T790M Mutation-positive Non-small Cell Research Articles

PP229 Surrogate Outcomes In Health Technology Assessments Of Oncology Drugs: The Osimertinib Case

IntroductionDecision making in publicly funded healthcare systems must rely on patient-relevant outcomes that directly measure clinical benefit, such as overall survival and quality of life (QoL). However, studies that support market authorization of oncology drugs usually assess surrogate outcomes, without having previously demonstrated that these intermediate outcomes reliably predict clinical outcomes. As part of an HTA process, we evaluated the clinical benefit of osimertinib, compared with platinum-pemetrexed combination chemotherapy, in patients with epidermal growth factor receptor (EGFR) T790M mutation-positive advanced non-small cell lung cancer (NSCLC) that has progressed after first-line EGFR tyrosine kinase inhibitor (TKI) therapy.MethodsWe conducted a systematic search of the PubMed database for randomized controlled trials (RCT) published from inception to January 2019. The clinical outcomes of interest were overall survival and QoL. Where trials reported surrogate outcomes, we conducted additional PubMed searches for evidence of validity for predicting clinical outcomes and used guidance on surrogate outcome validation in oncology from the Institute for Quality and Efficiency in Health Care.ResultsEvidence on osimertinib, compared with chemotherapy, for patients with T790M-positive advanced NSCLC that has progressed after EGFR-TKI therapy was obtained from the AURA3 trial. In this study, overall survival data were immature and the results for QoL and symptom domains were not clinically meaningful. In addition, median progression-free survival (PFS) was six months longer for osimertinib than for chemotherapy. However, to date, no study has demonstrated that PFS reliably predicts longer survival or better QoL.ConclusionsOur HTA suggested that, unless proven, PFS should not be used as a valid surrogate outcome for decision making in public health. For example, the results of the AURA3 trial showed that osimertinib has an effect on the surrogate outcome of PFS in patients with EGFR T790M-positive advanced NSCLC that has progressed after first-line EGFR-TKI therapy, but not on the clinically relevant outcomes of overall survival and QoL. Furthermore, currently available evidence has failed to prove that PFS reliably predicts outcomes that are clinically relevant. Despite this, osimertinib has been given marketing authorization and is widely recommended in clinical guidelines.

Final analysis of a phase II, open label, randomized study of osimertinib versus osimertinib plus carboplatin/pemetrexed for patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed with previous EGFR-TKI and whose tumours harbour a T790M mutation (LOGIK1604/NEJ032A).

e21594 Background: Osimertinib is now available not only as a second line treatment for the patients with EGFR and T790M-mutation positive non-small cell lung cancer (NSCLC) after initial tyrosine kinase inhibitors (TKIs) but as a first line treantment for those who are TKI-naive. The efficacy and the safety of osimertinib plus palatinum-based chemotherapy has not yet been evaluated. Methods: This phase 2, open-label, randomized study enrolled adult patients (pts) with clinical stage IIIB or IV, or postoperative recurrent NSCLC harbouring susceptible EGFR and T790M mutations after preceded EGFR-TKI failure. Pts were randomly assigned to receive either an osimertinib [80 mg/day 1-21; q3w] or a combination of osimertinib [80 mg/day 1-21] with carboplatin/pemetrexed (hereafter combination) [area under the curve (AUC) = 5 and 500 mg/m2 day 1; q3w]. The primary endpoint was progression-free survival (PFS). Secondary endpoints included incidence of adverse events, response rate and overall survival. As indiction of osimertinib was expanded to a first line, we amended the protocol to discontinue the enrollment and perform final analyses. Results: From October 2016 to January 2019, 62 pts were enrolled [31 pts osimertinib; 31 pts combination] (median age 68 (37-80); 53.2% male; 83.3% stage IV; 100% adenocarcinoma; 59.7% exon 19 deletion and 40.3% L858R; 45.2% never smoker). The rate of grade (G) ≥ 3 treatment-related adverse events was 32.2% in the osimertinib group and 83.9% in the combination group. Neutropenia, anemia and thrombocytopenia were more common in the combination group and the rates of G ≥ 3 were 0%, 0% and 6.4% in the osimertinib group and 38.7%, 25.8% and 29.1% in the combination group, respectively. Three episodes (9.7%) of G ≥ 3 infection and one episode (3.2%) of G ≥ 3 febrile neutropenia were uniquely observed in the combination group, however, these were well managed. Two episodes (6.5%) of G ≥ 3 pneumonitis was observed only in the osimertinib group. Exaggeration of adverse events specific for osimertinib or any unknown adverse event was not observed in the combination group. Final PFS analysis is to be demonstrated in the presentation. Conclusions: Combination of osimertinib with carboplatin and pemetrexed demonstrated safety in patients with EGFR and T790M mutation-positive NSCLC and the efficacy should be validated in the future phase 3 study. Clinical trial information: 000024438.

