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Hirva Mamdani
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-67 - Molecular Profiling of K-Ras and Its Subtypes in NSCLC Patients with Liver Metastasis (Now Available) (ID 2802)
08:00 - 18:00 | Author(s): Hirva Mamdani
- Abstract
Background
Non-small cell lung cancer (NSCLC) tend to have a poor prognosis in the presence of liver metastasis. Molecular profiling of NSCLC has played a major role in identifying a number of oncogenic targets that have led to novel targeted therapies. KRAS is a frequently mutated gene in NSCLC, occurring in approximately 30% of lung adenocarcinomas and most commonly manifesting as the transversion mutations G12C, G12V, G12A. there are presently no targeted therapies approved for KRAS-mutant NSCLC. Immunotherapy has emerged as a standard of care for first-line treatment of advanced NSCLC, specifically through targeting the programmed cell death protein-1 (PD-1/PD-L1). Given the aggressive nature of KRAS-mutant NSCLC with liver metastases and the lack of approved therapies targeting the KRAS pathway, checkpoint blockade immunotherapy may represent an impactful primary therapeutic option for these patients.
Method
The CARIS database from 2016 - 2018 was queried and patients with NSCLC were identified. PD-L1 antibody 22c3 ≥1% was considered positive. PD-L1 expression as well as k-ras and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA
Result
We identified 361 patients with NSCLC having Liver metastasis. Median age was 67. Gender distribution was equal (51.4% males, 49.7% females). Of the 361 patients, we identified 74 patients with mutated K-ras. Thirty nine out of the 74 patients had PD-L1 expression (52.7%). Twenty one patients had the G12C sub-type (28%) with 14 patients (66%) having positive PD-L1 expression.Of the 287 patients with wild type K-ras, 115 patients had PD-L1 positive expression (40%) with no statistical significance (P=0.134) in comparison to the k-ras mutant population.We also studied 2237 K-ras mutant patients without liver metastases where 882 patients had the G12C subtype (39.4%). On the other hand, only 21 patients were positive for G12C k-ras subtype out of the 74 k-ras mutant patients with liver metastases.Among patients with liver metastases, adenocarcinoma was the most common histological subtype (223 patients), Carcinoma NOS was the second common histological subtype (61 patients).Patients with no liver metastasis had median age of 68. Gender distribution was equivocal.
Conclusion
Patients with k-ras mutant G12C subtype were associated with more frequent PD-L1 expression and less occurrence of liver metastases.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-74 - A Retrospective Study Evaluating Clinical Predictors of Duration of Response to Immune Checkpoint Inhibitors in Advanced NSCLC (Now Available) (ID 1016)
09:45 - 18:00 | Author(s): Hirva Mamdani
- Abstract
Background
Immune Checkpoint Inhibitors (ICI) with/without chemotherapy have become the standard of care for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Similar to the response rate, durability of response to ICI is quite variable. While PDL1 expression and Tumor Mutational Burden (TMB) have been described to predict response to ICI, little is known about the clinical predictors of duration of response (DoR).
Method
A retrospective chart review of patients (pts) with advanced NSCLC treated with ICI based therapy at Karmanos Cancer Institute was conducted. Data were collected on demographics, clinical characteristics, and tumor characteristics. Univariable and multivariable cox regression analyses were performed for six pre-chosen covariates (histology, prior radiation therapy, brain metastasis, occurrence of immune-related adverse events (irAEs), statin use and smoking status) to see the associations with the DoR to ICI.
Result
One hundred thirty-one pts were included in the analysis (68% adenocarcinoma, 60% received prior radiation, 20% had brain metastasis, 26% developed irAEs, 33% were on a statin, 69% former smokers, 12% current smokers and 19% never smokers). Overall median DoR was 149 days (range, 14-1934). On multivariable analysis, longer DoR to ICI was observed in pts with non-adenocarcinoma histology (HR: 0.65; p = 0.050; CI: 0.42-1.00, median DoR 242.5 days) and current smokers (HR: 0.53; p = 0.031; CI: 0.30-0.95, median DoR 206.5 days). Other variables, including the presence of brain metastasis, prior radiation therapy, occurrence of irAEs and statin use had no significant relationship with the DoR.
Conclusion
Tumor histology and smoking status were statistically and clinically significant predictors of durability of response to ICI in advanced NSCLC, presumably secondary to higher TMB. Presence of brain metastasis did not adversely impact DoR to ICI.
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P1.01-84 - Interaction of Lorlatinib with CYP2B6, CYP2C9, UGT, and P-gp Probe Drugs in Patients with Advanced Non-Small Cell Lung Cancer (ID 293)
09:45 - 18:00 | Author(s): Hirva Mamdani
- Abstract
Background
Lorlatinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). Because lorlatinib is an inducer and inhibitor of various cytochrome P450 (CYP) enzymes and transporters, an evaluation of its effect on these substrates at steady state is warranted. A drug-drug interaction (DDI) sub-study was conducted in patients with advanced NSCLC to evaluate the net effect of these interactions.
