Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20618-e20618
Author(s):  
Bo Yang ◽  
Yaping Long ◽  
Yi Hu
Keyword(s):  
Egfr Mutation ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Combination Group ◽  
Metastatic Nsclc ◽  
Number Of Patients ◽  
Grade 3 ◽  
Egfr Mutant ◽  
Nsclc Patients

e20618 Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.

scholarly journals Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

2020 ◽  
Author(s):  
Qianqian Wang ◽  
Wen Gao ◽  
Fangyan Gao ◽  
Shidai Jin ◽  
Tianyu Qu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Small Cell ◽  
Combination Group ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Circulating tumor cells and T790M in metastatic non-small cell lung cancer patients with EGFR mutations and acquired resistance to TKI.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18127-e18127
Author(s):  
Kazutoshi Isobe ◽  
Yoshinobu Hata ◽  
Keita Sato ◽  
Keishi Sugino ◽  
Go Sano ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Acquired Resistance ◽  
Stage Iv ◽  
Distant Metastases ◽  
Egfr Mutations ◽  
Cellsearch System ◽  
Metastatic Nsclc ◽  
Nsclc Patients ◽  
Egfr Tki

e18127 Background: This study assessed correlations between the presence of circulating tumor cells (CTCs), detection of T790M in organs with metastases or circulating-free DNA (cfDNA), and prognosis in metastatic NSCLC patients with acquired resistance to EGFR-TKI. Methods: Metastatic NSCLC patients with activating EGFR mutations, who initially responded but subsequently experienced disease progression while on EGFR-TKI treatment, were defined as having ‘acquired resistance’. Blood samples were collected after development of such acquired resistance and CTCs were counted using the CellSearch system (Veridex). At the same time, T790M in affected organs or cfDNA was analyzed with cycleave real-time PCR assay and fragment analysis. Results: : Six men and 14 women with a mean age of 63.5 yrs (22-84) were enrolled. Histological subtypes were adenocarcinoma in 19 and squamous cell carcinoma in the remaining one. Clinical stages were stage IV in 14 and recurrence with distant metastases after surgical resection in 6. EGFR mutations in tumors at the primary site were G719C in 1, exon 19 deletion in 7, L858R in 10, and G791C + L858R in 2. CTCs were detected in 8 (40%). Numbers of CTCs (per 7.5 ml blood) were 1 in 4 cases, and 3, 4, 8, and 24 in 1 case each. Patients without CTCs survived significantly longer than those with CTCs (≥1 per 7.5 ml). Mean survival time from first detection of CTCs was 3.0 months in patients with CTCs and not reached in patients without CTCs (p < 0.001). T790M was detected in 6 cases (30%). T790M was found in 75% (n = 6/8) of patients without CTCs but in 0% (n = 0/12) of those with CTCs (p < 0.05). Conclusions: The presence of CTCs was correlated with poorly prognosis and lack of T790M in affected organs or cfDNA. The presence of CTCs was informative for distinguishing patients with or without T790M.

EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18035-e18035
Author(s):  
Zhijie Wang ◽  
Jie Wang ◽  
Yi Long Wu ◽  
Hua Bai ◽  
Xu-Chao Zhang ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Alk Rearrangement ◽  
Mutant Type ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki

e18035 Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.

scholarly journals Front-Line ICI-Based Combination Therapy Post-TKI Resistance May Improve Survival in NSCLC Patients With EGFR Mutation

2021 ◽  
Vol 11 ◽  
Author(s):  
Tian Tian ◽  
Min Yu ◽  
Juan Li ◽  
Maoqiong Jiang ◽  
Daiyuan Ma ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Egfr Mutation ◽  
Objective Response ◽  
Progression Free Survival ◽  
Influential Factors ◽  
Front Line ◽  
Free Survival ◽  
Tki Resistance ◽  
Egfr Mutant ◽  
Nsclc Patients

