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Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

BRAF V600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized. Significance: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care. See related commentary by Ribas and Lo, p. 640. This article is highlighted in the In This Issue feature, p. 627

Patient-reported outcomes (PROs) are increasingly relevant endpoints in clinical trials, contributing to our understanding of risk-benefit profiles, in addition to efficacy and safety data. We investigated the impact of entrectinib on patient-reported symptoms, functioning, and health-related quality of life. STARTRK-2 is a phase II basket study in patients with locally advanced/metastatic neurotrophic receptor tyrosine kinase 1/2/3 (NTRK1/2/3) and ROS proto-oncogene 1 (ROS1) fusion-positive solid tumours. PROs (prespecified secondary endpoint) were evaluated using the European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ-C30), lung cancer module (QLQ-LC13), and colorectal cancer module (QLQ-CR29), and the EuroQoL 5-Dimension 3-Level instruments, completed before cycle 1 day 1 and each subsequent 4-week cycle of entrectinib dosing, and the end of treatment. Adverse events and treatment-related symptoms were assessed in the safety analysis (SA)-PRO population. Tumour-related symptoms, functioning, and global health status were assessed in the efficacy analysis (EA)-PRO population. Data cut-offs: 31 October 2018 NTRK cohort; 01 May 2019 ROS1 cohort. SA-PRO populations comprised patients with NTRK fusion-positive solid tumours (N = 88) or ROS1 fusion-positive non-small-cell lung cancer (N = 180) who received one or more doses of entrectinib, completed PRO questionnaires on cycle 1 day 1 and answered one or more questions on-study. EA-PRO populations (N = 71) and (N = 145), respectively, comprised SA-PRO patients with measurable baseline disease. Moderate-to-high baseline global health status scores were maintained in EA-PRO populations during treatment. Role and physical functioning scores were moderate-to-high at baseline, with trends towards clinical improvement during treatment. Both cohorts reported low-to-moderate symptom burden at baseline, which was maintained or trended towards clinically meaningful improvement. Symptoms commonly associated with cancer treatment (e.g. nausea, fatigue) remained stable or improved during treatment. All SA-PRO patients experienced one or more adverse events, most frequently constipation or diarrhoea. PRO findings were consistent with the favourable safety profile of entrectinib, and further reinforce the positive benefit-risk profile of this treatment, indicating minimal overall treatment burden. This study was supported by F. Hoffmann-La Roche Ltd. Sí

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR−/ALK−), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR−/ALK− NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7–21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8–23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2–43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [

Aims The advent of specific ALK-targeting drugs has radically changed the outcome of patients with ALK translocated non-small-cell lung cancer (NSCLC). However, emerging resistance to treatment with ALK inhibitors in these patients remains a major concern. In previous studies, we analysed two ALK+ patient cohorts (TP53 wild-type/TP53 mutated) in terms of copy number alterations. All patients belonging to the TP53 wild-type group had mainly genetically stable genomes, with one exception showing chromosomal instability and amplifications of several gene loci, including TERT. Here, we aimed to determine the prevalence of TERT amplifications in these ALK+ lung cancer patients by analysing an independent cohort of 109 ALK translocated cases. We further analysed the copy numbers of numerous cancer-relevant genes and other genetic aberrations. Methods and results The prevalence of TERT amplifications was determined by means of FISH analyses. Copy numbers of 87 cancer-relevant genes were determined by NanoString nCounter® technology, FoundationOne® and lung-specific NGS panels in some of these TERT-amplified samples, and clinical data on patients with TERT-amplified tumours were collected. Our data revealed that five (4.6%) of all 109 analysed ALK+ patients harboured amplification of TERT and that these patients had genetically unstable genomes. Conclusions Our preliminary study shows that ALK+ adenocarcinomas should be evaluated in the context of their genomic background in order to more clearly understand and predict patients' individual course of disease.

