Mutant Advanced Non-small Cell Lung Cancer Research Articles

Efficacy of nivolumab in comparison to chemotherapy and gefitinib for advanced NSCLC

Background: Lung cancer is one of the major causes of cancer related death worldwide, while non-small cell lung cancer (NSCLC) consists of 85% of all lung cancer cases. Despite adequate treatment, most of the NSCLC patients progress to advance stages. Single or doublet-chemotherapy are considered as standard care for advance NSCLC patients. Gefitinib is considered as standard therapy for EGFR mutant advanced NSCLC. Recently, a human monoclonal antibody called Nivolumab has shown encouraging efficacy for advanced NSCLC patients. The aim of this systematic review is to show the efficacy of nivolumab in comparison to single or doublet chemotherapy and gefitinib. Method: A systematic search was performed in PubMed, Google Scholar and Cochrane Library to identify primary research, published in English language between 2000 and 2018, involving Nivolumab, chemotherapy and gefitinib for advanced NSCLC patients. The primary outcome of interest was median overall survival (mOS). The secondary outcome of interest were progression free survival, objective response rate and grade-3 and treatment related adverse effects. Results: After screening 600 full-text articles, 17 clinical studies involving 9284 patients of advanced NSCLC were included. All treatment regimen seemed to be feasible. The mOS for nivolumab was ranging between 9.2 months and 16.2 months; for chemotherapy between 6 months and 18.8 months; and for gefitinib between 7.6 months and 30.5 months. Conclusion: Nivolumab is more effective and safe for EGFR non-mutant advanced NSCLC patients than either chemotherapy or gefitinib. However, gefitinib is more effective than nivolumab for EGFR-mutant NSCLC patients. J Bangladesh Coll Phys Surg 2024; 42: 176-188

Sotorasib in KRASp.G12C mutated advanced NSCLC: Real-world data from the Italian expanded access program

BackgroundSotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C–mutated advanced non–small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP). MethodsSotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed. ResultsA total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33–86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4–7.0). Median PFS and OS were 5.8 months (95 % CI: 5 – 6.5) and 8.2 months (95 % CI: 6.3 – 9.9). Grade 3–4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases. ConclusionReal-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients.

Efficacy of Osimertinib Continuation Plus Metronomic Oral Vinorelbine for EGFRmutant Advanced NSCLC Beyond Limited Progression on Osimertinib.

Treatment options for advanced non-small-cell lung cancer (NSCLC) after osimertinib failure are limited, and osimertinib continuation is recommended for selected patients. Metronomic oral vinorelbine is an effective treatment with less toxicity for advanced NSCLC. The objective of the study was to investigate the effects of osimertinib plus metronomic oral vinorelbine on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC beyond limited progression on osimertinib. We have reviewed the medical records of 28 patients with EGFR-mutant advanced NSCLC who had received osimertinib continuation plus metronomic oral vinorelbine beyond limited progression on osimertinib. We also evaluated the clinicopathological characteristics of enrolled patients, as well as the efficacy and toxicity of the treatment. After a median follow-up period of 14.1 months, 57.1% (16/28) of cases showed NSCLC progression. The median progression-free survival (PFS) period under osimertinib plus metronomic oral vinorelbine was 9.4 months (95% confidence interval, 1.562-17.238 months), with a disease control rate of 89.3% and objective response rate of 17.9%. PFS did not differ between patients who had previously received osimertinib as first- (n = 16) and second-line (n = 12) therapy (median, 11.4 and 4.7 months, P = 0.391). In addition, the median PFS duration did not differ according to the efficacy (PFS2 ≥ 6 months vs. <6 months) of previous osimertinib monotherapy (median, 5.8 and 9.4 months, P = 0.677). Osimertinib continuation in conjunction with metronomic oral vinorelbine may enable overcoming TKI resistance and prolong the survival of patients with EGFR-mutant advanced NSCLC beyond limited progression on osimertinib treatment.

Prediction Model for Tumor Volume Nadir in EGFR -mutant NSCLC Patients Treated With EGFR Tyrosine Kinase Inhibitors.

