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Purpose: Leptomeningeal metastasis (LM) is a serious complication of non-small cell lung cancer (NSCLC), particularly in patients with EGFR mutations. In this study, we investigated the survival outcomes of patients with EGFR-mutant NSCLC who have developed LM and explored the factors associated with their survival. Methods: From April 2018 to November 2021, patients with EGFR-mutant NSCLC who underwent cerebrospinal fluid (CSF) sampling under the clinical suspicion of LM were enrolled. The patients' clinicodemographic characteristics, treatment history including whole-brain radiation therapy (WBRT), overall survival (OS), and intracranial progression-free survival (icPFS) were measured. EGFR mutations in cell-free tumor DNA (ctDNA) of CSF, including T790M mutation, were analyzed. Results: We enrolled 62 patients with NSCLC. The median time form diagnosis to LM was 23.1 months and 16 (25.8%) patients had history of prior third-generation EGFR-TKI use. EGFR mutation in CSF ctDNA was detected in 53 patients (85.5%); of them, 10 (16.1%) had T790M mutation. The patients' icPFS and OS after osimertinib were 6.43 and 9.37 months, respectively, and were comparable among patients with different sensitive EGFR mutations, indicating that EGFR mutation status did not affect osimertinib efficacy. Patients who received WBRT after LM had numerically higher icPFS and OS compared to those without. Multivariate analysis revealed that lack of prior exposure to third-generation EGFR-TKI was associated with better OS. Conclusions: Osimertinib is effective in patients with EGFR-mutant NSCLC who developed LM and prior third-generation EGFR-TKI use was associated with poor survival in these patients. The role of WBRT warrants further investigation. [ABSTRACT FROM AUTHOR]

Assessing tumor EGFR mutation status is necessary for the proper management of patients with advanced non–small cell lung cancer (NSCLC). We evaluated the impact of dynamic analyses of the plasma and tissue EGFR mutation using ultra-sensitive droplet digital PCR (ddPCR) assays to manage NSCLC patients treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). Paired tumor tissues and plasma samples from 137 EGFR-mutated lung adenocarcinoma patients prior to the first-line EGFR-TKIs treatment (at baseline) and at disease progression were subjected to EGFR mutation analysis using ddPCR, together with the analyses of the clinicopathological characteristics and treatment outcomes. Patients with EGFR-activating mutations detected in baseline plasma were associated with bone metastasis (p = 0.002) and had shorter progression-free survival (12.9 vs. 17.7 months, p = 0.02) and overall survival (24.0 vs. 39.4 months, p = 0.02) compared to those without. Pre-treatment EGFR T790M mutation found in baseline tumor tissues of 28 patients (20.4%; 28/137) was significantly associated with brain metastasis (p = 0.005) and a shorter brain metastasis-free survival (p = 0.001). The presence of EGFR T790M mutations in baseline tumor tissues did not correlate with the emergence of acquired EGFR T790M mutations detected at progression. At disease progression, acquired EGFR T790M mutations were detected in 26.6% (21/79) of the plasma samples and 42.9% (15/35) of the rebiopsy tissues, with a concordance rate of 71.4% (25/35). The dynamic monitoring of tissue and plasma EGFR mutation status at baseline and progression using ddPCR has a clinical impact on the evaluation of EGFR-TKIs treatment efficacy and patient outcomes, as well as the emergence of resistance in NSCLC. [ABSTRACT FROM AUTHOR]

Detection of driver gene mutations is important in advanced NSCLC. The cobas EGFR mutation test is a mutant allele-specific real-time PCR assay with limitation owing to its primer design. Next-generation sequencing-based assay has a higher mutation detection coverage; however, its clinical impact remains unclear. We retrospectively collected the records of stage IV NSCLC patients with wild-type EGFR tested by cobas test. FoundationOne CDx was used for comprehensive genomic profiles. We then evaluated the missed EGFR mutations by the cobas test. We studied 62 patients. The median age was 60 (range: 35–86 years). Most patients were male and 58.1% were smokers. 91.9% were adenocarcinomas. Of the 62 samples, 7 (11.3%) were detected with EGFR mutations by NGS. Among these overlooked EGFR mutations, five were exon 20 insertions, and two were exon 19 deletions. Two patients received EGFR TKIs and showed durable response with PFS 5.9 months and 10.1 months, respectively. Using NGS as the standard, the false-negative rate of the cobas EGFR mutation test was 11.3%—in a population with a high prevalence of EGFR mutations. The most overlooked mutations were exon 20 insertions. A comprehensive EGFR mutation assay can provide significant benefits to patients with NSCLC. [ABSTRACT FROM AUTHOR]