9509 Background: In the ongoing, multicohort, phase 2 GEOMETRY mono-1 study, capmatinib (INC280) has shown efficacy in METex14–mutated NSCLC patients (pts) who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b). Here, we report the efficacy and safety of capmatinib in pts with high-level MET-amplified (gene copy number [GCN] ≥10) advanced NSCLC who were either pretreated with 1 or 2 prior lines of systemic therapy (cohort 1a) or tx-naïve (cohort 5a). Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV (any histology) MET-amplified NSCLC with GCN≥10 received capmatinib 400 mg twice daily (fasting). Primary and key secondary endpoints were overall response rate (ORR) and duration of response (DOR), respectively, by blinded independent review committee (BIRC) assessment per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS, BIRC and investigator assessment), overall survival, and safety. Results: As of Jan 06, 2020, 84 pts were evaluable for efficacy (cohort 1a [2nd/3rd line], 69 pts; Cohort 5a [1st line], 15 pts). Tx was ongoing for 3 pts in cohort 1a, none in cohort 5a. Per BIRC assessment in cohorts 1a and 5a, respectively, ORR was 29% and 40%, median DOR was 8.31 months (mo, 20 responders, 95% CI: 4.17–15.44) and 7.54 mo (6 responders, 95% CI: 2.56–14.26), and median PFS was 4.07 (95% CI: 2.86–4.83) and 4.17 (95% CI: 1.45–6.87) mo. Investigator assessment was in line with BIRC assessment (Table). The most common adverse events across all cohorts (≥25%, all grades, N = 364) were peripheral edema (51.1%), nausea (44.8%) and vomiting (28.0%). Data for biomarker analysis and pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusion: Capmatinib has demonstrated activity in the subset of pts with high-level MET-amplified (GCN≥10) NSCLC, with a higher response rate in tx-naïve pts. Safety profile remains favorable and similar to previous reports of capmatinib. Clinical trial information: NCT02414139 . [Table: see text]

e13525 Background: Due to the lack of specificity of contrast-enhanced (CE) MRI, the differentiation of progression from pseudoprogression (PsP) following immunotherapy using checkpoint inhibitors (IT) or targeted therapy (TT) may be challenging, especially when IT or TT is applied in combination with radiotherapy (RT). Similarly, for response assessment of RT plus IT or targeted therapy (TT), the use of CE MRI alone may also be difficult. For problem solving, the integration of advanced imaging methods may add valuable information. Here, we evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in comparison to CE MRI for these important clinical situations in patients with brain metastases (BM) secondary to malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Methods: From 2015-2018, we retrospectively identified 31 patients with 74 BM secondary to MM (n = 20 with 42 BM) and NSCLC (n = 11 with 32 BM) who underwent 52 FET PET scans during the course of disease. All patients had RT prior to IT or TT initiation (61%) or RT concurrent to IT or TT (39%). In 13 patients, FET PET was performed for treatment response assessment of IT or TT using baseline and follow-up scans (median time between scans, 4.2 months). In the remaining 18 patients, FET PET was used for the differentiation of progression from PsP related to RT plus IT or TT. In all BM, metabolic activity on FET PET was evaluated by calculation of tumor/brain ratios. FET PET imaging findings were compared to CE MRI and correlated to the clinical follow-up or neuropathological findings after neuroimaging. Results: In 4 of 13 patients (31%), FET PET provided additional information for treatment response evaluation beyond the information provided by CE MRI alone. Furthermore, responding patients on FET PET had a median stable clinical follow-up of 10 months. In 10 of 18 patients (56%) with CE MRI findings suggesting progression, FET PET detected PsP. In 9 of these 10 patients, PsP was confirmed by a median stable clinical follow-up of 11 months. Conclusions: FET PET may add valuable information for treatment monitoring in individual BM patients undergoing RT in combination with IT or TT.

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812–21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781

