Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis.

BACKGROUND: First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival. PATIENTS AND METHODS: Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed. RESULTS: In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population. CONCLUSION: Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors.

Patients with non-small-cell lung cancer (NSCLC) whose tumours harbour activating mutations within the epidermal growth factor receptor (EGFR) frequently derive significant clinical and radiographic benefits from treatment with EGFR tyrosine kinase inhibitors (TKIs). As such, prospective identification of EGFR mutations is now the standard of care worldwide. However, acquired therapeutic resistance to these agents invariably develops. Over the past 10 years, great strides have been made in defining the molecular mechanisms of EGFR TKI resistance in an effort to design rational strategies to overcome this acquired drug resistance. Approximately 60% of patients with acquired resistance to the EGFR TKIs (erlotinib, gefitinib, and afatinib) develop a new mutation within the drug target. This mutation-T790M-has been shown to alter drug binding and enzymatic activity of the mutant EGF receptor. Less common mechanisms of acquired resistance include MET amplification, ERBB2 amplification, transformation to small-cell lung cancer, and others. Here, we present a condensed overview of the literature on EGFR-mutant NSCLC, paying particular attention to mechanisms of drug resistance, recent clinical trial results, and novel strategies for identifying and confronting drug resistance, while also striving to identify gaps in current knowledge. These advances are rapidly altering the treatment landscape for EGFR-mutant NSCLC, expanding the armamentarium of available therapies to maximize patient benefit.

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab.

BACKGROUND: Ramucirumab, the human immunoglobulin G1 monoclonal antibody receptor antagonist of vascular endothelial growth factor receptor 2, has been approved for treating gastric/gastroesophageal junction, non-small-cell lung, and metastatic colorectal cancers. With the completion of six global, randomized, double-blind, placebo-controlled, phase III trials across multiple tumor types, an opportunity now exists to further establish the safety parameters of ramucirumab across a large patient population. MATERIALS AND METHODS: An individual patient meta-analysis across the six completed phase III trials was conducted and the relative risk (RR) and associated 95% confidence intervals (CIs) were derived using fixed-effects or mixed-effects models for all-grade and high-grade adverse events (AEs) possibly related to vascular endothelial growth factor pathway inhibition. The number needed to harm was also calculable due to the placebo-controlled nature of all six registration standard trials. RESULTS: A total of 4996 treated patients (N = 2748 in the ramucirumab arm and N = 2248 in the control, placebo arm) were included in this meta-analysis. Arterial thromboembolic events [ATE; all-grade, RR: 0.8, 95% CI 0.5-1.3; high-grade (grade ≥3), RR: 0.9, 95% CI 0.5-1.7], venous thromboembolic events (VTE; all-grade, RR: 0.7, 95% CI 0.5-1.1; high-grade, RR: 0.7, 95% CI 0.4-1.2), high-grade bleeding (RR: 1.1, 95% CI 0.8-1.5), and high-grade gastrointestinal (GI) bleeding (RR: 1.1, 95% CI 0.7-1.7) did not demonstrate a definite increased risk with ramucirumab. A higher percentage of hypertension, proteinuria, low-grade (grade 1-2) bleeding, GI perforation, infusion-related reaction, and wound-healing complications were observed in the ramucirumab arm compared with the control arm. CONCLUSIONS: Ramucirumab may be distinct among antiangiogenic agents in terms of ATE, VTE, high-grade bleeding, or high-grade GI bleeding by showing no clear evidence for an increased risk of these AEs in this meta-analysis of a large and diverse patient population. Ramucirumab is consistent with other angiogenic inhibitors in the risk of developing certain AEs. Clinical Trial Numbers: NCT00917384 (REGARD), NCT01170663 (RAINBOW), NCT01168973 (REVEL), NCT01183780 (RAISE), NCT01140347 (REACH), and NCT00703326 (ROSE).

Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial.

Background: In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods: LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results: Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Conclusion: In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib. Clinicaltrials.gov identifier: NCT01466660.

Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.

BACKGROUND: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. METHODS: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. RESULTS: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. CONCLUSIONS: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). CLINICAL TRIALS NUMBER: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer.

BACKGROUND: SQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression. PATIENTS AND METHODS: Patients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m(2) i.v., days 1 and 8) and cisplatin (75 mg/m(2) i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors. RESULTS: A total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine-cisplatin group than in the gemcitabine-cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%). CONCLUSIONS: In line with SQUIRE ITT, addition of necitumumab to gemcitabine-cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors. CLINICAL TRIAL: NCT00981058.

2nd ESMO Consensus Conference on Lung Cancer: non-small-cell lung cancer first-line/second and further lines of treatment in advanced disease.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.

Ramucirumab plus erlotinib versus placebo plus erlotinib in previously untreated EGFR-mutated metastatic non-small-cell lung cancer (RELAY): exploratory analysis of next-generation sequencing results.

