Metastatic EGFR-mutant NSCLC Research Articles

PS1-3 RELAY: final overall survival with erlotinib+ramucirumab or placebo in untreated, EGFR-mutated metastatic NSCLC (mNSCLC)

PS1-3 RELAY: final overall survival with erlotinib+ramucirumab or placebo in untreated, EGFR-mutated metastatic NSCLC (mNSCLC)

P1.09C.01 A Multicenter, Randomized, Phase II Trial of EGFR TKI with Primary Tumor Resection for EGFR-Mutant Metastatic NSCLC Patients

P1.09C.01 A Multicenter, Randomized, Phase II Trial of EGFR TKI with Primary Tumor Resection for EGFR-Mutant Metastatic NSCLC Patients

HERTHENA-PanTumor01: A global, multicohort, phase 2 trial of HER3-DXd in relapsed/refractory metastatic solid tumors.

TPS3164 Background: Human epidermal growth factor receptor 3 (HER3) is a member of the HER/EGFR family of receptor tyrosine kinases. HER3 is expressed in numerous solid tumors, including melanoma, head and neck squamous cell cancer (HNSCC), and gastric cancer, and high levels of HER3 expression in multiple tumor types are associated with poor clinical outcomes. HER3-DXd is a potential first-in-class HER3-directed antibody-drug conjugate (ADC) composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a potent topoisomerase I inhibitor payload via a tumor-selective cleavable linker. HER3-DXd has shown antitumor activity and a manageable safety profile in previously treated EGFR-mutated metastatic NSCLC and metastatic breast cancer. Based on clinical data and exposure-response analyses, HER3-DXd 5.6 mg/kg IV every 3 weeks (Q3W) was selected as the monotherapy dose for investigation in new indications. HERTHENA-PanTumor01 (NCT06172478) is a global, multicohort, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of HER3-DXd in previously treated patients (pts) with cutaneous melanoma, HER2-negative gastric cancer, or HNSCC. Methods: Each cohort of HERTHENA-PanTumor01 will enroll 40 pts. Study sites are in Australia, Belgium, France, Japan, South Korea, Spain, Taiwan, the UK, and the US. Key inclusion criteria for melanoma include cutaneous or acral subtype, BRAF–wild-type or -mutant status, and progression on or after ≥1 anti–PD-(L)1 therapy. Key inclusion criteria for HNSCC include HPV+ or negative status and progression after platinum-based chemotherapy (PBC) ± anti–PD-(L)1 therapy; pts with nasopharyngeal cancer are excluded. Key inclusion criteria for gastric or gastroesophageal junction cancer include confirmed HER2-negative tumor status (immunohistochemistry [IHC] 0/1+ or IHC 2+/in situ hybridization negative) and progression after PBC ± anti–PD-(L)1 therapy; pts with HER2+ cancer are excluded. Other key exclusion criteria for all cohorts include any history of, suspected, or current interstitial lung disease; active brain metastases (treated/asymptomatic brain metastases are allowed); or prior treatment with an anti-HER3 antibody and/or ADC containing an exatecan derivative. A fresh biopsy or pretreatment archival biopsy performed since progression on or after treatment with the most recent cancer therapy is required for all cohorts. Pts will be treated with HER3-DXd 5.6 mg/kg IV Q3W; tumor assessments will occur every 6 wks for the first 48 wks, then every 12 wks until disease progression, adverse events, or other discontinuation criteria are met. The primary endpoint for each cohort is ORR by investigator per RECIST version 1.1. Secondary endpoints include safety and tolerability, DOR, DCR, PFS, overall survival, pharmacokinetics, and the correlation between HER3 IHC protein expression and efficacy. Clinical trial information: NCT06172478 .

Characteristics of Long-Term Survivors With EGFR-Mutant Metastatic NSCLC

IntroductionCharacteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. MethodsClinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. ResultsOverall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). ConclusionsWithin patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.