IntroductionCapmatinib, a highly selective and potent MET inhibitor, was approved for patients with advanced METex14 NSCLC in the US and Japan in 2020, with the FoundationOne® CDx (F1CDx; a next-generation sequencing assay using DNA isolated from FFPE tumor tissue), based on results of the ongoing phase 2 GEOMETRY mono-1 study (NCT02414139). Previously, the F1CDx demonstrated 99% concordance with the METex14 RT-PCR clinical trial assay (CTA) used in the GEOMETRY mono-1 study. Here, we report findings of METex14 detection using the an NGS-based liquid biopsy assay (LDx), which detects MET single nucleotide variants and indels that lead to METex14 in circulating tumor (ct)DNA. MethodsDuring the GEOMETRY mono-1 study, patients were screened for METex14 status using a METex14 RT-PCR CTA on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from patients enrolled in the GEOMETRY mono-1 study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and samples from commercial sources. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). Clinical utility of the LDx in identifying METex14 positive patients for treatment with capmatinib was evaluated by comparing overall response rate (ORR) by BIRC in METex14 positive patients by the CTA and LDx. ResultsOf the 97 patients with METex14 NSCLC in C4 (n=69) and C5b (n=28), 88 patients had plasma volume ≥2.5 mL and cell free DNA ≥20 ng (minimum input). Of the 88 CTA METex14 positive patients, 57 were LDx positive, 26 were LDx negative; 5 had invalid sequencing results. Review of the 26 CTA discordant (METex14-negative) cases on LDx identified 3 with an alternate MET alteration, while the vast majority had evidence of low ctDNA levels. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; the LDx identified no CTA METex14-negative patient as positive. The PPA and NPA for these were 68.7% (95% CI: 57.6%, 78.4%) and 100% (95% CI: 95.9%, 100%), respectively. A post-hoc analysis comparing LDx with F1CDx in patients with METex14 showed similar results. For patients identified as METex14-positive by the LDx, the ORR (95% CI) by BIRC was determined as 48.8% (32.9–64.9%; n=20/41) for C4, and 81.3% (54.4–96.0%; n=13/16) for C5b; corresponding ORRs for patients identified as METex14-positive by the CTA were 40.6% (28.9-53.1%; n=28/69) for C4 and 67.9% (47.6-84.1%; n=19/28) for C5b.ConclusionsCurrent findings from the GEOMETRY mono-1 study support the feasibility and clinical utility of identifying advanced NSCLC patients with METex14 in ctDNA using LDx. For patients identified as METex14-negative by LDx, further testing should be performed on tissue samples, as a negative liquid biopsy result does not preclude a positive result by tissue biopsy. Citation Format: Rebecca S. Heist, Edward B. Garon, Daniel S. Tan, Harry J. Groen, Takashi Seto, Egbert F. Smit, Mike Zou, Yiqun Yang, Ying Li, Andrea Chassot Agostinho, Juergen Wolf. Accurate detection of MET exon 14 skipping using a liquid biopsy assay in NSCLC patients in the GEOMETRY mono-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB056.

Summary Background The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase ( ALK )-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. Methods This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK -rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m 2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m 2 ] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. Findings Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42–0·73]; p Interpretation First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK -rearranged NSCLC. Funding Novartis Pharmaceuticals Corporation.

The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as ALK tyrosine kinase inhibitors lead to improved progression free survival and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify eligible patients in a timely fashion. While FISH techniques are commonly used to detect this translocation, the broad implementation of this type of ALK testing into routine diagnostics is not optimal due to technical, structural and financial reasons. Immunohistochemical techniques to screen for EML4-ALK translocations may therefore play an important role in the near future. This consensus paper provides recommendations for the test algorithm and quality of the respective test approaches, which are discussed in the light of the current literature.

Poster Abstract

Gent gran; Nivolumab; Càncer de pulmó de cèl·lules no petites Anciano; Nivolumab; Cáncer de pulmón de células no pequeñas Elderly; Nivolumab; Non-small cell lung cancer Background CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial. Methods Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0–2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3–4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety. Results Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3–4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2. Conclusion These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population. Funded by Bristol-Myers Squibb.

BACKGROUND Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here. METHODS GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed. RESULTS As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2. CONCLUSION These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.

Introduction Mutations in erb-b2 receptor tyrosine kinase 2 (HER2) oncogene are observed in approximately 3% of lung adenocarcinomas or mixed tumors with adenocarcinoma component. Activity of various biologically distinct HER2 inhibitors, including the pan-HER inhibitor afatinib, has been reported in several retrospective trials or small series in advanced pretreated NSCLC with HER2 mutations. We report the first prospective evaluation of afatinib for the treatment of this molecularly defined entity. Methods NICHE, a single-arm phase II trial using a two-stage Simon's design, explored the potential of afatinib to control disease in pretreated patients with advanced NSCLC harboring HER2 exon 20 mutations. A total of 13 patients entered the trial and were treated with afatinib 40 mg/day until tumor progression or lack of tolerability. Results The first-stage stopping boundary was crossed when five of nine patients did not achieve disease control at 12 weeks. The accrual into the trial was stopped with total 13 patients enrolled, with 7 (53.8%) achieving disease control at 12 weeks. Except for 1 patient with early death, progression was documented for all patients, with median progression-free survival of 15.9 weeks (95% confidence interval: 6.0–35.4), and median overall survival of 56.0 weeks (95% confidence interval: 16.3– upper limit not estimable). The toxicity profile was in the expected range. Conclusions Afatinib did not show the expected potential for disease control in NSCLC. However, more than half of the patients in the full cohort achieved disease control at 12 weeks.

Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody–drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting. Patients and Methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS). Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3–5 AEs were seen in 213 (63%) patients. Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.

Summary Background Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50–60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. Methods This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB–IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov ( NCT02108964 ); enrolment to phase 1 is complete and the study is ongoing. Findings By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52–69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1–2. Any-cause grade 3–4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. Interpretation Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. Funding Novartis Pharmaceuticals Corporation.

One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (ALK). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in ALK+-adenocarcinoma of the lung, highlighting the role of TP53 mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient's outcome.

e20577 Background: Multiple mechanisms of resistance to EGFR TKIs therapy in EGFR-mutant non-small cell lung cancer (NSCLC) have been described, most often including the acquisition of the secondary resistance mutations in exon 20 of EGFR. Preclinical models and clinical findings have also shown that co-occurring activation of the RAS/MEK pathway may result in reduced EGFR dependency, which may be overcome by co-inhibition of MEK. We thus hypothesize that the combined inhibition of EGFR and MEK may restore sensitivity to EGFR inhibition in patients with acquired resistance to EGFR inhibition and may as well prolong the acquisition of resistance in treatment-naïve patients. Methods: EATON is an international, multicenter, phase I, dose escalation investigator-initiated trial investigating the recommended phase 2 dose (RP2D), safety and preliminary efficacy of the combination of the third-generation EGFR inhibitor EGF816 with the MEK inhibitor trametinib (NCT03516214). Eligibility criteria: Advanced NSCLC harboring EGFR del19 or p.L858R, first-line or after failure of any EGFR TKI including osimertinib, independently of p.T790M status. Patients with high-level MET amplification are excluded. Dose level escalation will be based on a modified traditional cumulative 3+3 design, i.e. “up and down” (dose level 1: 100 mg nazartinib (EGF816) QD + 1 mg trametinib QD). A total number of 24 patients is planned to be enrolled in 8 trial sites in Germany and Spain. At a first stage, 18 (6´3) patients will be treated and evaluated. Exploratory endpoints aim at the identification of potential mechanisms of resistance to the trial treatment by massively parallel sequencing (MPS), FISH, phospho-protein analyses and whole exome/genome sequencing of baseline and PD biopsy tumour tissue. Additionally blood samples for MPS of cell free DNA will be collected throughout the trial treatment. Results: At the time of data-cut off for this abstract, one patient received treatment at dose-level 1. Treatment was withdrawn due to a serious, bacterial soft tissue infection of the hand outside the DLT period. Conclusions: Data on safety and tolerability of the combination of nazartinib and trametinib is premature. Updated results will be presented at the conference. Clinical trial information: NCT03516214.

e21098 Background: KEAP1 mutations have been shown to decrease the efficacy of both chemotherapy (CTX) and immune-checkpoint inhibition (ICI) in lung adenocarcinoma. However, few is known about their impact on systemic treatment of squamous cell lung cancer (SqCC). The aim of this study was to assess the impact of KEAP1 mutations on systemic treatment outcome in SqCC. Methods: Tumor biopsies of SqCC patients were analyzed within the German Network Genomic Medicine (NGM) using a next-generation DNA sequencing (NGS) panel comprising 17 genes. In subsets, PD-L1 expression was tested with immunohistochemistry (IHC). MET amplification and FGFR1 amplification was tested with fluorescence in situ hybridization (FISH). Overall survival was estimated using Kaplan Meier statistics. For comparisons, we used log rank. A cohort with KEAP1 wild-type patients from the same panel served as control group. Results: Out of 1399 SqCC patients analyzed, 151 had a KEAP1 mutation (11%). The most common co-occurring mutations besides TP53 were PTEN, KRAS and NFE2L2. The median overall survival (OS) of stage IV KEAP1 mutated patients (n = 82) compared to stage IV control group patients (n = 82) was 7.3 vs. 11.4 months (hazard ratio (HR) 0.87 [95% confidence interval (CI) 0.62-1.23], p = 0.43). The addition of a second treatment line with ICI led to marked OS improvements in both KEAP1 mutant patient group (18.7 vs. 6.6 months, HR 0.11, [95% CI 0.04-0.25], p < 0.0001) and control group (20.3 vs. 5.0 months, HR 0.12 [95% CI 0.06-0.24], p < 0.0001). PD-L1 expression did not differ significantly in both groups. Conclusions: KEAP1 mutations occur commonly in SqCC patients and do not impact the efficacy of ICI in terms of OS. To identify prognostic markers for response to ICI further research is needed.

