osimertinib
Regulatory sources consulted
Approved indications
- EGFR-mutated NSCLC: adjuvant treatment after resection with ex19del/L858R; unresectable stage III without progression after chemoradiation; advanced/metastatic ex19del/L858R disease as monotherapy or with pemetrexed and platinum; or T790M after an EGFR TKI. Confirm the relevant biomarker before treatment.
Contraindications
Absolute
- CIMA: hypersensitivity to the active substance or excipients and concomitant St John’s wort; the FDA label establishes no formal contraindications.
Clinical warnings
- Withhold for suspected ILD. Outside the branch with recent definitive platinum-based chemoradiation, discontinue if confirmed. After that chemoradiation, for grade 1 continue or withhold and restart according to the clinical situation; for grade ≥2 permanently discontinue. — OpenFDA, set_id 5e81b4a7-b971-45e1-9c31-29cea8c87ce7
- With osimertinib plus pemetrexed/platinum, assess LVEF at baseline and during treatment in all patients; with monotherapy, do so when cardiac risk factors are present. Monitor ECG and electrolytes when QT risk exists. — OpenFDA, set_id 5e81b4a7-b971-45e1-9c31-29cea8c87ce7
- For suspected aplastic anemia, withhold; if confirmed, permanently discontinue. For suspected erythema multiforme major, SJS, or TEN, withhold and discontinue if confirmed. For cutaneous vasculitis, withhold, assess systemic and dermatologic involvement, and consider discontinuation if no other cause is found. — OpenFDA, set_id 5e81b4a7-b971-45e1-9c31-29cea8c87ce7
Drug interactions
- HighStrong CYP3A inducers
Mechanism: They reduce osimertinib exposure.
Recommendation: Avoid; if unavoidable, increase to 160 mg/day and return to 80 mg 3 weeks after it is stopped.
OpenFDA, set_id 5e81b4a7-b971-45e1-9c31-29cea8c87ce7
- HighBCRP/P-gp substrates or QT-prolonging drugs
Mechanism: Osimertinib may increase substrate exposure and add QT risk.
Recommendation: Monitor toxicity of narrow-therapeutic-index substrates and avoid QT drugs when possible; otherwise monitor ECG/electrolytes.
OpenFDA, set_id 5e81b4a7-b971-45e1-9c31-29cea8c87ce7
Adverse events
Common (≥1%)
diarrhea · rash · musculoskeletal pain · nail toxicity · dry skin · stomatitis · fatigue
Pregnancy and lactation
Verify pregnancy. Women must use contraception during treatment and for 6 weeks afterward; men during treatment and for 4 months afterward. Do not breastfeed during treatment or for 2 weeks afterward.
Recent literature (PubMed)
Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR 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 EGFR-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 driv
Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3%
Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55
Previous results from this phase 3 trial showed that progression-free survival among participants with previously untreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC) was significantly improved with amivantamab-lazertinib as compared with osimertinib. Results of the protocol-specified final overall survival analysis in this trial have not been reported. We randomly assigned, in a 2:2:1 ratio, participants with previously untreated EGFR-mutated (exon 19 deletion or L858R substitution), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib, osimertinib, or lazertinib. Overall survival (assessed in an analysis of the time from randomization to death from any cause) in the amivantamab-lazertinib group as compared with the osimertinib group was a key secondary end point. Additional end points included safety. A total of 429 participants each were assigned to receive amivantamab-lazertinib or osimertinib. Over a median follow-up of 37.8 months, amivantamab-lazertinib led to significantly longer overall survival than osimertinib (hazard ratio for death, 0.75; 95% confidence interval, 0.61 to 0.92; P = 0.005); 3-year overall survival was 60% and 51%, respectively. At the clinical cutoff date, 38% of participants in the amivantamab-lazertinib group and 28% in the osimertinib group were still receiving the assigned treatment. Adverse events of grade 3 or higher were more common with amivantamab-lazertinib (in 80% of participants) than with osimertinib (in 52%), particularly skin-related events, venous thromboembolism, and infusion-related events; these findings were consistent with the established safety profile of each treatment. No new safety signals were observed with additional follow-up. Amivantamab-lazertinib led to significantly longer overall survival among participants with previously untreated EGFR-mutated advanced NSCLC than osimertinib but was associated with an increased risk of adverse events of g
The primary analysis of this trial showed that first-line treatment with osimertinib plus chemotherapy with a platinum-based agent and pemetrexed led to significantly longer progression-free survival than osimertinib monotherapy among patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). Results from the planned final analysis of overall survival are needed. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC who had not previously received treatment for advanced disease to receive either osimertinib (80 mg once daily) plus chemotherapy with pemetrexed (500 mg per square meter of body-surface area) and a platinum-based agent (cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or osimertinib monotherapy (80 mg once daily). The key secondary end point was overall survival. A total of 557 patients were randomly assigned to the osimertinib plus platinum-pemetrexed group (279 patients) or the osimertinib monotherapy group (278 patients). The median overall survival was 47.5 months in the osimertinib plus platinum-pemetrexed group and 37.6 months in the osimertinib monotherapy group (hazard ratio for death, 0.77; 95% confidence interval, 0.61 to 0.96; P = 0.02). Grade 3 or higher adverse events of any cause were reported in 70% of the patients in the osimertinib plus platinum-pemetrexed group and in 34% of the patients in the osimertinib monotherapy group; adverse events leading to the discontinuation of osimertinib were reported in 12% and 7%, respectively. Among patients with EGFR-mutated advanced NSCLC, first-line treatment with osimertinib plus platinum-pemetrexed led to significantly longer overall survival than osimertinib monotherapy and was associated with an increased risk of reversible adverse events of grade 3 or higher. (Funded by AstraZeneca; FLAURA2 ClinicalTrials