Jean-Marc Maurel

BACKGROUND: T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: -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. RESULTS: 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. CONCLUSIONS: -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

PURPOSE We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ( EGFR)–mutated advanced non–small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

Letter (no abstract).

What was the purpose of the FLAURA2 study? This is a summary of the main results of the FLAURA2 clinical study in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC). The results were published in full in 2023. NSCLC is the most common type of lung cancer, but is often not diagnosed until the cancer has spread beyond the lungs described as ‘metastastic’ or ‘advanced’ disease. Epidermal growth factor (EGF) binds to the EGFR (epidermal growth factor receptor) and leads to signaling events that control how cells grow and divide.Healthy cells transform into cancer cells when changes (mutations) occur in the EGFR gene, in NSCLC this is known as EGFR-mutated NSCLC. Osimertinib (TAGRISSO®) is a drug that has already been shown to treat EGFR-mutated NSCLC by blocking the effects of mutated EGFR, and preventing, slowing or stopping the growth of cancer cells. Osimertinib is approved and recommended by international treatment guidelines as initial (first-line) treatment for EGFR-mutated advanced NSCLC, but when osimertinib stops working, chemotherapy is usually recommended as the next treatment. However, many patients with EGFR-mutated NSCLC do not receive another treatment after first-line osimertinib, mainly because their health has become too poor. This means that it is important to make sure the best treatment is given first. The FLAURA2 study assessed whether adding chemotherapy to osimertinib as first-line treatment for patients with EGFR-mutated advanced NSCLC could extend the time before cancer cells grew/spread,or prolong the time before patients died. What were the results? In the FLAURA2 study, patients with EGFR-mutated advanced NSCLC received first-line treatment consisting of either chemotherapy (a platinum drug plus pemetrexed) added to osimertinib, or osimertinib alone. Osimertinib plus chemotherapy extended the time from when patients were assigned a treatment until the cancer grew/spread, or until death, compared with osimertinib alone. What do the results of the study mean? The results show that addition of chemotherapy to first-line osimertinib could be beneficial for patients with EGFR-mutated advanced NSCLC. Side effects of the combination were similar to those of either chemotherapy or osimertinib alone, and the combination was considered tolerable. The findings led to osimertinib plus chemotherapy being approved in a number of countries, including China, Japan, the USA, and the European Union, as a new first-line treatment option. The FLAURA2 study is ongoing, and more results are expected to be released in the future.

What was the purpose of the FLAURA2 study? This is a summary of results from the FLAURA2 clinical study in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC). The results were published in full in 2023. NSCLC represents 85% of lung cancer cases, but is often not diagnosed until the cancer has spread beyond the lungs, known as ‘metastatic’ or ‘advanced disease’.EGFR(‘epidermal growth factor receptor’) controls how cells grow and divide.Changes (mutations) in the EGFR gene alter the EGFR-receptor, transforming healthy cells into cancer cells, as occurs in EGFR-mutated NSCLC. Osimertinib (TAGRISSO®) is a drug that has already been shown to treat EGFR-mutated NSCLC by blocking the effects of mutated EGFR, and preventing, slowing or stopping the growth of cancer cells. Osimertinib is approved and recommended by international treatment guidelines as initial (first-line) treatment for EGFR-mutated advanced NSCLC. EGFR-mutated NSCLC is particularly prone to spreading to the brain or spinal cord (known as central nervous system [CNS] metastases). The FLAURA2 study assessed if adding chemotherapy to osimertinib treatment could improve outcomes for patients, compared to osimertinib alone. Patients with brain metastases could participate as long as they were asymptomatic (not experiencing symptoms because of the brain metastases) or the brain metastases had been treated and were stable (not increasing in size or getting worse). The primary findings of FLAURA2 were that osimertinib plus chemotherapy extended the time before NSCLC tumor growth/spread, or patient death compared to osimertinib alone. What were the results in patients with and without brain metastases? In patients with brain metastases before treatment, those who were treated with osimertinib plus chemotherapy had a lower risk of their brain tumors growing/spreading, or death compared with patients who received osimertinib alone. Of those without brain metastases before treatment, very few in either treatment group developed a brain metastasis during the study. What do the results of the study mean? Based on the primary results of FLAURA2, osimertinib plus chemotherapy was approved for first-line treatment of EGFR-mutated advanced NSCLC. At the time of publication the FLAURA2 study is ongoing; more results, including survival rates, are expected to be released in the future.