15–40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations. [ABSTRACT FROM AUTHOR]

Introduction: Malignant pleural effusions are common in non–small cell lung cancer (NSCLC). Molecular testing is among the most critical steps in the management of patients with advanced NSCLC. However, the optimal approach for epidermal growth factor receptor (EGFR) mutation testing in such effusion samples remains unclear. Methods: We prospectively collected effusion samples from patients with EGFR–mutant NSCLC. Following sample centrifugation, genomic DNA and cell–free DNA were respectively extracted from the sediment and supernatants. EGFR mutation was detected through a real–time PCR assay. Results: A total of 108 effusions from 78 patients were examined, with 12 and 96 obtained before and after EGFR tyrosine kinase inhibitor treatment, respectively. Carcinoma cells or atypical cells were identified in 73 effusions (67.6%). EGFR mutations were detected in 86 (79.6%) sediment and 84 (77.8%) supernatant samples. Among the effusions with positive cytological findings, the EGFR mutation detection rates were 95.9% (70/73) and 86.3% (63/73) in the sediment and supernatants, respectively. Among the effusions with negative cytological findings, the corresponding detection rates were 45.7% (16/35) and 60% (21/35), respectively. Current clinical practice is to arrange EGFR mutation testing only for sediment from cytologically positive effusions. Through the proposed cytology–based specimen triage, wherein sediment and supernatants with positive and negative cytological findings, respectively, are tested, the detection rate was increased from 64.8% (70/108) to 84.3% (91/108). At half of the cost, this strategy provided a detection rate only slightly lower than the rate in a combined test of all the sediment and supernatants (87.0%, 94/108). Conclusions: The separate extraction of DNA from sediment and supernatants obtained from centrifuged effusion samples can improve the overall EGFR mutation detection rate. The present cytology–based specimen triage is an efficient strategy for EGFR mutation testing in patients with EGFR–mutant NSCLC. [ABSTRACT FROM AUTHOR]

Whether ICIs combined with chemotherapy can improve outcomes in EGFR-mutant non-small cell lung cancer (NSCLC) remains uncertain. Patients with EGFR-mutant NSCLC and who progressed on first-line EGFR-TKIs treatment were retrospectively collected. We reviewed the outcome of these patients treated with ICIs or ICIs combined chemotherapy (ICI + C). Total 30 patients were included. The ORR were 9.1% and 25.0% for the ICI and ICI + C groups. The ICI + C group showed the trend of longer progression-free survival and overall survival periods. Patients without the T790M mutation had a significantly longer PFS than did those without this mutation (4.23 [95% CI: 2.75–5.72] vs. 1.70 [95% CI: 0.00–3.51] months, HR:4.45, p = 0.019). ICIs combined with chemotherapy tended to be more effective than ICIs alone in pretreated EGFR-mutant NSCLC. The T790M mutation may be a potential biomarker. [ABSTRACT FROM AUTHOR]

