Loading ...

The combination of osimertinib (Tagrisso, AstraZenca) plus chemotherapy is associated with continued benefits in previously untreated advanced EGFR-mutated non–small-cell lung cancer (NSCLC) even after disease progression, according to a postprogression analysis of the FLAURA2 trial.

The results, presented on March 21 at the European Lung Cancer Congress 2024 (Abstract4O), also suggest a potential overall survival benefit with the addition of chemotherapy to the third-generation EGFR-tyrosine kinase inhibitor.

Giving the combination as first-line treatment "provides long-term clinically meaningful benefits beyond that seen for the initial progression-free survival," said study presenter Natalia Isabel Valdiviezo Lama, MD, a medical oncologist from the National Institute of Neoplastic Diseases in Lima, Peru. 

As previously reported by Medscape Medical News, osimertinib was recently approved by the US Food and Drug Administration in combination with platinum-based chemotherapy for first-line treatment of patients with EGFR-mutated locally advanced or metastatic NSCLC.

This approval was based on results from FLAURA2, which showed that adding platinum-based chemotherapy to osimertinib improved median progression-free survival by 38%. At the time, the overall survival data were immature but suggested a benefit with the combination compared with osimertinib alone.

The current results examined postprogression outcomes from FLAURA2 as well as a second interim overall survival analysis.

The trial included 557 advanced-NSCLC patients with EGFR exon 19 deletions or exon 21 L858R mutations who had received no prior systemic therapy. The patients could have also had stable central nervous system metastases and underwent brain imaging at baseline.

Study participants were randomly assigned to osimertinib plus pemetrexed and carboplatin or cisplatin, followed by maintenance osimertinib plus pemetrexed or osimertinib monotherapy until radiologically defined disease progression or other withdrawal criteria were met.

The combination therapy was associated with a longer time to second-line treatment at a median of 30.7 months vs 25.4 months for osimertinib alone (hazard ratio [HR], 0.73). 

There was also an improvement in the time to third-line treatment with osimertinib plus chemotherapy, with the median not reached vs 33.2 months with osimertinib monotherapy (HR, 0.69).

The researchers noted a difference in the choice of second-line treatment between the two study arms.

Of the 46% of patients in the combination group who started second-line therapy, 37% received a non–platinum-based chemotherapy and 32% received a platinum-based chemotherapy; 14% began an EGFR tyrosine kinase inhibitor other than osimertinib.

In the osimertinib monotherapy arm, of the 60% of patients who began second-line treatment, 81% were given a platinum-based chemotherapy, 3% were given a non–platinum-based chemotherapy, and 7% were given another EGFR tyrosine kinase inhibitor.

Even after starting second-line therapy, patients in the osimertinib-plus-chemotherapy group continued to show an improvement in outcomes, with a median second progression-free survival of 30.6 months vs 27.8 months (HR, 0.70) with osimertinib monotherapy. 

Finally, the second interim overall survival analysis revealed an "encouraging trend" in favor of the combination, said Lama, after a median follow-up of approximately 31 months in both study arms and a data maturity of 41%.

So far, the median overall survival has not been reached with osimertinib plus chemotherapy compared with 36.7 months in the osimertinib-alone group (HR, 0.75; P = .0280). This overall survival benefit was seen across all prespecified subgroups.

Consistent Benefit but More Toxicity

The magnitude of benefit seen with osimertinib plus chemotherapy is in line with expectations given the results of previous combination therapy trials, said Joop de Langen, MD, PhD, a thoracic oncologist at the Netherlands Cancer Institute in Amsterdam, who was not involved in the trial.

Moreover, the outcomes achieved in the standard-of-care osimertinib monotherapy control arm, with approximately 60% of patients progressing after 2 years, show that there was "clearly room for improvement."

But, de Langen asked, is the benefit seen with this combination large enough to justify providing it as first-line treatment for all our patients? The chemotherapy is "an [intravenous] treatment with cytotoxic side effects, and patients have to go into the clinic every 3 weeks."

He noted that 64% patients in FLAURA2 who were given osimertinib plus chemotherapy experienced any grade 3 or higher adverse event compared with 27% in the osimertinib-alone arm, with the majority of events typical of chemotherapy toxicity.

In addition, the progression-free survival data indicate that a sizable proportion of patients do well with osimertinib alone, with 41% remaining progression-free at 2 years, he added.

Although the results show a consistent benefit in favor of osimertinib plus chemotherapy, it comes "at the cost of additional toxicity," de Langen said.

"You can ask yourself whether these patients need to be treated with chemotherapy," de Langen added. "Ideally, we would select those patients up front," but that is difficult based on the currently available data.

He suggested that the dilemma may be partially answered by an upcoming randomized trial, in which patients with EGFR-mutated NSCLC will be started on three cycles of osimertinib then will undergo circulating tumor DNA testing.

The results from this trial, said de Langen, "might lead to a more personalized approach to balancing efficacy and toxicity for each patient that we see in our clinic."

FLAURA2 was funded by AstraZeneca. Lama declares no relevant financial relationships. Other authors declare numerous financial relationships, including AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Pfizer, Eisai, Sanofi, BeiGene, Chugai Pharmaceutical Co., Ltd., Takeda, Ono Pharmaceutical Co., Ltd., Novartis, Lilly, Amgen, Yuhan Pharmaceutical, Alpha Pharmaceuticals.

De Langen declares relationships with AstraZeneca, BMA, Boehringer, Pfizer, Lilly, and MSD.