In patients with advanced non-small cell lung cancer (NSCLC) and oncogenic driver mutations treated with effective targeted therapy, a characteristic pattern of tumor volume dynamics with an initial regression, nadir, and subsequent regrowth is observed on serial computed tomography (CT) scans. We developed and validated a linear model to predict the tumor volume nadir in EGFR -mutant advanced NSCLC patients treated with EGFR tyrosine kinase inhibitors (TKI). Patients with EGFR -mutant advanced NSCLC treated with EGFR-TKI as their first EGFR-directed therapy were studied for CT tumor volume kinetics during therapy, using a previously validated CT tumor measurement technique. A linear regression model was built to predict tumor volume nadir in a training cohort of 34 patients, and then was validated in an independent cohort of 84 patients. The linear model for tumor nadir prediction was obtained in the training cohort of 34 patients, which utilizes the baseline tumor volume before initiating therapy (V 0 ) to predict the volume decrease (mm 3 ) when the nadir volume (V p ) was reached: V 0 -V p =0.717×V 0 -1347 ( P =2×10 -16 ; R2 =0.916). The model was tested in the validation cohort, resulting in the R2 value of 0.953, indicating that the prediction model generalizes well to another cohort of EGFR -mutant patients treated with EGFR-TKI. Clinical variables were not significant predictors of tumor volume nadir. The linear model was built to predict the tumor volume nadir in EGFR -mutant advanced NSCLC patients treated with EGFR-TKIs, which provide an important metrics in treatment monitoring and therapeutic decisions at nadir such as additional local abrasive therapy.

1226P Efficacy and safety of Anti-EGFR TKIs combined with bevacizumab or ramucirumab in the first-line treatment of non-small cell lung cancer: Meta-analysis of randomized controlled trials

Anti-EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy in the first-line treatment of EGFR mutant non-small cell lung cancer (NSCLC). It was aimed to increase the efficacy by adding anti-angiogenic antibodies to these agents, and several randomized controlled trials (RCTs)have been conducted in this area in recent years. Here, we performed an efficacy and safety analysis of RCTs investigating the addition of bevacizumab or ramucirumab to EGFR-TKIs in EGFR mutant advanced NSCLC.

Anti PD-(L)1 in KRAS mutant advanced nsclcs: A meta-analysis of randomized controlled trials.

9025 Background: KRAS comprise the most frequently found oncogene driver mutation in non-small cell lung cancer (NSCLC), accounting for 20-25% of these patients. Single-agent Anti PD-(L)1 clinical efficacy against KRAS mutant NSCLC is a topic of debate. Methods: This meta-analysis examined randomized-trial data comparing first-or second line Anti PD-(L)1 +/- chemotherapy (CT) vs CT alone for KRAS mutant advanced NSCLCs. Outcome measures included overall survival (OS) and progression-free survival (PFS). Analyses were computed using the Cochrane method of collaboration for meta-analyses, with Review Manager software (RevMan version 5.3; Oxford, UK). Results: We analyzed 3 trials in first line (IMPOWER-150, KEYNOTE-189 and KEYNOTE-042), as well as 3 trials in second line (OAK, POPLAR and CHECKMATE-057) including 1313 NSCLCs (386 KRAS mutant and 927 KRAS wild-type tumor). Anti PD-(L)1 +/- CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS (0.59 [0.49-0.72]; p &lt; 0.00001) and PFS (0.58 [0.43-0.78]; p = 0.0003) compared to CT alone in KRAS mutant NSCLCs. Survival benefits occured in both first and second line. Survival benefits observed in KRAS wild-type NSCLCs were (0.87 [0.76-0.99]; p = 0.03) and (0.79 [0.56-1.11]; p = 0.17) respectively. OS benefit in KRAS mutant was significantly superior compared to OS benefit in KRAS wild-type (p = 0,001). Conclusions: Anti PD-(L)1 (+/- CT) appears superior to CT alone both for mutant and wild-type KRAS in advanced NSCLCs for OS and PFS with higher magnitude of benefit in KRAS mutated group for OS.