9065 Background: Selpercatinib, a first-in-class highly selective and potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Here we report an update of efficacy and safety results which provide a longer follow up and increased number of patients (safety population: N = 345 vs N = 329). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, ongoing LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites) were included in this analysis. Pts with the opportunity to be followed ≥6 months from their first dose were included in the efficacy-evaluable population for these analyses. Integrated analysis set (IAS) included 218 NSCLC pts with prior platinum-chemotherapy. Primary analysis set (PAS) was a subset of the IAS and included the first 105 consecutively enrolled pts. The treatment-naïve population included 48 efficacy-evaluable pts. Primary endpoint was objective response rate (ORR, RECIST v1.1) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DoR), progression-free survival (PFS), clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), and safety. Safety population (N = 345) included all pts with NSCLC who received ≥1 selpercatinib dose by data cutoff (30 Mar 2020). Results: In pts with prior treatment (N = 218) and treatment-naïve (N = 48) pts, 56% and 60% were female, with a median pt age of 61 and 64 years, respectively. The ORR with selpercatinib was 57% in the IAS, 64% in the PAS, and 85% in the treatment-naïve population (Table). In both the IAS and PAS, the median DoR was 17.5 months, median PFS was 19.3 months at median follow-up of 12.0 and 15.7 months, respectively (Table). The most common treatment-emergent adverse events (TEAEs) reported in ≥25% of pts were dry mouth, diarrhea, hypertension, increased ALT/AST, edema peripheral, and fatigue. Twenty-five pts (7%) permanently discontinued due to TEAEs, with 10 pts (3%) discontinuing selpercatinib due to treatment-related AEs as per investigator. Conclusions: In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC. Selpercatinib was well-tolerated with a safety profile consistent with previous reports. A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing. Clinical trial information: NCT03157128. [Table: see text]

9032 Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.

9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-independent proliferation. Results: In total, 834 cases with uncommon EGFR mutations were reported. Follow-up data after EGFR-TKI (Erlotinib, Gefitinib, Afatinib and Osimertinib), chemotherapy and/or mono-PD(L)1 blockade was available for 252 patients. Mean progression free survival (mPFS) on EGFR-TKIs vs. chemotherapy was 6.6 months vs. 5.0 months (HR 0.54, 95%CI 0.35 to 0.81, P =.003) in group 1 (n = 84), and 6.7 months vs. 3.4 months (HR 0.66, 95%CI 0.47 to 0.92, P =.015) in group 3 (n = 104). Mono-anti-PD(L1) blockade was not superior to chemotherapy (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 – 3.15, P =.535 and group3, mPFS 4.3 months, HR 1.02, 95% CI 0.64 – 1.62, P = 0.951). Exon 20 insertions (group 2, n = 63) did not benefit from EGFR-TKIs or anti-PD(L1) blockade vs. chemotherapy. Overall survival (OS) analysis (n = 218) following chemotherapy (56%) or EGFR-TKI treatment (44%) showed median OS (mOS) of 18.0 months vs. 13.9 months in patients treated with EGFR-TKI and chemotherapy, respectively in group 1 (HR 0.97, 95%CI 0.54 to 1.75, P =.929). In group 3 patients treated with EGFR-TKI and chemotherapy had a mOS of 35.4 months vs. 12.0 months, respectively (HR 0.59, 95%CI 0.35 to 1.01, P =.056). In the Ba/F3 system we could identify 8 recurrent driver and 12 non-driver mutations with a clinically applicable assay turnaround time of 4 weeks to inform clinical decision-making in the future. Conclusions: This real-world dataset confirms that patients with group 1(uncommon) EGFR mutations benefit from EGFR-TKIs and indicates that mono-anti PD(L)1 blockade is not superior to chemotherapy. Furthermore, patients with very rare EGFR mutations (group 3) also experienced a PFS benefit from EGFR-TKI compared to chemotherapy while immune therapy was not beneficial.