Method
Probe drugs utilized included bupropion for CYP2B6, tolbutamide for CYP2C9, acetaminophen for uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT), and fexofenadine for P-glycoprotein-1 (P-gp). Thirty-two patients (to have at least 6 evaluable patients per probe drug) were administered a single dose of a probe drug alone on Day −2 to determine plasma exposure of the probe drug alone. Starting on Cycle 1 Day 1, patients began lorlatinib tablets 100 mg daily. On Cycle 1 Day 15, another single dose of the same probe drug was administered concurrently with lorlatinib.
Result
Co-administration of lorlatinib 100 mg with bupropion, a sensitive CYP2B6 probe drug, decreased bupropion geometric mean plasma AUCinf and Cmax by 25% and 27%, respectively. For tolbutamide, a sensitive CYP2C9 probe drug, lorlatinib decreased tolbutamide AUCinf and Cmax by 43% and 15%, respectively. Likewise, for acetaminophen, a sensitive UGT substrate, lorlatinib decreased acetaminophen AUCinf and Cmax by 45% and 28%, respectively. Finally, for fexofenadine, a sensitive P-gp substrate, lorlatinib decreased fexofenadine AUCinf and Cmax by 67% and 63%, respectively.
Conclusion
Critical steady-state–based DDI evaluations can be conducted in patients with cancer in carefully designed studies. Per FDA guidance, strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Based on these criteria, lorlatinib behaved as a net weak inducer of CYP2B6, CYP2C9, and UGT; and a net moderate inducer of P-gp. The results of this sub-study can help guide recommendations for dose modifications when lorlatinib is given concomitantly with drugs that are metabolized by these enzymes or transporters. Based on the current results, only drugs that are P-gp substrates of narrow therapeutic index may require dose adjustments when used concomitantly with lorlatinib.
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-27 - Risk Factors Associated with a Second Primary Lung Cancer (SPLC) in Patients (Pts) with an Initial Primary Lung Cancer (IPLC) (ID 607)
09:45 - 18:00 | Author(s): Hirva Mamdani
- Abstract
Background
The risk for development of a SPLC after treatment of an IPLC is around 1% to 2% per pt per year. The aim of this study was to characterize the risk factors associated with the development of a SPLC.
Method
Pts registered in the Karmanos Cancer Institute Tumor Registry diagnosed with an IPLC between 2000 and 2017 were included in this study. Pts with an IPLC who later developed a SPLC were matched for age, histology and stage to pts with an IPLC who did not develop a SPLC. SPLC was defined as a second lung cancer with a different pathology or if the same pathology, anatomically, molecularly, or chronologically distinct. Six variables including: stage at IPLC, histology, family history, surgery as a primary treatment for IPLC, and smoking history (determined by pack years, and continued tobacco use after first diagnosis) were reviewed. Logistic and Cox regression analyses were performed to determine the relationship of these characteristics with the development of a SPLC, and their association with overall survival (OS).
Result
121 pts with IPLC who later developed an SPLC were identified and compared to 120 pts with IPLC who did not develop a SPLC. Logistic regression analyses did not show that stage at first diagnosis, histology, family history, smoking history, and continued tobacco use after first diagnosis to be relevant for increased risk of SPLC (Table 1). Pts who were primarily treated with surgical resection had a significantly higher probability of developing a SPLC (Odds Ratio, 0.24; 95% CI, 0.12 to 0.48; p<0.001, see Table 1). Pts who did not have surgical resection as their primary mode of treatment for IPLC had a significantly higher hazard of death than those who received surgical resection (Hazard Ratio, 3.02; 95% CI, 1.99 to 4.57; p<0.001).
Conclusion
Based on our findings, pts who had surgical resection for an IPLC were found to have improved OS and a higher possibility of developing a SPLC. Stage at first diagnosis of IPLC, histology, family history, smoking history and continued use of tobacco after first diagnosis did not correlate with increased risk for SPLC. These results warrant further investigation and if confirmed could have an impact on surveillance recommendations post resection of initial lung cancers.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-100 - Spectrum of EGFR Exon 20 Insertion Mutations and Co-Occurring Genetic Alterations in Patients with Non-Small-Cell Lung Cancer (ID 2538)
10:15 - 18:15 | Author(s): Hirva Mamdani
- Abstract
Background
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are associated with a low response rate to approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) and short progression-free survival. Pre-clinical studies have shown differences in the affinity of EGFR exon 20 insertion mutations for EGFR-TKIs, suggesting that the location of the insertion within the C-helix may play an important role in determining EGFR-TKI sensitivity. Several EGFR-TKIs designed to target EGFR exon 20 insertion mutations are in clinical development. Comprehensive genomic profiling has allowed for identification of co-occurring genomic alterations, which may help us identify additional pathways that may drive disease progression and drug resistance.