P90.02 BRAF Mutation And Peridiagnosis Thromboembolic Events In Advanced NSCLC Patients

Metastatic lung cancer is associated with an increased risk of thromboembolic events (TEE). Certain molecular subtypes of lung cancer, as patients with tumors harboring ALK or ROS1 gene rearrangements, have been recently associated with higher risk of TEE, in the range of 20-30%. Whether BRAF mutant lung cancer is associated with higher risk of TEE is unknown. We aimed to describe the incidence, characteristics, and time of onset of TEE in advanced BRAF mutant non-small-cell lung cancer (NSCLC) patients. We performed a retrospective search of BRAF mutant advanced NSCLC patients (stage IIIB or greater) diagnosed in our institution between October 2016 and February 2020. BRAF status was assessed by NGS in tissue/plasma or both as part of molecular pre-screening for clinical trials (Oncomine Focus Assay®; FoundationOne®; Guardant360®). Clinicopathologic and molecular data were extracted from electronic medical records. BRAF mutations were annotated and divided into Class I (V600) and Class II/III/VUS (non-V600) using OncoKB database. Venous TEE (deep venous thrombosis [DVT], superficial venous thrombosis [SVT] or pulmonary embolism [PE]) and arterial TEE (myocardial infarction [MI], cerebrovascular accident [CVA], peripheral arterial disease [PAD] or mesenteric ischemia [MIS]), number of events and dates were annotated. BRAF mutation was identified in 11/192 patients (incidence 5.7%): BRAF V600E in 2 cases (1%), and non-V600 in 9 cases (4.7%). Adenocarcinoma was the histology for all the cases. The incidence rate of TEE was 36.4% (4/11 patients). A total of 9 TEE were documented among 4 patients, as 3 of them developed several events, both arterial and venous. The TEE were DVT (n=2), SVT (n=1), PE (n=2), CVA (n=3), MIS (n=1). TEE was the form of disease presentation in 3/4 cases (acute stroke in 2 cases). TEE were found in 1 patient with V600E mutation and in 3 with non-V600. TEE were found more frequently in patients with PS ≥1, low albumin and Khorana score ≥2. Type of treatment was not related to TEE: 1 patient BRAF V600E mutated was treated with dabrafenib + trametinib without TEE, 4 patients were treated with immune-checkpoint inhibitors (1 with TEE) and 2 cases of TEE were detected before the initiation of treatment. Median overall survival was shorter in patients with TEE vs. without-TEE: 2.3 months vs 29 months (p=0.047). BRAF mutant lung cancer could be associated with a higher risk of TEE, both arterial and venous, and worse survival. If these results are confirmed in larger cohorts, prophylactic anticoagulation may be recommended in these patients.

MO01.32 CodeBreaK 200: A Phase 3 Multicenter Study of Sotorasib, a KRAS(G12C) Inhibitor, versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS p.G12C Mutation

Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation is an oncogenic driver mutation that occurs in approximately 13% of NSCLC and is often associated with poor prognosis. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRAS(G12C) by locking it in its inactive GDP-bound state. Results from the first-in-human trial of sotorasib (CodeBreak 100, NCT03600883) demonstrated a favorable safety profile and promising and durable antitumor activity in patients with KRAS p.G12C mutant advanced NSCLC.

CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on epidermal growth factor receptor mutant non-small cell lung cancer in vitro and in vivo.

