High-Dose Osimertinib Shows Limited Benefit in EGFR+ NSCLC With CNS Involvement

In a real-world retrospective study, the dose osimertinib was raised from 60 mg to 160 mg, based on earlier findings from the BLOOM trial (NCT04148898), which demonstrated that high-dose osimertinib (Tagrisso) had activity in osimertinib-naïve patients with EGFR-mutant non–small cell lung cancer, but only a modest benefit was seen in real-world patients.

The real-world multi-institutional, retrospective study included 105 patients, 69 of whom had CNS progressive disease (PD) as the primary indication for beginning treatment with osimertinib. Patients were divided into 3 cohorts. Cohort A was compiled of patients who were treated without the addition of chemotherapy or radiotherapy. Cohort B included 34 patients who did receive chemotherapy and/or radiotherapy, and cohort C included patients who did not receive any overlapping therapies.

Of the 69 patients, 43 were women and 26 were men who showed a median age of 57 years (range, 36-79) at the time of diagnosis. Eighteen of the patients enrolled received prior osimertinib in a clinical trial, 3 of whom previously progressed on high-dose osimertinib.

In the 3 cohorts combined, EGFR mutations observed were deletion 19 in 42% of patients, L858R in 45%, and other in 13%. Thirty-three percent of patients in the study had parenchymal CNSPD type, while 39% had LMD, and 28% had both parenchymal and LMD CNS PD type. Concurrent therapy for patients in cohort B consisted of whole-brain radiotherapy (24%), stereotactic radiosurgery in 41%, and chemotherapy in 41%. The median prior line of therapy in the study overall was 1 (range 1-8). In terms of prior exposure to tyrosine kinase inhibitors, 52% of the study population had received erlotinib (Tarceva), 3% received gefitinib (Iressa) 19% had prior afatinib (Gilotrif), and 7% received rociletinib (Xegafri).

In terms of efficacy, the median overall survival for cohort A was 14.8 months (95% CI, 7.0 months to not reached [NR]). In cohort B, the median OS was 10.5 months (95% CI, 7.0-25.3). The median OS was not assessed in cohort C.

CNS control length differed between the 3 cohorts. In cohort A, the median duration of CNS control was 3.8 months (95% CI, 1.7-5.8 months). Cohort B showed a median CNS control duration of 5.2 months (95% CI, 3.1-6.5 months). Finally, cohort C achieved a 4.2-months median duration of CNS control (95% CI, 1-6 to not reached [NR]).

The subset of 27 participants who had CNS leptomeningeal-only PD had a combined median duration of CNS control of 6.0 months (95% CI, 5.1-9.0). Cohort B had the longest duration of 7.1 months (95% CI, 5.0 months-NR). For the subset of patients who had CNS parenchymal-only PD, the combined median duration of CNS control was 3.3 months (95% CI, 1.0-3.1 months), with longer duration observed in cohort B at 3.1 months (95% CI, 0.8 months-NR).

Investigators led by Andrew Piper-Vallillo noted that although the high-dose osimertinib demonstrated a trend toward longer disease control for the 2 CNS PD sub-populations, the findings were not statistically significant. However, Piper-Vallillo et al consider it notable that the subset of patients who were osimertinib naïve experienced 4.2 months of CNS control.

Overall, due to the small sample size and the fact that the study reviewed data retrospectively was a limitation. The activity demonstrated does however warrant future prospective studies of dose escalation to 160 mg osimertinib.

_Reference:

_{Piper-Vallillo AJ, Rotow JK, Aredo JV, et al. High-dose osimertinib for CNS progression in EGFR+ non-small cell lung cancer (NSCLC): A multi-institutional experience. J Clin Oncol 38: 2020 (suppl; abstr 9586). doi: 10.1200/JCO.2020.38.15_suppl.9586}

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