Hintergrund Antikorper gegen PD-1 oder PD-L1 konnen beim nichtkleinzelligen Bronchialkarzinom (NSCLC) starke und dauerhafte antitumorale Immunreaktionen hervorrufen. Die immunhistochemische Untersuchung von PD-L1 (PD-L1-Immunhistochemie [IHC]) wird als pradiktiver Biomarker getestet; in klinischen Studien wurden mehrere IHC-Assays und Auswertekriterien parallel eingesetzt.

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]

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

Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1–targeted therapy synergistically improves treatment outcome compared with anti–PD-L1 and anti-VEGF monotherapy. Mice treated with anti–PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double-positive exhausted T-cell phenotype. This exhausted T-cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF–targeted treatment. We confirmed a similar TIM-3–positive T-cell phenotype in peripheral blood mononuclear cells of patients with SCLC with adaptive resistance to anti–PD-1 treatment. Mechanistically, we show that VEGFA enhances coexpression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in patients with SCLC during anti–PD-1-targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti–PD-L1 therapies can be an effective treatment strategy in patients with SCLC. Significance: Combining VEGF and PD-L1 blockade could be of therapeutic benefit to patients with small cell lung cancer. Cancer Res; 78(15); 4270–81. ©2018 AACR.

Background Entrectinib is a potent inhibitor of ROS1 (in addition to TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumor activity in multiple intracranial tumor models. We present an updated integrated safety and efficacy analysis from three Phase I/II studies of entrectinib (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in patients with locally advanced or metastatic ROS1 fusion-positive NSCLCs. Methods The analysis included patients with ROS1 inhibitor-naive NSCLC harboring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included patients with ROS1 fusion-positive NSCLC who received ≥1 dose of entrectinib; the integrated efficacy analysis included patients with at least 6 months of follow-up. Tumor assessments were done at week 4 and every 8 weeks thereafter. Blinded independent central review (BICR), RECIST v1.1 was performed. Primary endpoints by BICR: overall response rate (ORR) and duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial responses), DOR in patients with an intracranial response, PFS in patients with baseline CNS disease. Results In the ROS1 safety-evaluable population (n=134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of patients. Patients with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of patients, respectively. In the efficacy-evaluable population (n=53 patients with treatment-naive, ROS1 fusion-positive NSCLC; median age 53 years, 64% female, 59% never smokers), BICR-assessed ORR was 77% (95% CI 64-88), complete responses n=3 (6%). Median BICR-assessed DOR: 25 mo (95% CI 11-35). Median BICR-assessed PFS: 26 mo (95% CI 16-37) and 14 mo (95% CI 5-NR) for patients without (n=30) and with CNS disease (n=23) at baseline, respectively. In patients with baseline CNS disease (per BICR assessment, n=20), intracranial ORR was 55% (95% CI 32-77) and median intracranial DOR in patients with an intracranial response (n=11) was 13 mo (95% CI 6-not reached). Conclusion Entrectinib is highly active in patients with ROS1 fusion-positive NSCLC, including those with CNS disease. Entrectinib is well tolerated and has a manageable safety profile. Citation Format: Alexander Drilon, Fabrice Barlesi, Filippo De Braud, Byoung Chul Cho, Myung-Ju Ahn, Salvatore Siena, Matthew G. Krebs, Chia-Chi Lin, Tom John, Daniel SW Tan, Takashi Seto, Rafal Dziadziuszko, Hendrick-Tobias Arkenau, Christian Rolfo, Jurgen Wolf, Chenglin Ye, Todd Riehl, Susan Eng, Robert C. Doebele. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT192.

Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALIC-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as a new standard of care for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit. (C) 2014 The Authors. Published by Elsevier Ireland Ltd.