BackgroundCM082 is a novel angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR) and platelet‐derived growth factor receptor (PDGFR). The purpose of this research was to evaluate the antitumor activity of CM082 combined with gefitinib on epidermal growth factor receptor (EGFR) mutant non‐small cell lung cancer (NSCLC) in vitro and in vivo.MethodsThe effect of CM082 on human umbilical vein endothelial cells (HUVECs) was assessed. In vitro and in vivo efficacy of CM082 combined with gefitinib on EGFR NSCLC cell lines (HCC827 harboring E746_A750 deletion and H3255 harboring L858R) and a xenograft model was evaluated.ResultsCM082 inhibited VEGF‐induced cell growth, phosphorylation of VEGFR and downstream signaling molecules, tube formation, and cell migration of HUVECs. Furthermore, CM082 combined with gefitinib was more effective in inhibiting growth and colony formation and inducing apoptosis of H3255 and HCC827 cells in vitro than monotherapy. Moreover, tumor growth inhibition by the combination in a H3255 xenograft model was 107.7% more than that by gefitinib (93.6%) (P < 0.0001) and CM082 (51.4%) (P < 0.0001) alone. In addition, coadministration had a better effect on inhibiting cell proliferation, inducing apoptosis, and inhibiting the expression of CD31 and VEGF‐A. The combination therapy had a stronger inhibition effect on STAT3 phosphorylation than monotherapy.ConclusionsCM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on EGFR mutant NSCLC by inhibiting proliferation and angiogenesis and promoting apoptosis of tumor cells.Key points Significant findings of the study CM082, a novel angiogenesis inhibitor, enhances the antitumor activity of gefitinib on EGFR mutant NSCLC by inhibiting proliferation and angiogenesis and promoting apoptosis of tumor cells. What this study adds These findings justify evaluation of the efficacy of CM082 combined with gefitinib in patients with EGFR mutant advanced NSCLC in clinical trials.

Concomitant genetic alterations having greater impact on the clinical benefit of EGFR-TKIs in EGFR-mutant advanced NSCLC than BIM deletion polymorphism.

BackgroundIn previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown.MethodsData from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR‐mutant non‐small cell lung cancer (NSCLC) patients treated with first‐ and second‐generation EGFR‐TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty‐eight patients were treated with third‐generation EGFR‐TKIs in the GLCI cohort. The BIM gene status was examined by next‐generation sequencing.ResultsThe frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first‐ and second‐generation EGFR‐TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild‐type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression‐free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third‐generation EGFR‐TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR‐TKIs, but not BIM deletion.ConclusionsThe presence of BIM deletion showed no relation to an impaired response to first‐, second‐, and third‐generation EGFR‐TKIs in NSCLC patients. The factors influencing the response of EGFR‐TKIs were concomitant genetic alterations, but not BIM deletion.

492P - Feasibility of rebiopsy and sequential treatment of EGFR tyrosine kinase inhibitors in real world patients with EGFR mutant non-small cell lung cancer

BackgroundThe third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is a standard treatment in case of T790M mutation positive after failure to first or second generation EGFR TKI in patients with EGFR-mutant non-small cell lung cancer (NSCLC). We investigated a success rate of rebiopsy and sequential EGFR TKI treatment in real world setting in Korea. MethodsWe retrospectively reviewed medical records of patients with EGFR mutant advanced NSCLC who received first- or second- generation EGFR TKI between Jan 2012 and Jun 2018 at a single center in Korea. ResultsAmong 221 patients with EGFR-mutant NSCLC, 68 patients who were lost to follow up (n = 19) or still on 1st- or 2nd- generation TKI (n = 49) at time of analysis were excluded. Forty-three out of remaining 153 patients (28%) did not have a chance of consideration for second line treatment because of deterioration of performance status (n = 21) or death (n = 22), especially in elderly over 70 years. Tests for acquired EGFR mutation were performed in 76% (84/110), among which 73 cases were tissue rebiopsy and 11 cases were plasma EGFR mutation analysis. Acquisition of tumor tissue in rebiopsy was successful in 93% (68/73). The most common reason of not doing rebiopsy was lack of sequential treatment options (n = 24). Ten patients with negative T790M or failure at initial rebiopsy underwent more than two times of repeated EGFR mutation analysis, among which four patients had eventually positive T790M at some point of disease course. Overall T790M positive rate was 54% (45/84). Among 7 patients with initially negative T790M mutation in plasma analysis, further rebiopsy from tumor tissue was performed only in one patients because of patient's refusal (n = 2), physician's decision to continue post-progression EGFR TKI (n = 2), poor performance status (n = 1), and unaccessibility to tumor tissue (n = 1). ConclusionsAbout 30% of patients with EGFR mutant NSCLC did not have a chance of consideration for second line EGFR TKI treatment, especially in elderly over 70 years. Success rate of tumor tissue rebiopsy was over 90% in real world setting, and repeated rebiopsy may increase detection rate of acquired T790M mutation. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Microwave ablation as local consolidative therapy for patients with extracranial oligometastatic EGFR-mutant non-small cell lung cancer without progression after first-line EGFR-TKIs treatment.