Background: Definitive chemoradiotherapy (dCRT) is the first choice treatment for patients with locally advanced non-small cell lung cancer (NSCLC), but up to 35% of dCRT-treated tumors may have persistent or recurrent disease. Since the last decades, multimodality therapy showing potential for cure has become the mainstream for treatment of locally advanced NSCLCs, even some that were initially inoperable. Although salvage lung resection after dCRT has been reported with acceptable survivals, experiences in this respect are still limited. Other concerns remain debatable and inconclusive, such as dosage of radiation exposure, long interval between dCRT and surgery, and surgical comorbidity. Case presentation: A 73-year-old male former smoker with diagnosis of right lower lobe of lung squamous cell carcinoma (SqCC) with multiple mediastinal lymphadenopathy, cT4N2M0, stage IIIB, received salvage right lower lobe + right middle lobe bilobectomy through video-assisted thoracoscopic surgery (VATS) after dCRT and adjuvant CRT to a total of 9000 cGy dosage of radiation. The interval from the 1st and 2nd ends of radiation to the salvage surgery was 980 and 164 days, respectively. The pre-operative forced expiratory volume in the first second was 2.33 L (101% predicted) and the diffusing capacity of the lungs for carbon monoxide was 56% predicted. The operating time was 6.5 h, and the total estimated blood loss was 50 ml. The patient was discharged on the 7th postoperative day without major complications or bronchopleural fistulas. The patient was still alive 42 months after the initial diagnosis of advanced N2 lung SqCC, and kept progression-free for 7 months after salvage lung resection. Conclusions: Salvage lung resection performed long after high-dose radiation therapy of dCRT is technically feasible through VATS approach in a patient with initially inoperable cT4N2M0 stage IIIB NSCLC, and can be an alternative consolidative treatment for locally advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background/purpose: There is a lack of data on nivolumab treatment outcomes in Taiwanese patients with advanced or recurrent non-small cell lung cancer (NSCLC) ineligible for radical radiotherapy and resistant to platinum-based chemotherapy. We investigated the safety and efficacy of nivolumab in this population.Methods: In this ongoing, multicenter, open-label, single-arm, phase II study, patients aged ≥20 years with a performance status of 0-1 and stage IIIB/IV or recurrent NSCLC received nivolumab 3 mg/kg every 2 weeks in 6-week cycles. Interim data obtained between 27 January 2016 and 21 May 2017 were analyzed. Safety, based on adverse event (AE) reporting, was the primary endpoint. Efficacy assessment parameters included overall response rate (ORR), overall survival (OS), and progression-free survival (PFS).Results: Among 53 treated patients with advanced NSCLC (median age 61.0 years; 62.3% male), mean treatment duration was 99.7 days. AEs (any grade) and serious AEs were reported by 92.5% and 47.2% of patients, respectively. Adverse drug reactions (ADRs; any) occurred in 58.5% of patients; grade ≥3 ADRs occurred in 13.2% of patients. Five deaths occurred; two cases (neoplasm progression and septic shock) were considered treatment-emergent. Common ADRs were fatigue (17.0%) and rash (13.2%). Common immune-related treatment-emergent AEs were rash (17.0%) and pruritus (13.2%). The centrally assessed ORR was 9.4% (5/53). The median OS and median PFS were 11.5 months and 1.4 months, respectively.Conclusion: Nivolumab appeared to be safe and effective in Taiwanese patients. These interim results suggest that nivolumab is a suitable treatment option for this population.Clinical Trial Registration: NCT02582125. [ABSTRACT FROM AUTHOR]

Background: The treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) discussion results in better patient survival. Materials and methods: MDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018. Results: A total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (p<0.001), T staging (p = 0.009), performance status (p<0.001), and surgery (p = 0.016) to be significant prognostic factors. Conclusion: The results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC. [ABSTRACT FROM AUTHOR]

• Updated analysis of entrectinib in patients with NTRK -fp NSCLC (data cutoff Aug 2022) • Patients with NTRK -fp NSCLC had deep and durable overall and intracranial responses. • Entrectinib had a manageable safety profile in patients with NTRK -fp NSCLC. • Data confirm that entrectinib is a relevant drug for patients with NTRK -fp NSCLC. • Data in NSCLC are consistent with those for the overall NTRK -fp study population. NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK -fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. The efficacy-evaluable population included 51 patients with NTRK -fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK -fp NSCLC. [ABSTRACT FROM AUTHOR]

Background Radiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an effective treatment for advanced nonsmall-cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR-TKI-related RRP in patients with NSCLC remain unclear. Methods Clinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR-TKI treatment were retrospectively reviewed. EGFR-TKI-related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed. Results In total, 160 patients with NSCLC who received EGFR-TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR-TKI-related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80–635 days) and that between the initiation of EGFR-TKI and RRP was 43 days (range, 18–65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR-TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR-TKI treatment after 90 days (21% vs. 2.1%, p = 0.005). Conclusion In patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR-TKI. [ABSTRACT FROM AUTHOR]

• Durvalumab plus simultaneous cCRT was assessed in unresectable stage III NSCLC. • Safety was consistent with known profiles for durvalumab and cCRT in this setting. • No new safety signals; rate of grade 3 pneumonitis/radiation pneumonitis was 7.8% • Durvalumab plus cCRT showed encouraging antitumor activity. • ORR was 60.9 %, median PFS 13.4 months, and median OS not reached. For patients with unresectable, stage III non-small-cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort. CLOVER comprised a dose-limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability. Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post-hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9–72.9); median duration of response was 15.8 months (95 % CI, 9.0–not estimable [NE]). Median progression-free survival was 13.4 months (95 % CI, 8.8–20.1) and median overall survival was not reached (95 % CI, 21.9–NE). Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC. [ABSTRACT FROM AUTHOR]