BackgroundData on the use of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation are limited. The current study aimed to assess the efficacy of ICIs in EGFR-mutant advanced NSCLC and explore the relevant influential factors.Materials and MethodsRelevant clinical data of EGFR-mutant NSCLC patients who had received ICIs were collected from multiple hospitals. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and relevant influential factors.ResultsA total of 122 advanced EGFR-mutant NSCLC patients were included in the final analysis. The total cohort had an objective response rate (ORR) of 32.0%, a median progression-free survival (mPFS) of 5.0 months, and a median overall survival (mOS) of 14.4 months. Among 96 patients with common EGFR mutations (19Del, 52 patients; L858R, 44 patients), those who were administered front-line ICI exhibited better survival benefits than those who received later-line ICI after disease progression on tyrosine kinase inhibitors (TKIs) treatment (mPFS: 7.2 months vs. 3.4 months, respectively, P &lt; 0.0001; mOS: 15.1 months vs. 8.4 months, respectively, P &lt;0.0001). Moreover, the efficacy of ICI-based combination therapy was better than that of ICI monotherapy (mPFS: 5.0 months vs. 2.2 months, respectively, P = 0.002; mOS: 14.4 months vs. 7.0 months, respectively, P = 0.001). Multivariate analysis showed that ICI-based combination therapy and front-line ICI administration after progression on EGFR-TKI were associated with significant improvements in both PFS and OS (P &lt; 0.05). A high PD-L1 expression (tumor proportion score, TPS≥50%) and the EGFR L858R mutation were only significantly associated with a better PFS (P &lt;0.05). A better Eastern Cooperative Oncology Group (ECOG) status was independently associated with a favorable OS (P &lt;0.05).ConclusionsTaken together, combination immunotherapy in front-line was associated with improvement of survival in EGFR-mutant NSCLC patients post-TKI resistance. Further prospective studies with large sample sizes are required to identify the optimal combinatorial treatment strategy.

scholarly journals Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance

2022 ◽  
Vol 12 ◽  
Author(s):  
Qingli Cui ◽  
Yanhui Hu ◽  
Qingan Cui ◽  
Daoyuan Wu ◽  
Yuefeng Mao ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Vegf Inhibitors ◽  
Clinical Benefits ◽  
Grade 3 ◽  
Egfr Mutant

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non–small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252–0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266–0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

NGR-hTNF plus chemotherapy as first-line therapy of non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7581-7581
Author(s):  
Vanesa Gregorc ◽  
Nicoletta Zilembo ◽  
Francesco Grossi ◽  
Tommaso M De Pas ◽  
Gilda Rossoni ◽  
...  
Keyword(s):  
Human Tumor ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line Therapy ◽  
Phase 2 Trial ◽  
Younger Age ◽  
Common Grade ◽  
Study Population ◽  
Grade 3 ◽  
Nsclc Patients

7581 Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is a selective vascular targeting agent able to improve intratumoral chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC patients (pts), stratified by histology (nonsquamous or squamous) and PS (0 or 1), were randomized to cisplatin 80 mg/m2/day(d)1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or without (arm B) NGR-hTNF 0.8 μg/m2/d1 q3w until progression. Progression free survival (PFS) was primary end point of this phase 2 trial (β=20%, α=20%, HR=0.62, and n=102). Secondary end points included adverse events (AEs), response rate (RR) and overall survival (OS). Results: 59 pts were assigned to arm A and 57 to arm B. Baseline characteristics in arm A/B were: median age 62/63; male 34/37; PS 1 21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group, 88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue 7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to NGR-hTNF or bleeding in pts with squamous histology were noted. Median follow-up was 12.4 months. In the whole study population, median (m)PFS was 5.8 vs 5.7 months (HR=0.95), RR was 23% vs 19%, and 1-year OS was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset, a trend toward longer mPFS in arm A compared to arm B was noted in pts with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs 3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the squamous subset, mPFS was 5.1 vs 3.9 months (HR=0.71) and mOS was 14.2 vs 10.8 months (HR=0.73) in arm A and B, respectively. In these pts, ORR was 36% in arm A and 23% in arm B, while median changes from baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and -41%, respectively in arm A, and -18%, -22%, and -14%, respectively in arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given with standard chemotherapy, showing tolerability and hint of activity in squamous NSCLC.

Nazartinib (EGF816) in patients with treatment-naïve EGFR-mutant non-small cell lung cancer (NSCLC): Updated phase II results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9574-9574
Author(s):  
Daniel Shao-Weng Tan ◽  
Natasha B. Leighl ◽  
James Chih-Hsin Yang ◽  
Gregory J. Riely ◽  
Lecia V. Sequist ◽  
...  
Keyword(s):  
Phase Ii ◽  
Safety Profile ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Maculopapular Rash ◽  
Egfr Mutations ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Egfr Mutant