Evidence from multiple clinical trials showed that local consolidative therapy (LCT) improved survival in oligometastatic non-small cell lung cancer (NSCLC) patients. In the present study, we aim to explore the potential role of microwave ablation (MWA) as LCT for epidermal growth factor receptor (EGFR)-mutant advanced NSCLC patients with extracranial oligometastasis. From January 2015 to December 2018, a total of 86 EGFR-mutant stage IIIB or IV NSCLC patients with extracranial oligometastasis were enrolled for retrospective analysis. MWA was used as LCT for all oligometastatic lesions and/or primary tumors in 34 patients without progression after first-line EGFR-TKIs therapy (consolidation group), while the other 52 patients received only TKIs until disease progression (monotherapy group). We calculated and compared the progression-free survival (PFS) and overall survival (OS) of the two groups. Patients with MWA consolidation therapy had significantly improved PFS (median 16.7 vs. 12.9months, HR 0.44, 95% CI 0.22-0.88, P = 0.02) and OS (median: 34.8 vs. 22.7months, HR 0.45, 95% CI 0.24-0.88, P = 0.04) than monotherapy group. MWA for LCT was identified as the independent predictive factor for better PFS (HR 0.46, 95% CI 0.37-0.82, P < 0.01) and OS (HR 0.57, 95% CI 0.33-0.91, P = 0.02). Most toxicities were mild and well tolerated. No patient had to discontinue EGFR-TKIs because of MWA complications. These findings suggest that MWA as local consolidative therapy after first-line EGFR-TKIs treatment leads to better disease control and survival than TKIs monotherapy in EGFR-mutant advanced NSCLC patients with extracranial oligometastasis. MWA as a novel option of LCT might be considered for clinical management of these patients.

&lt;p&gt;Brigatinib for &lt;em&gt;ALK&lt;/em&gt;-positive metastatic non-small-cell lung cancer: design, development and place in therapy&lt;/p&gt;

Despite the benefits of first and second generation anaplastic lymphoma kinase (ALK) inhibitors in the management of ALK-rearranged advanced non-small-cell lung cancer (NSCLC), the development of acquired resistance poses an ongoing dilemma. Brigatinib has demonstrated a wider spectrum of preclinical activity against crizotinib-resistant ALK mutant advanced NSCLC. The current review narrates a brief history of tyrosine kinases, the development and clinical background of brigatinib (including its pharmacology and molecular structure) and its use in ALK-positive NSCLC.

Neutrophil to Lymphocyte Ratio as a Prognostic Factor in European Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitors

Background: A high neutrophil to lymphocyte ratio (NLR) has been associated with adverse outcomes in non-small cell lung cancer (NSCLC). However, information on epidermal growth factor receptor (EGFR)-mutant advanced NSCLC is scarce, and most of the studies published have been conducted in Asian populations. We aimed to assess the influence of pretreatment NLR on progression-free survival (PFS) and overall survival (OS) in Western European patients treated with EGFR tyrosine kinase inhibitors (TKIs). Methods: A retrospective evaluation of 41 patients with EGFR-mutant advanced NSCLC treated with EGFR TKIs between June 2010 and May 2016 was carried out. The association between several prognostic factors including pretreatment NLR and survival was analyzed. Results: Median PFS and OS were 10.58 and 20.84 months, respectively. OS for patients with a high NLR was 7.4 months, compared to 24.6 months for patients with a low NLR (p = 0.0122). In multivariate analysis, poor performance status (ECOG PS ≥ 2) and presence of ≥ 3 metastatic locations were identified as significant independent prognostic factors for worse PFS. For OS, unfavorable prognostic factors were a high NLR and central nervous system metastasis at diagnosis. Conclusion: Pretreatment NLR is an independent prognostic factor for OS in Western European patients with EGFR-mutant NSCLC treated with EGFR TKIs.

Impact of Weight Loss at Presentation on Survival in Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI) Sensitive Mutant Advanced Non-small Cell Lung Cancer (NSCLC) Treated with First-line EGFR-TKI.

