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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Osimertinib is an EGFR TKI that is active against T790M, the most common resistance mutation seen in patients who have progressed following first line EGFR-TKI therapy. In a phase I/II study of 253 patients who had progressed on an EGFR-TKI, osimertinib demonstrated a response rate of 51% [28]. Among 127 patients with a confirmed EGFR T790M, the response rate was 61%. The median progression-free survival was 9.6 months in EGFR T790M-positive patients. The benefit of osimertinib in EGFRT790M positive lung cancer was confirmed in a phase III trial against chemotherapy following first-line EGFR TKI therapy [29]. In this trial of 419 patients, osimertinib had a PFS of 10.1 months vs. 4.4 months with platinum-pemetrexed (HR 0.30; 95% CI 0.23 to 0.41; P<0.001). The corresponding response rates were 71% and 31%, respectively. In a phase III trial in treatment naïve patients with activating EGFR mutations, osimertinib had a superior PFS compared to standard of care TKIs (18.9 vs. 10.2 months; HR 0.46 (0.37, 0.57); p<0.0001)
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Common side effects of osimertinib include GI symptoms (e.g., diarrhea and stomatitis), skin and nail disorders (e.g., pruritus and rash), and interstitial lung disease (including pneumonitis).
Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Penelope Bradbury, John Hilton, Janet E. Dancey
Osimertinib is an oral, irreversible EGFR-TKI that selectively inhibits both the sensitizing EGFR mutations and the T790M resistance mutation, but with less activity against the wildtype EGFR. In a phase I trial of osimertinib, 253 patients (31 in a dose escalation cohort and 253 in an expansion cohort), with advanced or metastatic EGFR mutation positive NSCLC, or prior benefit from an EGFR-TKI, following failure of a prior EGFR-TKI were enrolled. Of the 127 patients with T790M disease, the response rate was 61% (95% CI 52–70) and 21% (95% CI 12–34) in evaluable patients with T790M negative disease (Jänne, 2015). Given data from the expansion of the phase I trial demonstrating a high response rate in patients with EGFR mutation positive NSCLC and the acquired T790M resistance mutation, a randomized phase III trial to compare osimertinib versus standard chemotherapy after failure of first-line EGFR-TKI therapy was undertaken. The AURA3 trial demonstrated a significant improvement in the progression-free survival, the primary endpoint of the trial, for patients enrolled on the osimertinib arm (10.1 months versus 4.4 months, HR 0.30 (95% CI 0.23–0.41; p < 0.001). The objective response rate was also significantly higher with osimertinib versus chemotherapy (71% versus 31%, respectively (Mok, 2017)).
An updated patent review of small-molecule ROS1 kinase inhibitors (2015–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Meng Liu, Jintian Dai, Mudan Wei, Qingshan Pan, Wufu Zhu
Primegene (BEIJING) company has applied for a total of 25 compounds containing macrocyclic skeletons with excellent potency in the patent WO2019206069A1. Among all these compounds, only compound 5 exhibited potent activity on TRK and ROS1 kinase, as well as ROS1G2032R mutant kinase at the same time. In particular, it has shown more potency than control TPX-0005 (IC50 = 1.01 nM) against ROS1G2032R mutant kinase with an IC50 valued 0.36 nM. Meanwhile, the patent also introduced the potential of compound 5 in overcoming EGFR resistance. Osimertinib (showed in Figure 8), as a third-generation EGFR inhibitor, has emerged inevitable drug resistance problems in clinical. In vitro, in the cell viability test of H1975 cells (expressing EGFR L858R and T790M mutations), compound 5 and Osimertinib demonstrated a high degree of synergy against this double mutant cells, indicating that the combination of compound 5 and Osimertinib have the ability to overcome EGFR resistance. Overcoming resistance to EGFR mutations was presumed to inhibit its downstream signaling pathway by ROS1 inhibitors, which provided a new idea for clinically overcoming EGFR resistance mutations. In the following pharmacokinetic study of male SD rats, the oral pharmacokinetic performance of compound 5 was better than that of the control, with the bioavailability high up to 100%. At the same time, due to the design of the rigid macrocyclic structure, the drug brain/blood ratio of this compound (1.14) was 6 times higher than that of the control (0.17) [53].
Intracranial effect of osimertinib in relapsed EGFR-mutated T790M-positive and -negative non-small cell lung cancer patients: results from a phase II study
Published in Acta Oncologica, 2021
Inger Johanne Zwicky Eide, Harald Grut, Åslaug Helland, Simon Ekman, Jens Benn Sørensen, Karin Holmskov Hansen, Bjørn Henning Grønberg, Saulius Cicenas, Jussi Pekka Koivunen, Anders Mellemgaard, Odd Terje Brustugun
A rebiopsy was done before commencement on osimertinib, but patients were enrolled regardless of the presence of T790M. If a tissue biopsy was not considered feasible, a plasma sample could be analyzed for mutations. T790M-negativity was defined as negative in tissue biopsy. In cases where a tissue biopsy were insufficient for assessing mutational status and a supplementary liquid biopsy negative or not available, T790M-status were regarded unknown. All patients received treatment with osimertinib 80 mg administered orally once daily. Toxicity-triggered dose reduction to 40 mg daily was allowed. Treatment continued until radiological progression according to RECIST 1.1 or death. Treatment beyond RECIST-defined progression was allowed if the patient was deemed by the investigator to derive clinical benefit. A baseline MRI or CT scan of the brain was mandated in cases with known or suspected brain metastases. If the presence of brain metastases was confirmed, the brain scan was to be repeated at the time for overall tumor assessments every 8 weeks the first year and thereafter every 12 weeks until progression at any site.
An overview of osimertinib as a treatment of non-small cell lung cancer (NSCLC): an update
Published in Expert Opinion on Pharmacotherapy, 2021
Luigi Cerbone, Jose Carlos Benitez, David Planchard, Carlo Genova
A population pharmacokinetics (PK) model was developed from data obtained from the healthy volunteer phase 1 PK study (including 32 patients), the phase 1/2 trial AURA 1 and the phase 2 trial AURA 2, including in total 738 patients. The patients in the phase 1 study took osimertinib at a dose ranging from 20 to 240 mg daily, while patients in the phase 2 study took the drug at 80 mg daily. In this model, the PK of osimertinib was well described as a two-compartment model, one each for osimertinib and its active metabolite AZ5154. In the final population pharmacokinetics (popPK) analysis, the typical (±standard error) value of clearance, volume of distribution, and t1/2 for osimertinib were 14.2 (±0.3) L* h−1, 986 (±28) L, and 48 (±2) h, respectively. Key patients features that influenced PK parameters were the race, with an area under the curve at ss (AUCss) of AZ5154 that was 10–23% lower in non-Caucasian patients, and body weight, with a modification of AUCss ranging from −20% to +30% for native osimertinib and from −40% to +50% for AZ5154 for body weight 5–95% interval (43–90 kg) [7]. In the exposure response analysis, a greater exposure to osimertinib did not reflect on a greater drug efficacy in terms of objective response, duration of response (DoR), or best percentage change in target-lesion size. However, a greater AUCss was linearly correlated to an increased risk of developing rash and diarrhea. Regarding the QTcF/exposure relationship, a linear increase of QTcF from baseline was demonstrated, with a mean increase of QTcF of 14.8 ms from baseline at the ss of the approved dose of 80 mg daily [7].