To evaluate efficacy and toxicity of stereotactic body radiation therapy (SBRT) with CyberKnife® (Accuray, Sunnyvale, CA, USA) in a selected cohort of primary, medically inoperable early-stage non-small cell lung cancer (NSCLC) patients. From 2012 to 2016, 106 patients (median age 74 years, range 50–94 years) with primary NSCLC were treated with SBRT using CyberKnife®. Histologic confirmation was available in 87 patients (82%). For mediastinal staging, 92 patients (87%) underwent 18F-fluorodeoxyglucose positron-emission tomography (18-FDG-PET) and/or endobronchial ultrasound (EBUS)-guided lymph node biopsy or mediastinoscopy. Tumor stage (UICC8, 2017) was IA/B (T1a-c, 1–3 cm) in 86 patients (81%) and IIA (T2a/b, 3–5 cm) in 20 patients (19%). Depending on tumor localization, three different fractionation schedules were used: 3 fractions of 17Gy, 5 fractions of 11Gy, or 8 fractions of 7.5 Gy. Tracking was based on fiducial implants in 13 patients (12%) and on image guidance without markers in 88%. Median follow-up was 15 months (range 0.5–46 months). Acute side effects were mild (fatigue grade 1–2 in 20% and dyspnea grade 1–2 in 17%). Late effects were observed in 4 patients (4%): 3 patients developed pneumonitis requiring therapy (grade 2) and 1 patient suffered a rib fracture (grade 3). In total, 9/106 patients (8%) experienced a local recurrence, actuarial local control rates were 88% (95% confidence interval, CI, 80–96%) at 2 years and 77% (95%CI 56–98%) at 3 years. The median disease-free survival time was 27 months (95%CI 23–31 months). Overall survival was 77% (95%CI 65–85%) at 2 years and 56% (95%CI 39–73%) at 3 years. CyberKnife® lung SBRT which allows for real-time tumor tracking and risk-adapted fractionation achieves satisfactory local control and low toxicity rates in inoperable early-stage primary lung cancer patients.

Objectives The recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected small patient subgroups. This analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). Methods The profit margins between recruiting groups with ≤3 and >3 patients were compared. Clinical and economic data from clinical trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. Results 161 patients were enrolled in 27 clinical trials. The key economic parameter determining costs and payments was the ‘trial visits’. In comparison of the two groups (A ≤ 3; B > 3 patients enrolled) we found negative profit margins for the low recruiting group (€ −1444). Concerning the number of visits significant differences were found between PhST and IIT (p = 0.009). Additionally, sub-analysis show structural differences in cost composition by conducting PhST and IIT. Conclusion Trials with low patient numbers and IIT, do not cover the cost. To ensure adequate, cost-covering compensation by pharmaceutical companies CCCs have to thoroughly calculate the cost of early proof of concept trials. The findings of this study also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine.

e20550 Background: Patient selection, dosing regimens and resistance mechanisms for immune checkpoint inhibitor combination therapy remain unmet medical needs in lung cancer. Combining blockade of PD-1 and CTLA-4 can be more effective than monotherapy but is accompanied by an increase in toxicity. Thus, to circumvent unnecessary toxicity it is of great interest to identify patients who will benefit from PD-1/PD-L1 blockade alone and to add ipilimumab only in case of primary or secondary progression. We present interim data from the non-small-cell lung cancer (NSCLC) cohort of the ongoing BIOLUMA trial which evaluates efficacy and safety of nivolumab and ipilimumab in lung cancer with a broad translational program to identify potential biomarkers predictive of response and/or resistance including whole exome sequencing (WES) of serial biopsies, functional analysis of peripheral T-cells and gut microbiome analyses. Methods: BIOLUMA is a multicentre non-randomised phase II trial in 2nd line patients with non-squamous NSCLC. Patients are treated with nivolumab 240 mg until disease progression and subsequently with a combination therapy of nivolumab 3 mg/kg q2w and ipilimumab 1mg/kg q6w. Primary endpoint is overall response rate (ORR) after addition of ipilimumab to nivolumab treatment. Analysis of sequential tumor biopsies, blood and gut microbiome is performed at different timepoints. Results: To date, 26 patients have been enrolled and 9 patients were transferred to the combination therapy after progression on nivolumab monotherapy. Drop out rate between the treatment arms is high, mainly due to rapid disease progression and adverse events which don’t allow addition of ipilimumab. ORR is available for 8 of these patients: 6 patients (75%) had PD as best response, and 1 (12.5%) each had a stable disease and partial response, respectively. The patient who achieved a PR had experienced primary tumor progression on nivolumab monotherapy before. Toxicity rate was similar to what has been reported from other trials. Conclusions: In NSCLC, addition of ipilimumab to nivolumab in nivolumab refractory patients seems to be safe, but the response rate is low and the drop out between the treatment parts high. Given these data, early termination of this cohort is currently discussed. Clinical trial information: NCT03083691.