2 mutations was 16.6 months for all patients. Median OS was 20 months for Hispanics and 15.4 months for NHWs. (p=0.99).
Conclusion
KEAP1/NRF2 mutations portend poor prognosis and treatment resistance for both Hispanics and NHWs in this cohort. There was no statistical difference in prevalence of KEAP/NRF2 mutations and median overall survival for Hispanics when compared to NHWs with KEAP1/NRF2 mutations.
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P37 - Pathology - Biomarker Testing (ID 107)
- Event: WCLC 2020
- Type: Posters
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P37.12 - Concordance of Next-Generation Sequencing Between Tissue and Liquid Biopsies in Non-Small Cell Lung Cancer (ID 1560)
00:00 - 00:00 | Author(s): Gilberto Lopes
- Abstract
Introduction
While genetic profiling has become standard of care for patients diagnosed with non-small cell lung cancer (NSCLC), next-generation sequencing (NGS) provides a wealth of information about targetable mutations. Advances in genetic testing have led to sequencing platforms that utilize tissue itself or extracellular circulating tumor DNA in the blood, known as a “liquid biopsy.”
Methods
We identified 55 patients with NSCLC who had undergone both tissue and liquid biopsy, using Foundation One and Guardant 360 at the University of Miami / Sylvester Comprehensive Cancer Center between January 2016 and December 2018, and performed retrospective analysis to determine patient characteristics as well concordance between different NGS platforms.
Results
In our patient population, 34% of patients had never smoked prior to diagnosis, while 22% had more than a 30 pack-year smoking history. 64% of patients had no treatment prior to initial NGS. 40% of patients had both testing done essentially simultaneously, while 60% of patients had one test done after disease progression. Of these patients, therapy was changed as a result in 73%. Median number of days between tests was 21 days, with 56% of testing done within 90 days of the previous testing. Nine patients had an additional Foundation One tissue NGS performed. Concordance across all genes tested in both platforms was 98 ± 0.2%. Concordance with consideration of genetic alterations detected in both assays was 24.5 ± 3.0%. The median number of gene alterations determined by Foundation One testing was 4 (range 1-9), while the median for gene alterations detected by Guardant 360 was 3 (range 1-13). The median number of variants of unknown significance (VUS) was 10 (range 5-25). We also calculated sensitivity and specificity across 8 genes, using tissue-based NGS as the gold standard, as shown in Table 1.
Table 1. Sensitivity, sensitivity, and diagnostic accuracy across 8 genes in NSCLC.
ConclusionGene
Sensitivity
Specificity
Positive Predictive Value
Negative Predictive Value
EGFR
78.3%
97.1%
94.7%
86.8%
TP53
59.4%
84.6%
82.6%
62.%
ALK
100%
98.1%
66.7%
100%
KRAS
58.3%
95.5%
77.8%
89.4%
BRAF
50%
94.2%
40%
96.1%
ROS
n/a
98.2%
n/a
100%
RET
100%
98.1%
50%
100%
MET
100%
92.6%
20%
100%
Our analysis indicates a role for both tissue-based and circulating tumor DNA-based NGS for determination of targetable mutations and thus appropriate treatment regimens. Low levels of concordance are potentially related to post-treatment changes in the tumor genetic profile as well as evolution in the testing itself.
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P87 - Targeted Therapy - Clinically Focused - RET (ID 264)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P87.04 - Chemotherapy and Immunotherapy Outcomes of RET-Rearranged Lung Cancers: A Case Series (ID 2459)
00:00 - 00:00 | Author(s): Gilberto Lopes
- Abstract
Introduction
RET rearrangement is detected in 1% to 2% of lung adenocarcinomas. RET fusions correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage. Prior studies have reported potential higher chemosensitivity and low response to immunotherapy. Given the rarity of these tumors, the natural history, and the role of chemotherapy and immunotherapy in the context of new selective RET inhibitors is still being defined.
Methods
We performed a retrospective review of RET-rearranged lung cancer cases treated at the University of Miami from 2013 to 2020. RET rearrangements were identified using targeted next-generation sequencing of DNA (FoundationOne or Caris). Clinicopathologic characteristics and response to chemotherapy and immunotherapy were analyzed. PFS was defined as the time from therapy initiation to radiologic progression or death. Overall survival (OS) was defined as time from diagnosis of metastatic disease to death. For PFS, and OS analyses, Kaplan-Meier curves were compared using the Mantel-Cox log-rank test.
Results
A total of 15 patients with a median age of 64 (range 50-83) were identified in a cohort of 617 sequenced lung cancers (representing a prevalence of 2.4%). There were 9 women; 11 never smokers; 1 light smoker (<1pack/day) and 3 former smokers (>1pack/day). The patients came from a diverse background (7 Non-Hispanic whites, 5 Hispanics, 1 Asian, 2 African Americans). The majority of cases had adenocarcinoma histology and KIF5B-RET fusions (n=14)). In 10 patients with sufficient tissue for PD-L1testing, PD-L1 expression was 0%, low (1-49%), and high (50% or greater) in 50% (n=5 of 10), 10% (n=1 of 10), and 40% (n=4 of 10) of cases, respectively. Twelve patients (80%) presented with metastatic disease and three (20%) with locally advanced disease. The most common sites of metastases were lung (15), followed by bone (10), brain (6), malignant pleural effusion (6), and liver (3). The median overall survival was 33 months (range 6 to 87). Five out of six patients with malignant pleural effusion had prolonged survival greater than 32 months. Eleven patients received platinum-based chemotherapy and 7 patients received immunotherapy during their course of treatment. Nine patients who received platinum-pemetrexed chemotherapy in the first line setting had prolonged responses with a median PFS of 19 months (range 5-53 mos), while those who received immunotherapy (n=6) had lower median PFS of 9 months (range 4-13 mos). Three patients with tumors that showed high PDL1 expression responded to immunotherapy for an average of 10 months.
Conclusion
RET-rearranged lung cancer in our series presented with adenocarcinoma, never smoking status, younger age and advanced disease. PFS after treatment with pemetrexed based chemotherapy in RET cases was longer than after immunotherapy. However, no patients in this series received combination chemotherapy and immunotherapy which is currently a standard of care. Unlike prior reports, patients with RET arranged lung cancers and high PDL1 expression responded to immunotherapy in this series. More data is needed to define the role of chemotherapy and immunotherapy in the context of new selective RET inhibitors.