Method
Formalin-fixed paraffin-embedded (FFPE) samples from patients with non-small cell lung cancer (NSCLC) were profiled by targeted next-generation sequencing (NGS) using Caris Molecular Intelligence (Caris Life Sciences, Phoenix, AZ). Mutations and copy number variations (CNV) were assessed for each gene included in the NGS panel. Gene amplification (including low amplifications) was defined as gene copy number ≥ 4 and copy number loss as gene copy number < -1.4.
Result
Among the 1,556 patients with EGFR mutations, 104 (6.7%) patients were found to harbor an EGFR exon 20 insertion mutation. There were 70 (67.3%) females and 34 (32.7%) males with a mean age 62 (± 11.5 years). 61 (58.7%) samples came from primary lung sites and 43 samples (41.3%) came from metastatic sites. The main histological types were: adenocarcinoma 89 (85.5%), acinar adenocarcinoma 6 (5.7%), papillary adenocarcinoma 5 (4.8%), adenocarcinoma with bronchoalveolar features 1 (1%), squamous cell carcinoma 1 (1%) and carcinoma not otherwise specified 2 (2%). The most common exon 20 insertion mutation was A767_V769dup (25%), followed by S768_D770dup (13%), H773_V774insAH (5%) and H773dup (5%). The most common pathogenic mutations (including presumed pathogenic) included TP53 (51%), followed by CTNNB1 (6%), PIK3CA (4%), PTEN (3%), SMAD4 (3%), and CHEK2 (2%). Of the 104 cases, CNVs were available from 54 patients. Among these patients, commonly amplified genes included CDK4 (11%), EGFR (9%), MDM2 (9%), FOXA1 (7%), and HMGA2 (6%). Copy number loss was observed with CDKN2A (7%), CTNNB1 (2%), ATR (2%), BRCA2 (2%), and FANCL (2%).
Conclusion
The diverse spectrum of EGFR exon 20 insertion mutations shows molecular heterogeneity of this rare type of EGFR mutations. The presence of co-occurring genomic alterations that may promote tumor progression and drug resistance suggests that combination approaches may be necessary to overcome resistance to EGFR-TKI therapy in some patients with an EGFR exon 20 insertion mutation.
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P2.01-29 - The Correlation Between K-Ras Mutant Subsets with TP53 Mutation and PD-L1 in Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2756)
10:15 - 18:15 | Author(s): Hirva Mamdani
- Abstract
Background
Despite its role in non-small cell lung cancer (NSCLC), K-ras gene mutations are considered is a non-targetable with no established predictive value. And so far, programmed death ligand-1 (PD-L1) is the only approved predictive marker for immunotherapy in NSCLC patients and has been associated with smoking, while TP53 mutations has been linked to neoplasms with aggressive nature. Meanwhile, K-ras mutation has been identified with smoking and linked to aggressive NSCLC. Accordingly, we hypothesized that k-ras mutant NSCLC has higher PD-L1 expression which suggests an improved response to immunotherapy in these patients.
Method
The CARIS database from 2016 - 2018 was queried and patients with NSCLC were identified. PD-L1 antibody 22c3 ≥1% was considered positive. PD-L1 expression as well as k-ras and TP53 mutation status were analyzed and correlation between different variables were identified using ANOVA.
Result
Table 1: showing the percentage expression of PD-L1 in each K-ras mutation subtype K-ras mutation sub-type PD-L1 negative (n,%) PD-L1 positive (n,%) Total (n,%) G12V 205 (20.8%)
239 (18%) 444 (19.2%) G12D 142 (14.4%) 194 (14.6%) 336 (14.5%) G12A 56 (5.7%) 72 (5.4%) 128 (5.5%) G12C 337 (34.2%) 566 (42.7%) 903(39.1%) G13C 51 (5.2%) 46 (3.5%) 97 (4.2%) Q6H 54 (5.5%) 67 (5.1%) 121 (5.2%) G12R 18 (1.8%) 18 (1.4%) 36 (1.6%) G12S 18 (1.8%) 16 (1.2%) 34 (1.5%) Non-Specified 104 (10.6%) 108 (8.1%) 212 (9.2%) Total 985 (100%) 1326 (100%) 2311 (100%) We identified 8,471 patients with NSCLC. TP53 mutation was detected in 66% where k-ras mutation in 26.9%. Combined K-ras and TP53 mutations was detected in 12% where 71.48% were PD-L1 positive in this combined category. There was female predominance with a female to male ratio of 1.4:1. We looked for the eight main K-ras mutation subsets and G12C was the most common identified mutation. G12C was associated with a higher occurrence of PD-L1 positivity (42.7%), followed by G12V (18.0%) with a significant difference in PD-L1 expression among K-ras mutations subtypes with P value of 0.004. (table 1). PD-L1 expression in wild type K-ras tumors was 69.4% and although high, wild type K-ras cases showed higher percentage of PD-L1 expression negativity (76.2%).
Conclusion
Patients with G12C, amongst other k-ras mutation subsets, have higher occurrence of PD-L1 expression which is suggestive of improved response to immunotherapy. The subset of combined K-ras and p-53 mutations showed 71.48% positive PD-L1 expression.