Abstract 5162: Tumor transcriptional identity as a key predictor of clinical outcome in EGFR-Mutant non-small cell lung cancer

Abstract Background: EGFR tyrosine-kinase inhibitors (TKIs) produce significant clinical benefit in patients (pts) harboring EGFR-activating mutations, however, patient outcomes remain heterogeneous, highlighting the need to identify novel biomarkers for treatment response prediction. We aim to investigate the association of tumor transcriptional identity with clinical outcomes in EGFR-mutant NSCLC. Methods: We used consensus classification to derive unsupervised transcriptionally distinct clusters in EGFR-mutant NSCLC from the TCGA (N= 44). Then, we built a predictive model using extreme-gradient boosting to (1) classify an additional 88 surgically resected tumors from the LCCS study and analyzed for overall survival (OS) prediction; (2) classify metastatic EGFR-mutant NSCLC from the RELAY trial with available RNAseq data (N = 106) and analyzed for progression-free survival (PFS) with erlotinib treatment. Results: Consensus clustering revealed two distinct clusters, one associated with more lineage-preserving features and one with more lineage-independent features that could transcriptionally distinguish EGFR-mutant lung cancer. No differences in primary EGFR mutations were detected across the two clusters. Ingenuity Pathway Analysis revealed TGFB1 as the most significantly enriched pathway in the lineage-independent cluster which was also significantly more mesenchymal (p = 0.0028). For surgically resectioned EGFR-mutant NSCLC, OS was consistently shorter in the lineage-independent cluster for TCGA (23.6 vs 58.3 mo; p = 0.049; HR = 0.4) and the LCCS cohort (55.7 vs not-reached; p = 0.0073; HR = 0.27). In the metastatic setting with erlotinib treatment, there was a trend for PFS to be shorter in the lineage-independent cluster (15.2 vs 19.4 mo; p = 0.12; HR = 0.61). Conclusions: Transcriptional identity in EGFR-mutant lung cancer are prognostic of clinical outcome. The lineage-independent tumors have inferior benefit to EGFR TKI as well as inferior OS, indicating that transcriptional biomarkers can be independent of oncogene biomarkers. These transcriptional biomarkers may help identify pts with poor outcome for future intensification of therapies. Citation Format: Simon Heeke, Monique Nilsson, Don Gibbons, Jianjun Zhang, Ignatio I. Wistuba, Keunchil Park, John V. Heymach, Xiuning Le. Tumor transcriptional identity as a key predictor of clinical outcome in EGFR-Mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5162.

Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer

IntroductionPatients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited. MethodsPatients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53mut/TSGmut), those having a TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and those with TP53wt. Patient characteristics and clinical outcomes were assessed in two independent cohorts. ResultsA total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53mut/TSGmut and 42 were TP53mut/TSGwt. Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53mut tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53mut/TSGmut tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53mut/TSGwt (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12–3.69, p < 0.01, OS: HR = 1.58, CI: 0.82–3.04, p = 0.12) or TP53wt cases (PFS: HR 2.4, CI: 1.28–4.47, p < 0.001, OS: HR = 2.54, CI: 1.21–5.34, p < 0.005). Inferior outcomes in patients with TP53mut/TSGmut tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort. ConclusionsPatients with TP53mut/TSGmut tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy.

LBA71 A multi-centre open-label randomized phase II study of osimertinib with and without ramucirumab in TKI-naïve EGFR-mutant metastatic NSCLC (RAMOSE trial interim analysis)

LBA71 A multi-centre open-label randomized phase II study of osimertinib with and without ramucirumab in TKI-naïve EGFR-mutant metastatic NSCLC (RAMOSE trial interim analysis)

UCLA l-08: A phase ib/II study of combined HER inhibition adding necitumumab and trastuzumab to osimertinib in patients with refractory EGFR-mutated lung cancer.