Purpose The aim of this study is to evaluate the impact of weight loss at presentation on treatment outcomes of first-line EGFR-tyrosine kinase inhibitors (EGFR-TKI) in EGFR-TKI sensitive mutant NSCLC patients.Methods We retrospectively analyzed the clinical outcomes of 75 consecutive advanced NSCLC patients with EGFR-TKI sensitive mutations (exon 19 deletion or exon 21 L858R) received first-line gefitinib or erlotinib therapy according to weight loss status at presentation in our single center.Results Of 75 EGFR-TKI sensitive mutant NSCLC patients, 49 (65.3%) patients had no weight loss and 26 (34.7%) had weight loss at presentation, the objective response rate (ORR) to EGFR-TKI treatment were similar between the two groups (79.6% vs. 76.9%, p = 0.533). Patients without weight loss at presentation had significantly longer median progression free survival (PFS) (12.4 months vs. 7.6 months; hazard ratio [HR] 0.356, 95% confidence interval [CI] 0.212-0.596, p < 0.001) and overall survival (OS) (28.5 months vs. 20.7 months; HR 0.408, 95% CI 0.215-0.776, p = 0.006) than those with weight loss at presentation; moreover, the stratified analysis by EGFR-TKI sensitive mutation types also found similar trend between these two groups except for OS in EGFR exon 21 L858R mutation patients. Multivariate analysis identified weight loss at presentation and EGFR-TKI sensitive mutation types were independent predictive factors for PFS and OS.Conclusions Weight loss at presentation had a detrimental impact on PFS and OS in EGFR-TKI sensitive mutant advanced NSCLC patients treated with first-line EGFR-TKI. It should be considered as an important factor in the treatment decision or designing of EGFR-TKI clinical trials.

P3.15-014 Case Series of Small Cell Lung Cancer Transformation as Resistance Mechanism to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor

Patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) developed resistance to first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) after 9-13 months and third-generation EGFR-TKI after 10 months, respectively. Small cell lung cancer (SCLC) transformation is a rare resistance mechanism in these patients. Tissue re-biopsy was performed in 35 patients with EGFR mutant advanced NSCLC who failed first-line EGFR-TKI; and 4 patients with acquired T790M mutant advanced NSCLC who failed third-generation EGFR-TKI, to look for SCLC transformation SCLC transformation was identified in 2 out of 35 (5.7%) patients who failed first-line EGFR-TKI and 1 out of 4 (25.0%) patients who failed third-generation EGFR-TKI. The first patient was a 70-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in April 2014. He had partial response (PR) to gefitinib 250 mg daily but developed symptomatic progressive disease (PD) after 26 months. Re-biopsy of his enlarging primary lung lesion showed SCLC transformation. The second patient was a 43-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in November 2015. He had PR to gefitinib 250 mg daily but developed symptomatic PD after 15 months. Re-biopsy of his rapidly enlarging primary lung lesion showed SCLC transformation. His plasma cell-free tumor DNA (cftDNA) was positive for T790M mutation. The third patient was a 62-year-old never-smoker female who was diagnosed with stage IV lung adenocarcinoma harboring exon 21 L858R mutation in November 2015. She had PR to gefitinib 250 mg daily but experienced symptomatic PD after 8 months’ of gefitinib therapy. Re-biopsy of her primary lung tumor revealed the presence of T790M mutation and her treatment was switched to osimertinib 80 mg daily. After an initial PR, she developed PR in the 12th month of osimertinib treatment. Biopsy from a metastatic inguinal lymph node showed SCLC. The first and second patients were given standard SCLC chemotherapy with carboplatin and etoposide but did not respond. The third patient sought treatment in another hospital. Re-biopsy is recommended in all patients with symptomatic PD while on EGFR-TKI treatment. SCLC transformation under the pressure of first, second and third-generation EGFR-TKI is an emerging challenge to the management of advanced NSCLC. Other than conventional carboplatin and etoposide chemotherapy, new treatment strategies should be explored to improve the outcome of patients who develop SCLC transformation.

Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: rationale, evidence and place in therapy.

The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9–14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC.

PL03.05: BRAIN: A Phase III Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201)

Non-small cell lung cancer (NSCLC) with brain metastases (M) had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M. Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events (AEs)(CTCAE v4). From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity. Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).

