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Osimertinib was compared with standard EGFR blockers among patients with non–small-cell lung cancer with activating mutations in EGFR . The median overall survival was 38.6 months with osimertinib and 31.8 months with erlotinib or gefitinib. This 20% lower risk of death was noted despite the crossover of patients from standard therapy to osimertinib during subsequent therapy.

The incidence of recurrence after curative resection among patients with stage IB, II, or IIIA non–small-cell lung cancer is high and is only slightly lower with adjuvant chemotherapy. A randomized trial of adjuvant osimertinib involving patients with EGFR mutation–positive NSCLC showed a substantial decrease in recurrence. Central nervous system relapses were also significantly reduced.

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification ( n  = 17; 16%) and EGFR C797S mutations ( n  = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted. In the phase III FLAURA study (NCT02296125), the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib provided superior progression-free survival versus comparator EGFR-TKIs in patients with NSCLC. Here, by next-generation sequencing of circulating tumor DNA, the authors assess candidate mechanisms of acquired resistance to first-line osimertinib in patients from the FLAURA trial.

Population pharmacokinetics (popPK) modeling for osimertinib, a third‐generation, irreversible, oral epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR‐TKI sensitizing mutations and EGFR T790M, was previously reported utilizing AURA and AURA2 data (advanced non‐small cell lung cancer [NSCLC]). We report updated popPK modeling incorporating AURA3 and FLAURA data (advanced NSCLC); model validation used ADAURA data (resected stage IB–IIIA NSCLC). Updated popPK analyses were based on patients from AURA (n = 599), AURA2 (n = 210), AURA3 (n = 277), and FLAURA (n = 278) using a linear one‐compartmental disposition model for osimertinib and its metabolite, AZ5104, with first‐order oral absorption. A full covariate model, using Monte Carlo simulations, was developed to assess the effects of covariates on osimertinib and AZ5104 clearance. External validation was conducted using ADAURA study data (n = 325). In the final popPK model, the apparent clearance and volume of distribution of osimertinib (14.3 L/h; 918 L) and AZ5104 (31.3 L/h; 143 L) were comparable to previous analyses. Albumin levels and body weight influenced osimertinib PK, but the effects were not considered clinically meaningful; other covariates had no impact on PK. Goodness‐of‐fit plots indicated that the model adequately described all data. Visual predictive checks showed that the final model validated osimertinib steady‐state PK for adjuvant treatment. PopPK modeling indicated that osimertinib dose adjustment is not required for patients' age, sex, body weight, race, smoking status, or line of therapy, confirming that a fixed 80 mg once‐daily dose is optimal for osimertinib. Osimertinib has proven efficacy in EGFR mutation‐positive NSCLC; a popPK model was previously developed using data from 2nd‐/later‐line settings. We updated this model with additional data, confirming that a fixed 80 mg once‐daily dose is optimal for osimertinib across all lines of treatment.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Patients with resected, EGFR -mutated, stage IB to IIIA NSCLC were randomly assigned to receive adjuvant osimertinib or placebo for 3 years. The 5-year overall survival was 88% with osimertinib and 78% with placebo.

In 556 patients with previously untreated lung cancer bearing EGFR mutations, osimertinib and the first-generation EGFR inhibitors erlotinib and gefitinib had similar response rates, but osimertinib resulted in longer progression-free survival and had somewhat less toxicity.

In EGFR -mutated non–small-cell lung cancer, first-line osimertinib plus platinum–pemetrexed extended overall survival to 47.5 months, as compared with 37.6 months with osimertinib alone, but increased the risk of adverse events.