e21165 Background: Patients (pts) with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR with HER2 blockade results in complete and long-term reversal of osimertinib resistance in preclinical models. Methods: This is an investigator-initiated, single arm, open label phase 1b/2 study to identify the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the combination of osimertinib, necitumumab, and trastuzumab (ONT) in adults with histologically confirmed, metastatic NSCLC with an activating and sensitizing EGFR mutation who have progressed on osimertinib as their most recent treatment. Study pts receive daily oral osimertinib in conjunction with necitumumab and trastuzumab intravenously every other week. In phase 1b, a 3+3 dose-escalation design is used to determine the RP2D (Table 1). In phase 2, if ≥ 2 responses are seen out of 10 pts treated at the RP2D, an additional 10 pts will be accrued. Patient reported outcomes (PRO-CTCAE) and quality of life (FACT-L) data are collected prospectively. Efficacy is assessed as objective response rate (ORR) based on RECIST 1.1 criteria. Results: 22 pts (median age = 63; range = 40-82) have been enrolled and treated. The most commonly observed treatment-related AEs seen at any DL included acneiform rash (63.6%), headache (45.5%), nausea (40.9%), dry skin (36.4%), diarrhea (31.8%), paronychia (27.3%), oral mucositis (27.3%), vomiting (22.7%), fatigue (18.2%), chills (18.2%), and anorexia (18.2%). Grade 3 treatment-related toxicities were acneiform rash (22.7%), diarrhea (4.5%), decreased lymphocyte count (4.5%) and hypertension (4.5%). There were no treatment-related Grade ≥ 4 AEs. 12 evaluable pts were enrolled in phase 1b [3 at Dose Level (DL) 1, 3 at DL 2, and 6 at DL 3]; 3 non-evaluable pts were replaced. Pts treated at DL 1 and DL 2 had no dose-limiting toxicities (DLTs) and 1/6 pts at DL 3 had a DLT (persistent grade 3 rash). Due to grade 2 and 3 rash and paronychiae occurring after cycle 1 at DL 3, DL2 was determined to be the RP2D.The proportion of evaluable phase 1b pts achieving partial response or stable disease was 58.3% (7/12). Seven pts have been enrolled at DL2. Conclusions: ONT toxicities are manageable, and the combination has promising preliminary efficacy in refractory EGFR-mutated metastatic NSCLC. Evaluation of phase 2, stage 1 is expected to be completed by April 2023 and will be reported at the meeting. Clinical trial information: NCT04285671 . [Table: see text]

79TiP Progress of a phase I trial (TOTEM) of repotrectinib in combination with osimertinib in advanced, metastatic EGFR mutant NSCLC

79TiP Progress of a phase I trial (TOTEM) of repotrectinib in combination with osimertinib in advanced, metastatic EGFR mutant NSCLC

RELAY, Ramucirumab Plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association Between TP53 Status and Clinical Outcome

Ramucirumab plus erlotinib (RAM+ERL) demonstrated superior progression-free survival (PFS) in RELAY, a randomised Phase III trial in patients with untreated, metastatic, EGFR-mutated, non-small-cell lung cancer (EGFR+ NSCLC). Here, we present the relationship between TP53 status and outcomes in RELAY. Patients received oral ERL plus intravenous RAM (10 mg/kg IV) or placebo (PBO+ERL) every 2 weeks. Plasma was assessed by Guardant 360 next-generation sequencing and patients with any gene alteration detected at baseline were included in this exploratory analysis. Endpoints included PFS, overall response rate (ORR), disease control rate (DCR), DoR, overall survival (OS), safety, and biomarker analysis. The association between TP53 status and outcomes was evaluated. Mutated TP53 was detected in 165 (42.7%; 74 RAM+ERL, 91 PBO+ERL) patients, wild-type TP53 in 221 (57.3%; 118 RAM+ERL, 103 PBO+ERL) patients. Patient and disease characteristics and concurrent gene alterations were comparable between those with mutant and wildtype TP53. Independent of treatment, TP53 mutations, most notably on exon 8, were associated with worse clinical outcomes. In all patients, RAM+ERL improved PFS. While ORR and DCR were comparable across all patients, DoR was superior with RAM+ERL. There were no clinically meaningful differences in the safety profiles between those with baseline TP53 mutation and wild-type. This analysis indicates that while TP53 mutations are a negative prognostic marker in EGFR+ NSCLC, the addition of a VEGF inhibitor improves outcomes in those with mutant TP53. RAM+ERL is an efficacious first-line treatment option for patients with EGFR+ NSCLC, independent of TP53 status.

LBA10 A multicenter, randomized, double-blind, phase III study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER)

Anlotinib（Catequentinib） is an oral multi-targeted tyrosine kinase inhibitor that effectively inhibits VEGFRs, FGFRs, PGFRs, c-kit and MET. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients (pts) with untreated EGFR-mutated metastatic NSCLC.

12P A phase II study of atezolizumab in combination with bevacizumab, carboplatin or cisplatin, and pemetrexed for EGFR-mutant metastatic NSCLC patients after failure of EGFR TKIs

Acquired resistance to EGFR TKI remains a significant barrier for patients with EGFR-mutated lung cancer, especially for those without acquired EGFRT790M. The current study explored the safety and efficacy of combinational treatment with atezolizumab, bevacizumab, and pemetrexed-platinum in patients with EGFR-mutated NSCLC after failure of EGFR TKIs.

