Ramalingam Discusses Osimertinib Efficacy and the Journey to Overcome Acquired Resistance

Kelly Davio
Published: Friday, Apr 12, 2019

Suresh S. Ramalingam, MD
Suresh S. Ramalingam, MD
The encouraging activity with osimertinib (Tagrisso) for patients with EGFR-mutant non–small cell lung cancer (NSCLC) continues to be highlighted in the form of prolonged progression-free survival (PFS); however, next steps are focusing on understanding the primary and acquired resistance mechanisms to the third-generation EGFR inhibitor.

Regarding its benefit, frontline osimertinib continued to show extended PFS in patients with advanced EGFR-mutant NSCLC, according to final efficacy and safety results from phase I expansion cohorts of the AURA trial that were presented at the 2019 European Lung Cancer Congress (ELCC).1

At a median follow-up of 19.1 months, the median PFS in patients who received the third-generation EGFR inhibitor at 80 mg was 22.1 months (95% CI, 12.3-30.2) and was 19.3 months (95% CI, 11.1-26.0) for those who received it at 160 mg, leading to an overall median PFS of 20.5 months (95% CI, 13.7-26.1).

The FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) in April 2018.

However, studies have emerged exploring primary and acquired resistance mechanisms to osimertinib. A Chinese study presented at the meeting evaluated targeted next-generation sequencing of patients with stage IIIb-IV EGFR-mutant T790M NSCLC to detect molecular marker status.

Findings showed that of the 117 patients who received osimertinib, 82.91% developed acquired resistance, and 7.69% had primary resistance.2 From the baseline samples, it was determined that there were 3 (33.33%) patients with MET amplification, 1 (11.11%) patient with BCL2L11 loss, 1 (11.11%) patient with ERBB2 amplification, 1 (11.11%) patient with PTEN mutation, 1 (11.11%) patient with EZH2 mutation, and 2 (22.22%) patients with unknown status. The data suggest that the mechanisms of this resistance could be highly heterogeneous.

“Acquired resistance to EGFR TKIs, or any other TKI for that matter, is matter of fact: it happens,” said Suresh S. Ramalingam, MD. “What we’re beginning to learn is what the resistance mechanisms to osimertinib are.”

In an interview with OncLive during the 2019 ELCC, Ramalingam, professor of hematology and medical oncology at the Emory University School of Medicine, described these findings with osimertinib, and discussed the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

OncLive: Could you discuss the data we have with frontline osimertinib in EGFR-mutant NSCLC?

Ramalingam: The FLAURA study demonstrated that osimertinib was superior in terms of PFS compared with either erlotinib (Tarceva) or gefitinib (Iressa). This has resulted in FDA approval of osimertinib in the United States and many other countries in the world. The study itself was a randomized, phase III trial in 556 patients who were randomized 1:1. Osimertinib was given at 80 mg per day in the experimental arm, and patients received standard doses of either erlotinib or gefitinib.

The primary endpoint was PFS, and we had independent assessment of radiographic images. Patients in the control group could cross over if they had progression and developed a T790M mechanism of resistance, and then receive osimertinib.

It was a very well-designed, phase III clinical trial that we reported, and it showed that the median PFS with osimertinib was 18.9 months, and the median PFS in the control group was 10.2 months. This represented a 54% reduction in the risk of disease progression or death for patients treated with osimertinib.

We also saw a very favorable toxicity profile for osimertinib. Since it’s a mutation-specific inhibitor, it has less of an effect on the wild-type receptor. Finally, the overall survival (OS) data suggested that there was a favorable outcome, though, from a statistical standpoint, the results are still very immature. We found a positive hazard ratio of 0.63, which did not quite meet the statistical significance at that level of low maturity, but it was still very promising regardless. Therefore, from all standpoints, we found that osimertinib came out ahead.

One problem that we see in lung cancer—specifically in EGFR-mutated patients—is brain metastases. Therefore, any agent we choose, we want to be effective against brain metastases. We saw that in the FLAURA study with osimertinib; we saw intracranial responses. For about 20% of the patients who came into the study with brain metastases, their PFS hazard ratio was similar to the overall patient population. We also saw less disease progression in the brain for patients with osimertinib. Therefore, another key piece of information that came out from the FLAURA study is that osimertinib has activity in the brain.

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