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Background Osimertinib is an EGFR TKI selective for both EGFR TKI sensitizing and Thr790Met resistance mutations. While intracranial activity of osimertinib has been observed in patient subgroups within larger trials, a study focusing exclusively on patients with brain metastases has not yet been reported. We assessed the intracranial activity of osimertinib in EGFR-mutant, NSCLC patients with asymptomatic brain metastases, either as first-line therapy or following progression in pre-treated Thr790Met-positive patients. Methods In this phase 2, open-label, two-arm study we enrolled patients with EGFR-mutant, metastatic NSCLC and at least one asymptomatic brain metastasis of 4 mm or larger in diameter. Treatment-naïve patients (arm A) and Thr790Met-positive patients who progressed on EGFR-TKI therapy (arm B) received osimertinib 80 mg once daily. Dose escalation to 160 mg once daily was performed in cases of intracranial progression without symptomatic systemic progression. The primary endpoint in both arms was intracranial metastasis response. Here we present a preliminary analysis upon the trial outstanding results. Results Between 31/05/16 - 30/08/18 (data cutoff) 21 patients with asymptomatic brain metastases started osimertinib treatment (arm A = 15, arm B = 5 arm C = 1). Median duration of follow-up was 43 weeks. Intracranial response was achieved in 11 (73%; 95% CI 45%-92%) of 15 treatment-naïve patients (arm A) and in four (80%; 95% CI 28%-99%) of five previously treated Thr790Met-positive patients (arm B). Dose escalation was performed in four patients (arm A = 2, Arm B = 2), with one continuous response. 10 of 15 patients (67%) in arm A and 1 of 5 patients (20%) in arm B continue responding to osimertinib 80 mg at data cutoff. Toxicity side effects were similar to previously reported studies. Conclusions Osimertinib shows equal intracranial and systemic activity with minor side effects in EGFR-mutant, treatment-naïve NSCLC and in previously treated Thr790Met-positive patients. Therefore, we suggest that osimertinib is a reasonable first treatment option for patients with EGFR-positive NSCLC and newly diagnosed asymptomatic brain metastases, and may postpone or even defer the need for brain irradiation. Clinical trial identification NCT02736513. Legal entity responsible for the study Nir Peled. Funding AstraZeneca. Disclosure N. Peled: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BI, BMS, Lilly, MSD, Novartis, Pfizer, Roche, FMI, NovellusDx, Gaurdant360, Takeda. E. Dudnik: Advisory / Consultancy, Travel / Accommodation / Expenses: BI, Merck/MSD, Roche Pharmaceuticals, AstraZeneca. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

BACKGROUND RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-OOl ClinicalTrials.gov number, NCT03157128.) [ABSTRACT FROM AUTHOR]

Background: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.Methods: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.Results: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.Conclusions: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .). [ABSTRACT FROM AUTHOR]

Background In the phase III FLAURA study (NCT02296125), the 3rd-generation EGFR-TKI osimertinib showed superior efficacy to comparator EGFR-TKIs in previously untreated EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC). Here we report results from an exploratory analysis of ctDNA for the early detection of disease progression (PD) in FLAURA. Methods Treatment-naïve patients (pts) with EGFRm (ex19del/L858R) locally advanced/metastatic NSCLC (n = 556) were randomised 1:1 (osimertinib 80 mg qd: comparator [gefitinib 250 mg qd/erlotinib 150 mg qd]). Plasma samples were collected on Days 1, 8 and 15, then every 21 days for weeks (W) 3–18, then every 6W thereafter. In pts who had a plasma sample on PD and/or discontinuation, ctDNA droplet digital PCR (ddPCR; Biodesix) for EGFRm (ex19del/L858R/T790M) was performed at all available time points and C797S for post-W6 time points. C797S and T790M were the only resistance mutations assayed. ctDNA progression was defined with respect to the nadir ctDNA result and its proximity to the ddPCR detection and quantification limits. Results The ctDNA progression analysis included 122/556 (22%) pts with valid longitudinal monitoring ddPCR data and RECIST PD by DCO1 (12 June 2017). Across both arms, ctDNA progression preceded or co-occurred with PD in 80/122 (66%) pts with 2.7 months (mo) median lead time; 9.5 mo median progression-free survival (mPFS; n = 80). Acquired C797S or T790M was detected in 57/122 (47%) pts with ctDNA progression (osimertinib 4/50 [8%] C797S, comparator 53/72 [74%] T790M); median time to detection was 16.7 and 8.4 mo for the osimertinib and comparator arms, respectively, mirroring overall mPFS. In pts with ctDNA progression and PD (n = 106), acquired T790M and C797S were detected either at the same time as, or earlier than PD in 41/106 (38%) pts (osimertinib 2/39 [5%], comparator 39/67 [58%]); median lead time was 1.4 mo. Conclusions ctDNA monitoring may allow for earlier identification of pts who progress on first-line EGFR-TKI therapy and the detection of EGFR-mediated resistance mechanisms in advance of PD in EGFRm NSCLC. Future work aims to explore early detection of non-EGFR-mediated resistance. Clinical trial identification NCT02296125. Editorial acknowledgement Donna Tillotson, PhD, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda. A. Markovets: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. N. Nogami: Honoraria (self): Pfizer Inc. Chugai Pharmaceutical Co. Ltd, Eli Lilly, Taiho Pharmaceutical Co. Ltd. AstraZeneca, Kyowa Hakko Kirin, Ono Pharmaceutical Co. Ltd. Bristol-Myers Squibb, MSD. B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. N. Peled: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Advisory / Consultancy: Eli Lilly; Honoraria (self): Foundation Medicine; Shareholder / Stockholder / Stock options: Novellus Dx; Honoraria (self): Guardant360. K. Vishwanathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Todd: Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Chmielecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Hartmaier: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options, Licensing / Royalties, Nfe2l2 exon 2 ano/or exon 3 loss from work conducted at Foundation Medicine; provisional patent filed: Foundation Medicine. S.S. Ramalingam: Advisory / Consultancy, Research grant / Funding (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Merck; Advisory / Consultancy: AbbVie, Celgene, Genentech, Lilly, Loxo, Takeda; Research grant / Funding (self): Tesaro. [ABSTRACT FROM AUTHOR]