9574 Background: Prior data from a phase I/II study showed durable responses, including efficacy in brain lesions, and a tolerable safety profile with nazartinib in treatment (tx)-naïve patients (pts) with EGFR-mutant (mut), locally advanced (adv)/metastatic NSCLC. Here we report updated phase II results, including overall survival (OS). Methods: Tx-naïve adult pts with activating EGFR-mut (L858R or ex19del), stage IIIB/IV adv NSCLC with neurologically stable and controlled brain metastasis (BM) received oral nazartinib 150 mg once daily (continuous schedule). Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1; secondary endpoints: disease control rate (DCR), duration of response (DOR), time to response, progression-free survival (PFS), OS, and safety. Results: At data cut-off (Nov 1, 2019), 45 pts were enrolled (median [range] age: 64 [28–83] years; 26 pts [58%] ECOG PS 1; 18 pts [40%] had baseline BM). EGFR mutations: 56% ex19del, 40% L858R, 4% other. 26/45 pts (58%) discontinued tx, with the primary reason being progressive disease in 19 pts (42%); 2 pts (4%) discontinued tx due to AEs. Median (range) follow-up for OS: 25 (0–33) months (mo); and for PFS: 17 (0–33) mo. ORR by BIRC: 69%; median PFS by BIRC: 18 mo; median OS was NE and at 33 mo, 56% of pts were alive (Table). BIRC results by baseline BM are shown in the Table. Median (range) duration of exposure: 24 (0–34) mo. Most frequent AEs (≥20% all grade, all causality): diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough and stomatitis (27% each), decreased appetite and pruritus (24% each), and dermatitis acneiform (22%). Most frequent grade 3/4 AEs (≥10%, all causality): maculopapular rash (5 pts [11%]; all grade 3) and increased lipase (5 pts [11%]; 1 pt with grade 4; no clinical pancreatitis AE was observed). Conclusions: After additional follow-up, median OS was still not reached and the safety profile was manageable. Nazartinib is a promising 3rd generation EGFR TKI for tx-naïve pts with adv EGFR-mut NSCLC, including pts with baseline BM. Clinical trial information: NCT02108964 . [Table: see text]

First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients with EGFR-mutant lung cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7530-7530 ◽  
Author(s):  
Mark G. Kris ◽  
Tony Mok ◽  
Sai-Hong Ignatius Ou ◽  
Renato Martins ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Open Label ◽  
Lung Cancers ◽  
Egfr Mutant ◽  
Exon 19

7530 Background: Dacomitinib irreversibly inhibits EGFR, HER2 and HER4, and showed superior activity vs. reversible EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer models, including resistant forms. This open-label Phase II study evaluates dacomitinib as 1st-line treatment (tx) for patients (pts) with lung cancers. Pts with sensitizing EGFR deletions/mutations in exons 19 or 21 are reported here. Methods: Pts had stage IIIB/IV adenocarcinoma, no prior systemic tx, had smoked <10 pack years (none within 15 years of enrollment) or had known EGFR mutation. Pts received dacomitinib orally once daily continuously at 45 mg, or 30 mg with the option to escalate to 45 mg; evaluation was every 28 days. Endpoints included progression-free survival rate at 4 months (PFS at 4M, primary); PFS, and partial response (PR) rate. Results: 92 pts enrolled; 47 had EGFR mutation in exons 19 (n=25) or 21 (n=22), 33 were female and 27 Asian. 34/46 evaluable pts with EGFR exon 19 or 21 mutations had a PR (PR rate = 74%; 95% CI: 59–86; exon 19 = 72%; exon 21 = 76%). PR rates and preliminary PFS were not significantly different for exons 19 and 21. Preliminary PFS at 4M was 96% (95% CI: 84–99), preliminary PFS rate at 1 year was 77% (95% CI: 61–87) and preliminary median PFS was 17 months (95% CI: 13–24). Median tx duration was 13.1 months. For pts with EGFR wild-type lung cancers, PR and PFS at 4M rates were 7% (n=14; 95% CI: 0–34) and 33% (n=14; 95% CI: 11–58), respectively, and for pts with EGFR unknown lung cancers, 46% (n=22; 95% CI: 24–68) and 68% (n=24; 95% CI: 45– 83), respectively. 7 pts had lung cancers with non-sensitizing EGFR mutations; 2 had a PR and 3 SD. For all 92 pts, common side effects included dermatitis acneiform (grade 3/4 = 17%/0) and diarrhea (14%/0). 3/46 pts with EGFR exon 19 or 21 mutations discontinued tx due to drug-related toxicity. Conclusions: 74% of pts in this cohort with EGFR exon 19 or 21 mutant lung cancers experienced PRs with 1st-line dacomitinib; preliminary PFS rate was 77% at 1 year; preliminary median PFS was 17 months; further research is planned in this pt population. As dacomitinib is well tolerated, with preclinical activity against HER2, a cohort of pts with HER2 mutant lung cancers is recruiting.

Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7525-7525 ◽  
Author(s):  
Stephanie Heon ◽  
Mizuki Nishino ◽  
Sarah B. Goldberg ◽  
Jennifer Porter ◽  
Lecia V. Sequist ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Acquired Resistance ◽  
Egfr Mutations ◽  
Free Interval ◽  
Egfr Mutant ◽  
The Impact ◽  
Drug Free ◽  
Egfr Tki

7525 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Anecdotal and retrospective reports suggest that EGFR-TKI resistant cancers can respond again to gefitinib or erlotinib after an interval off the TKI. This retrospective study was undertaken to investigate the impact of EGFR-TKI retreatment after a drug-free interval in EGFR mutant NSCLC with acquired resistance to gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at the DFCI/MGH between 8/00 and 8/11 who were retreated with single agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified from a prospective trial. The objective tumor response (CR, PR, SD, PD) was determined using RECIST 1.1. Results: 19 pts were eligible and had adequate scans for radiographic assessments after the reinstitution of an EGFR-TKI. The response rate and median PFS to the initial course of gefitinib (n=4) or erlotinib (n=15) were 16/19 (84%) and 9.8 months (95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 1 to 4 intervening systemic regimens. The median interval from EGFR-TKI discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 (74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without progression for 6 months. 3 pts had their tumors rebiopsied before (n=2) or during (n=1) erlotinib retreatment; 1 of the 3 had EGFR T790M in association with the initial sensitizing EGFR mutation, and another had a secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib retreatment is an option for EGFR mutated NSCLC with acquired resistance to EGFR-TKI after a drug-free interval and progression on intervening therapy. Additional advanced NSCLC pts without a documented EGFR mutation who fulfill the clinical definition of acquired resistance are undergoing review to expand our cohort.

TGFb expression as predictor of outcome in EGFR wild type (WT) metastatic non-small cell lung cancer (NSCLC) patients (PTS) treated with EGFR tyrosine kinase inhibitors (TKIs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18104-e18104
Author(s):  
Giovanna Finocchiaro ◽  
Luca Toschi ◽  
Letizia Gianoncelli ◽  
Barbara Canal ◽  
Luca Rubino ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Staining Intensity ◽  
Egfr Mutations ◽  
Study Cohort ◽  
Intrinsic Resistance ◽  
Alk Rearrangement ◽  
Primary Resistance ◽  
Metastatic Nsclc ◽  
Nsclc Patients

e18104 Background: Gefitinib and erlotinib have shown to be highly effective in pts harboring EGFR mutations, while the majority of EGFR wt pts does not respond to treatment.Preclinical data suggested that TGFb and HGF could affect response to TKIs. Aim of the present study is to investigate molecular predictors for primary resistance to TKIs in metastatic NSCLC pts. Methods: This retrospective study included 120 metastatic NSCLC patients treated with gefitinib (68/56.7%) or erlotinib (52/43.3%) in first line (20/16.7%) or after prior chemotherapy (100/83.4%) with at least one measurable lesion and availability of paraffin-embedded tumour tissue from primary cancer. Analyses included presence of mutations in EGFR and KRAS genes, assessment of ALK rearrangement by fluorescence in situ hybridization (FISH) and protein expression of HGF and TGFb by immunohistochemistry (IHC). Pts were grouped in IHC+ and IHC- according to staining intensity. Results: In the whole study cohort response rate (RR) was 9.2%, median progression free survival (PFS) 2.5 months, and overall survival (OS) 7.8 months. EGFR mutations were observed in 9.2% of pts and were significantly associated with better pts outcome. KRAS was mutated in 23.3% of pts without any correlation with clinical end points. ALK translocations were observed in 5 pts (4.2%), and none responded to treatment. IHC was successfully performed for HGF and TGFb in 95 and 75 pts respectively. No difference was seen in HGF+ (9/9.5%) vs HGF- pts in terms of RR, PFS and OS. TGFb+ pts (41/54.7%) had a significantly shorter OS than TGFb- pts (6.7 vs 10.3 months, p=0.020) although no difference in terms of RR and PFS was observed. When restricting survival analysis to EGFR wt/KRAS wt pts (n=80) TGFb+ subjects had a significantly worse PFS (1.9 vs 2.9 months, HR 2.16, CI 95% 1.18;3.95, p=0.013) and OS (5.3 vs 8.8 months, HR 2.07, CI 95% 1.10;3.91, p=0.025) when compared with the TGFb- group. Conclusions: Overexpression of TGFb is associated with a poor outcome in EGFR and KRAS wt pts treated with gefitinb or erlotinib. Prospective validation of the role of TGFb as a mediator of intrinsic resistance to EGFR TKIs in NSCLC is warranted.

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