Osimertinib at Lower Dose Effective in EGFR-Mutant NSCLC With Leptomeningeal Metastases

Myung-Ju Ahn, MD

Osimertinib (Tagrisso) at a once-daily dose of 80 mg demonstrated similar signs of activity, as well as a clinically meaningful benefit in patients with EGFR T790M—positive advanced non–small cell lung cancer (NSCLC) who had radiographically detected leptomeningeal metastases (LM) compared with the 160-mg dose observed in the AURA LM trial.¹

This trial was a retrospective analysis that treated 22 asymptomatic patients with 80 mg osimertinib. Radiologic LM response was assessed by neuroradiological blinded independent review. However, other endpoints, including LM objective response rate (ORR), LM duration of response (DoR), LM progression-free survival (PFS), and overall survival (OS), were assessed retrospectively. Data was compared in a longitudinal analysis to the BLOOM study, which looked at a 160-mg dose.

The median duration of treatment was 7.3 months (range, 2.3-16.5) in the AURA LM study. The LM ORR was reported at 55% with 6 patients experiencing a complete LM response and another 6 had a partial LM response. In addition, the median LM PFS was 11.1 months (95% CI, 4.6-not calculable [NC]) and the median OS was 18.8 months (95% CI, 6.3-NC). The median LM DoR was not reached.

In the BLOOM study,² EGFR-mutant patients with advanced NSCLC and confirmed LM received 160 mg of osimertinib. Only half of the patients had the T790M mutation though. According to longitudinal analysis, the efficacy of the 80-mg dose in the AURA LM study was similar to that of the 160-mg dose in the BLOOM study in terms of LM responses.¹ However, more prospective research is necessary to confirm these findings.

In an interview with OncLive, Myung-Ju Ahn, MD, of the Samsung Medical Center, Sungkyunkwan University School of Medicine, in Seoul, Republic of Korea, discussed the results from the AURA LM trial and the next steps that need to be taken in order to confirm the efficacy that was seen with the lower dose. In addition, she highlighted where research in the treatment landscape of advanced NSCLC is headed.

OncLive: Could you share the results from the AURA LM study, and what these data mean?

Ahn: [We studied] the efficacy of osimertinib 80 mg in patients with LM disease from 4 [studies across] the AURA program. We found that the LM response rate was 55%, and the LM PFS was 11.1 months. The median OS is 18.8 months, which is quite encouraging for this kind of patient with LM.

This study is looking at 80 mg of osimertinib, and whether there is potential efficacy compared to the 160-mg dose, which was done in the BLOOM study. We also performed an explorative analysis for whether the 80-mg dose might be similar to the 160 mg. Those analyses also showed that 80 mg might have similar efficacy to the 160 mg. That’s the main point.

Are they any next steps planned for this?

Ahn: This is a retrospective analysis, and those patients are asymptomatic, so the AURA LM study might not reflect the real LM patients that we are seeing in the clinic in our daily practice. That’s why I think we need more [data] to confirm the study. This will be investigated in the near future with 80 mg of osimertinib in patients with LM as a prospective study under the name of BLOSSOM.

What question still needs to be addressed in the future in regard to osimertinib?

LM disease is really hard to treat, and previously people thought that the doubled dose of osimertinib would be more effective than the 80 mg. This study shows that the 80-mg dose might have potential similar efficacy. That’s why we need prospective data to readout, not just a retrospective study.

Are there any ongoing trials that you are particularly hopeful for?

Right now, our institute in Korea has already finished a similar study, an investigator-initiated trial with [patients with] EGFR-mutant NSCLC with brain metastases or LM disease. Those patients have T790M-positive disease. We just finished the data for this study, and the abstract is actually up for the World [Conference] on Lung Cancer. We will see. That is the ongoing prospective study that is supposed to be looking at the brain metastasis efficacy and LM efficacy with 160 mg of osimertinib.

As I mentioned before, the BLOSSOM study will investigate the 80 mg dose of osimertinib in patients with LM disease. That’s the future study.

As you look at the landscape for advanced NSCLC, what are some of the emerging trends?

In the whole landscape, first of all, we have to do next-generation sequencing to select out the patients that can benefit with targeted agents first. For those that are negative without any oncogenic drivers, those patients should be going on to receive immunotherapy plus/minus chemotherapy.

The caveat is that in the patients that receive a targeted treatment, almost all patients will develop resistance. We have to look for the registered mechanism, then we can further develop other combinations to prolong PFS and improve the clinical efficacy.

On the other hand, in immunotherapy, a lot of patients have a benefit, but still some patients have very little progress or after a certain time on treatment, they develop resistance. I think we have to develop another strategy to help overcome or mitigate the resistance. That’s another big area where we have to do more research.

References:

1. Ahn MJ, Chiu C, Cheng Y, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) associated with EGFRm advanced NSCLC: the AURA LM study. Ann Oncol. 2019;30(suppl 2; abstr 105O):ii38-ii68. doi: 10.1093/annonc/mdz063.
2. Yang JCH, Cho BC, Kim DW, et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study. J Clin Oncol. 2017;35(suppl 15; abstr 2020). doi: 10.1200/JCO.2017.35.15_suppl.2020.