BACKGROUND: Ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) over placebo + ERL (PBO + ERL) in the phase III RELAY study of patients with epidermal growth factor receptor (EGFR)-mutated metastatic non-small-cell lung cancer (EGFR+ mNSCLC; NCT02411448). Next-generation sequencing (NGS) was used to identify clinically relevant alterations in circulating tumor DNA (ctDNA) and explore their impact on treatment outcomes. PATIENTS AND METHODS: Eligible patients with EGFR+ mNSCLC were randomized 1 : 1 to ERL (150 mg/day) plus RAM (10 mg/kg)/PBO every 2 weeks. Liquid biopsies were to be prospectively collected at baseline, cycle 4 (C4), and postdiscontinuation follow-up. EGFR and co-occurring/treatment-emergent (TE) genomic alterations in ctDNA were analyzed using Guardant360 NGS platform. RESULTS: In those with valid baseline samples, detectable activating EGFR alterations in ctDNA (aEGFR+) were associated with shorter PFS [aEGFR+: 12.7 months (n = 255) versus aEGFR-: 22.0 months (n = 131); hazard ratio (HR) = 1.87, 95% confidence interval (CI) 1.42-2.51]. Irrespective of detectable/undetectable baseline aEGFR, RAM + ERL was associated with longer PFS versus PBO + ERL [aEGFR+: median PFS (mPFS) = 15.2 versus 11.1 months, HR = 0.63, 95% CI 0.46-0.85; aEGFR-: mPFS = 22.1 versus 19.2 months, HR = 0.80, 95% CI 0.49-1.30]. Baseline alterations co-occurring with aEGFR were identified in 69 genes, most commonly TP53 (43%), EGFR (other than aEGFR; 25%), and PIK3CA (10%). PFS was longer in RAM + ERL, irrespective of baseline co-occurring alterations. Clearance of baseline aEGFR by C4 was associated with longer PFS (mPFS = 14.1 versus 7.0 months, HR = 0.481, 95% CI 0.33-0.71). RAM + ERL improved PFS outcomes, irrespective of aEGFR mutation clearance. TE gene alterations were most commonly in EGFR [T790M (29%), other (19%)] and TP53 (16%). CONCLUSIONS: Baseline aEGFR alterations in ctDNA were associated with shorter mPFS. RAM + ERL was associated with improved PFS outcomes, irrespective of detectable/undetectable aEGFR, co-occurring baseline alterations, or aEGFR+ clearance by C4. aEGFR+ clearance by C4 was associated with improved PFS outcomes. Monitoring co-occurring alterations and aEGFR+ clearance may provide insights into mechanisms of EGFR tyrosine kinase inhibitor resistance and the patients who may benefit from intensified treatment schedules.

Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation.

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial.

BACKGROUND: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. PATIENTS AND METHODS: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. RESULTS: At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CONCLUSIONS: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

Outcomes with durvalumab after chemoradiotherapy in stage IIIA-N2 non-small-cell lung cancer: an exploratory analysis from the PACIFIC trial.

BACKGROUND: The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. MATERIALS AND METHODS: Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. RESULTS: Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. CONCLUSIONS: Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer.

BACKGROUND: Liquid biopsy (LB) is a rapidly evolving diagnostic tool for precision oncology that has recently found its way into routine practice as an adjunct to tissue biopsy (TB). The concept of LB refers to any tumor-derived material, such as circulating tumor DNA (ctDNA) or circulating tumor cells that are detectable in blood. An LB is not limited to the blood and may include other fluids such as cerebrospinal fluid, pleural effusion, and urine, among others. PATIENTS AND METHODS: The objective of this paper, devised by international experts from various disciplines, is to review current challenges as well as state-of-the-art applications of ctDNA mutation testing in metastatic non-small-cell lung cancer (NSCLC). We consider pragmatic scenarios for the use of ctDNA from blood plasma to identify actionable targets for therapy selection in NSCLCs. RESULTS: Clinical scenarios where ctDNA mutation testing may be implemented in clinical practice include complementary tissue and LB testing to provide the full picture of patients' actual predictive profiles to identify resistance mechanism (i.e. secondary mutations), and ctDNA mutation testing to assist when a patient has a discordant clinical history and is suspected of showing intertumor or intratumor heterogeneity. ctDNA mutation testing may provide interesting insights into possible targets that may have been missed on the TB. Complementary ctDNA LB testing also provides an option if the tumor location is hard to biopsy or if an insufficient sample was taken. These clinical use cases highlight practical scenarios where ctDNA LB may be considered as a complementary tool to TB analysis. CONCLUSIONS: Proper implementation of ctDNA LB testing in routine clinical practice is envisioned in the near future. As the clinical evidence of utility expands, the use of LB alongside tissue sample analysis may occur in the patient cases detailed here.