P3.02b-069 To Assess Efficacy of First Line TKIs in EGFR Mutant Advanced NSCLC Patients from North India: Topic: EGFR Clinical

The reversible EGFR tyrosine kinase inhibitors gefitinib and erlotinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, here is paucity of data on their efficacy from the Indian subcontinent. This is a retrospective analysis including 43 patients. These patients were treated at a tertiary care center in north India. Advanced NSCLC patients (stage IV) having sensitive EGFR mutation who were treated with gefitinib (250 mg per day) or erlotinib (150 mg per day) were analyzed for their outcome. Subgroup analysis by EGFR mutation (18, 19, 20, 21), sex and status according to brain metastasis was also done using SPSS. 43 patients with stage IV non-squamous NSCLC with EGFR sensitive mutation were treated with first line TKI. There were 16 male and 27 female patients with mean age of 62.5 years (ranging from 43 to 85 years). Mean PFS for all the patients on first line TKI was 11.63 months Mean PFS for male patients was 9.93 months and for female patients it was 12.7 month. There were 26 patients with exon 19 deletions and 16 with exon 21 mutation and 1 with exon 18 mutation. Mean PFS in patients with exon 19 deletions was 11.11 months and 10.44 months in patients with exon 21 mutation. Mean PFS in patients on erlotinib was 12.27 months (CI 6.2-18.3) and 11.4 months in patients on gefitinib. Twelve patients (27.9%) out of 43 had brain metastases. PFS of these 12 patients was 10.33 months and 12.08 months for patients without brain metastases. Erlotinib and gefitinib significantly improves PFS in patients with sensitive EGFR mutations. PFS is better in female patients, exon 19 mutation/deletion and without brain metastases in North Indian population.

P3.02b-081 Comparative Outcome Assessment of EGFR TKIs for the Treatment of Advanced Non-Small-Cell Lung Cancer: A Network Meta-Analysis: Topic: EGFR Clinical

Patients with advanced non-small-cell lung cancer (NSCLC) whose tumors harbor activating mutations in the epidermal growth factor receptor (EGFR) gene, derive substantial clinical benefit from treatment with first and second-line EGFR tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib. However, their comparative effectiveness in this setting has not been evaluated, due to the paucity of randomized comparative clinical trials. We performed a comprehensive literature search in PUBMED, EMBASE, SCOPUS and ISI databases for randomized clinical trials evaluating either of the aforementioned EGFR-TKIs in first- and subsequent-lines treatment of EGFR-positive advanced NSCLC. All sensitizing mutations to EGFR-TKI inhibition were included in the current analysis. Patients with active brain metastases, with ECOG performance status of more than 2, as well as trials comparing the combination of EGFR-TKI with chemotherapy to chemotherapy alone were excluded. Comparative study outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and rate of adverse events (AE). Cochrane guidelines were used for statistical analysis. 13 randomized trials incorporating 3,853 patients were eligible for the analysis. In the first-line setting, all EGFR TKIs showed improved outcomes with respect to ORR and PFS when compared to standard platinum-doublet chemotherapy. Comparative ORR rates for gefitinib, erlotinib and afatinib in first-line were 71.5%, 70.2% and 50.1% respectively. HRs for PFS were 0.40 (95% CI: 0.31- 0.50) for gefitinib, 0.25 (0.11-0.56) for erlotinib and 0.40 (0.28-0.57) for afatinib, all three with p<0.001. Respective HRs for OS were 0.89 (0.72-1.10) for Gefitinib, 0.91 (0.76-1.13) for erlotinib and 1.05 (0.88-1.25) for afatinib. No significant differences were detected regarding common AEs (rash, diarrhea) among the three agents. Evidence data for gefitinib were less heterogeneous than those for erlotinib and afatinib. When compared indirectly, gefitinib exhibited the more consistent results from a statistical point of view and erlotinib had the more favorable profile regarding PFS prolongation. These data challenge the current landscape of first and second generation EGFR-TKIs in EGFR mutant advanced NSCLC and especially those of the recently reported LUX-LUNG 7 trial.