HSR22-154: Treatment Patterns Following Osimertinib Discontinuation in Patients With EGFR Mutated Metastatic NSCLC

HSR22-154: Treatment Patterns Following Osimertinib Discontinuation in Patients With EGFR Mutated Metastatic NSCLC

RELAY+: Exploratory Study of Ramucirumab Plus Gefitinib in Untreated Patients With EGFR-Mutated Metastatic NSCLC

IntroductionRamucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). MethodsPeriod 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. ResultsFrom December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3–73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). ConclusionsRELAY+ was found to have a favorable benefit–risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.

The EPICAL trial, a phase Ib study combining first line afatinib with anti-EGF vaccination in EGFR-mutant metastatic NSCLC

IntroductionCombination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed. Patients and methodsThe EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis. ResultsThe assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6–92.5) and 95.7% (95%CI = 78.1–99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5–20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0–30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0–23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient’s sera inhibited the EGFR pathway in tumor cells growing in vitro. ConclusionsCombination treatment with an anti–EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.

1209P RELAY, ramucirumab plus erlotinib (RAM+ERL) in untreated metastatic EGFR-mutant NSCLC (EGFR+NSCLC): Association between TP53 status and clinical outcome

Tumour Protein 53 (TP53) plays a role in angiogenesis by regulating vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2). In patients (pts) with EGFR+ NSCLC, TP53 mutations, notably on exon 8, are associated with poorer outcomes of EGFR tyrosine kinase inhibitor treatment and may be involved in primary resistance. We evaluated the relationship between TP53 status and outcomes in RELAY.

MO29-5 RELAY+: Exploratory study of RAM+GEF in untreated patients with EGFR M+ NSCLC: Updates on efficacy, safety and biomarker

The phase 3 RELAY study (NCT02411448) showed a superior progression-free survival (PFS) time for ramucirumab (RAM)+erlotinib (ERL) vs placebo+ERL in 449 untreated patients (pts) with EGFR-mutated metastatic NSCLC (median PFS: 19.4 vs 12.4 months [mo]; stratified hazard ratio: 0.59, 95% CI: 0.46-0.76, p <0.0001; 1-year [yr] PFS rate: 71.9% vs 50.7%). RELAY+ (an additional cohort of RELAY) is an exploratory study in East Asian pts evaluating RAM+gefitinib (GEF) followed by RAM+osimertinib (OSI) in T790M+ pts.

Upfront thoracic radiotherapy to primary lession improve outcomes in patients with stage IV non-small cell lung cancer harboring EGFR mutations.

e21167 Background: The role of thoracic radiotherapy in the treatment of metastatic EGFR mutant non-small cell lung cancer patients in literature datas are insufficient.The aim of this study was to examine the effectiveness of upfront thoracic radiotherapy in metastatic EGFR mutant NSCLC patients treated with chemotherapy or TKI. Methods: This study was designed as a hospital-based retrospective observational case-series study. A total of 141 patients with metastatic EGFR mutant non-small cell lung cancer who has followed in two different oncology centers at Turkey between 2014 and 2020. have been included to this study. Results: The median age of the patients was 63 (range 35-91) years. EGFR mutation results of exon 19 deletion, exon 21 mutation and exon 18 mutation were found in 82 (58.2%), 56 (39.7%) and 3 (2.1%) patients, respectively. The median follow-up time was 22 months and 94 (33.3%) patients died during follow-up. Median overall survival (OS) was 26 months and progression free survival (for first line treatment) (PFS) was 10 months for whole patients, respectively. Radiotherapy was given to the primary tumor site in 32 (22,6%) patients. Patients receiving radiotherapy to primary tumor site had better overall survival than those not (31 versus 23 months respectively and p = 0,02) The survival advantage was also seen for patients group taking TKI at upfront setting (33 versus 23 months respectively and p = 0.05). Conclusions: In this study, we have showed that upfront thoracic radiotherapy to primary lession as combination with EGFR-TKI treatment may improve the outcome in advanced stage IV NSCLC patients harboring EGFR mutations.

A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).

TPS9131 Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated Metastatic EGFR-Mutated NSCLC: RELAY Japanese Subset

IntroductionThe phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46–0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. MethodsPatients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. ResultsThe Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431–0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424–1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317–0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). ConclusionsClinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.