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.Funding: Ignyta/F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Background: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.Methods: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.Findings: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.Interpretation: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.Funding: Eli Lilly. [ABSTRACT FROM AUTHOR]

Objectives IFN-γ takes part in immunologic responses to cancer and its interactions with chemotherapy have also been described. Our previous study had showed an association between phytohemagglutinin (PHA)-stimulated IFN-γ (PSIG) response and overall survival in patients with advanced non-small-cell lung cancer (NSCLC). Here, we aimed to evaluate the correlation between PSIG and chemotherapy responses. Materials and methods From January 2011 to August 2012, 340 newly diagnosed patients with lung cancer were enrolled in a prospective latent tuberculosis observational study. Patients with advanced NSCLC who were treated with chemotherapy were included in this analysis. An IFN-γ release assay (IGRA) was used to evaluate pre-treatment PSIG levels. Patients were grouped into low and high PHA response groups according to their PSIG levels. Their demographic characteristics, tumor responses, and survival rates were investigated. Results Eighty-four patients were enrolled. The chemotherapy response rates in the high and low PHA response groups were 45.2% and 35.7% ( p = 0.190), respectively. The disease control rate in the high PHA response group was 76.2%, versus 52.4% in the low PHA response group ( p = 0. 023). In multivariate analysis, PHA response was an independent predictor of disease control (odds ratio = 3.017, 95% confidence interval = 1.115–8.165). The Kaplan-Meier method demonstrated both longer progression-free survival ( p = 0.008) and overall survival ( p = 0.003) in the high PHA response group. Conclusions A higher pre-treatment PSIG response, obtained using the IGRA, was associated with better disease control rate and survival among patients with advanced NSCLC treated with chemotherapy. [ABSTRACT FROM AUTHOR]

Background Dual blockade of the EGFR and VEGFR pathways in EGFR mutation-positive NSCLC is more effective than EGFR inhibition alone. EGFR mutations occur in 10–20% of Caucasian and 40–60% of East Asian (EA) patients (pts) with NSCLC. In the global phase 3 RELAY study (NCT02411448), ramucirumab + erlotinib (RAM+ERL) significantly improved progression-free survival (PFS) compared with placebo + erlotinib (PL+ERL) in pts with EGFR mutation-positive metastatic NSCLC. Here we report efficacy and safety results for the EA subset. Methods Previously untreated pts with metastatic NSCLC and EGFR exon 19 deletions or an exon 21 substitution mutation (L858R) were randomized (1:1) to receive ERL (150 mg/day) plus RAM (10 mg/kg Q2W) or placebo until disease progression or unacceptable toxicity. PFS (investigator-assessed, primary endpoint), duration of response (DoR), PFS2 (time to second disease progression), overall survival (OS), and safety were assessed. Results Of 449 pts randomized from Jan 2016 to Feb 2018, 336 pts (75%) were from East Asia (Japan: 211; Taiwan: 56; Korea: 54; Hong Kong: 15). In the RAM+ERL (n = 166)/PL+ERL (n = 170) arms in the EA subset, 64.5%/64.1% were female, 63.3%/64.1% were never-smokers, and 50.6%/49.4% had exon 19 deletions. RAM+ERL improved PFS (median: 19.4 [95% CI 15.2–22.0] vs 12.5 [95% CI 11.1–13.9] months; hazard ratio [HR]: 0.636, 95% CI 0.485–0.833, P = 0.0009) and DoR (median: 16.2 [95% CI 13.8–19.8] vs 11.1 [95% CI 9.7–12.5] months; HR: 0.646, 95% CI 0.481–0.868, P = 0.0036) compared with PL+ERL. PFS2 and OS data are immature, with 67.3% and 82.7% of pts censored. Grade ≥3 treatment-emergent adverse events reported in > 5% of pts (RAM+ERL vs PL+ERL) were hypertension (21.3% vs 4.7%), dermatitis acneiform (18.3% vs 8.8%), ALT increased (9.1% vs 9.4%), and diarrhea (5.5% vs 1.2%). Conclusions Consistent with the overall RELAY study population, RAM+ERL improved PFS compared with PL+ERL in the EA subset, with a manageable safety profile. This study was sponsored by Eli Lilly Japan K.K. Medical writing assistance was provided by Justine Southby, PhD, CMPP, and Tania Dickson, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly Japan K.K. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3). [ABSTRACT FROM AUTHOR]