Real-world use of osimertinib in non–small cell lung cancer: ASTRIS study Korean subgroup analysis

Objective: ASTRIS is a large real-world, open-label, multinational clinical study of osimertinib in patients with epidermal growth factor receptor (EGFR) T790M mutation-positive advanced non-small cell lung cancer (NSCLC) who have previously received a tyrosine kinase inhibitor (TKI). We report data from the Korean ASTRIS subgroup.Methods: Adult patients with locally advanced or metastatic NSCLC with a confirmed T790M mutation, WHO performance status of 0–2 and prior EGFR-TKI therapy, received osimertinib 80 mg once daily. Efficacy outcomes were overall survival (OS), investigator-assessed response rate (RR) and progression-free survival (PFS), and time to treatment discontinuation (TTD).Results: At data cut-off (20 October 2017), 466 Korean patients were enrolled. Baseline EGFR molecular testing was mainly performed on biopsied tissue (75.1%). Baseline mutations co-occurring with T790M included exon 19 deletions (60.7%) and L858R (32.8%). 1-year OS was 82.7% (OS data not matured at data cut-off). Overall, RR was 71.0%, median PFS was 12.4 months and median TTD was 15.0 months. In patients with/without CNS metastases, RR was 68.0% and 79.6%, respectively; median PFS, 10.8 and 11.0 months, respectively; and median TTD, 11.2 and 14.7 months, respectively. Overall, 31.1% of patients experienced ≥1 adverse event (AE), leading to dose modification (12.0%), discontinuation (5.2%) or death (2.8%). Serious AEs (24.9%) included pulmonary embolism (1.7%), pleural effusion (1.7%), and pneumonia (1.5%).Conclusion: In this real-world subgroup analysis of Korean patients in the ASTRIS study, osimertinib demonstrated comparable clinical efficacy to that attained in the global ASTRIS study and other clinical trials, with no new safety concerns.

Abstract CT013: Osimertinib displays high brain exposure in healthy subjects with intact blood-brain barrier: a microdose positron emission tomography (PET) study with 11C-labelled osimertinib

Abstract Introduction. Osimertinib is a third generation, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used for treatment of patients with locally advanced and metastatic T790M mutation positive non-small cell lung cancer (NSCLC). Osimertinib has shown efficacy superior to that of EGFR-TKIs (erlotinib and gefitinib) in the first-line treatment of EGFR mutation-positive advanced NSCLC and with reduced risk of CNS progression (Soria et al 2017). Furthermore, rapid osimertinib response on brain metastases has been reported (Koba et al 2017). Preliminary examination in non-human primates using 11C-labeled osimertinib indicates penetration of the intact blood brain barrier (BBB) and a high brain exposure compared to other EGFR-TKI agents, which may potentially contribute to improved efficacy in patients with brain metastases compared to other TKIs (Ballard et al 2016). Aim. The aim of this positron emission tomography (PET) study was to measure the brain exposure of [11C]osimertinib administered intravenously in healthy volunteers with an intact BBB. Methods. Eight male healthy volunteers (age 52±8 years) were examined for ~90 minutes with PET after single intravenous microdose of [11C]osimertinib. Concentration of [11C]osimertinib was also measured in arterial and venous blood and plasma. Brain MRI was acquired and used for co-registration of the PET data and automatic delineation of regions of interest in the brain. PK parameters Cmax (brain), Tmax (brain) and AUC0-90 min brain/blood ratio were calculated. Results. In all healthy volunteers, [11C]osimertinib distributed to the brain rapidly, with mean Tmax=13 min (range 5-30 min), Cmax= 1.4±0.3 SUV (range 1-1.8) corresponding to 2.2±0.2% of injected radioactivity and AUC0-90 min brain/blood ratio=3.8±0.3 (range 3.3-4.1). [11C]Osimertinib was distributed in all regions of the brain with uptake being highest in putamen followed by thalamus, frontal cortex, temporal cortex, caudate, cerebellum and white matter. Conclusions. This study indicates that [11C]osimertinib has a good brain exposure in human subjects with intact BBB and may potentially contribute to the efficacy of treatment with osimertinib. In NSCLC, patients with brain metastasis may benefit from treatment with osimertinib due to favorable brain exposure of the drug. Future studies in patients with NSCLC are required to examine uptake and kinetic properties of [11C]osimertinib in brain metastases.