Osimertinib Receives FDA Approval After Chemoradiotherapy in Stage-3 Lung Cancer

On September 25, 2024, the United States Food and Drug Administration (FDA) approved treatment for patients whose disease had not progressed during or after platinum-based chemoradiotherapy and whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations in locally advanced, unresectable (stage 3) non-small cell lung cancer (NSCLC): osimertinib (Tagrisso, AstraZeneca).

With this decision, osimertinib has FDA approval in all stages of lung cancer with particular EGFR mutations.

Unresectable stage III NSCLC is a stage in which cancer has spread within the lung and nearby lymph nodes but cannot be completely removed surgically. Surgery is generally not possible because of its extent, and options are usually limited to chemotherapy, radiotherapy, and other approaches such as durvalumab immunotherapy after chemoradiotherapy.

The First Approved Post-Chemoradiotherapy Treatment in EGFR-Mutant Stage 3 Lung Cancer

EGFR mutations are genetic changes that trigger uncontrolled cancer cell growth and rapid spread. Osimertinib is a third-generation tyrosine kinase inhibitor that inhibits tumors particularly in NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.

FDA-approved osimertinib (Tagrisso) became, for EGFR-mutant stage 3 NSCLC without progression after chemoradiotherapy, the first treatment approved in this setting.

Before This Study

Previously, standard treatment after chemoradiotherapy in unresectable EGFR-mutant stage III NSCLC was durvalumab immunotherapy for 1 year. However, it is known to have limited activity in EGFR-mutant disease and generally is not used for these patients. Osimertinib was therefore considered a potentially more effective option.

FDA Approval Based on LAURA

LAURA, which received a standing ovation at ASCO 2024, can be summarized in 3 key points:

1. A Dramatic Increase in Progression-Free Survival:

LAURA showed that, in unresectable stage III EGFR-positive NSCLC, median progression-free survival compared with placebo increased by 33.5 months to 39.1 months (39.1 months versus 5.6 months). This represents an 84% reduction in progression or death risk. The dramatic improvement substantially enhances quality of life and survival duration.

2. A New Standard in EGFR-Mutant Disease:

The findings established osimertinib after chemoradiotherapy as the new standard in EGFR-mutant stage III NSCLC. Given durvalumab's limited activity in this setting, osimertinib offers a more effective option and substantially changes treatment protocols.

3. Fewer Brain Metastases:

Osimertinib significantly reduced new lesions during the study, particularly brain metastases , which occurred in 29% of placebo recipients versus 8% with osimertinib. This finding substantially improves quality of life and highlights a protective effect against brain metastases.

Study Details

The study randomized 216 patients with nonprogressing stage III EGFR-mutant NSCLC to 80 mg osimertinib (143 patients) or placebo (73 patients). Baseline characteristics were generally balanced, with a mostly equal distribution of stage III subtypes.

Patients were staged using biopsy or CT and MRI to confirm the absence of brain metastases. Follow-up imaging was repeated regularly.

Blinded independent central review found 12-month PFS of 74% with osimertinib versus 22% with placebo. At 24 months, rates were 65% and 13%, respectively.

The PFS benefit persisted across many subgroups but was statistically significant only among Asian participants, who made up more than 80% of each arm.

Although data are immature, overall survival also trends toward improvement. This is difficult to interpret because 81% of placebo recipients crossed over to osimertinib after progression. Mature results are expected within 2 years.

The recommended osimertinib dose is 80 mg once daily, with or without food, until progression or unacceptable toxicity.

Conclusions and Commentary

EGFR testing has become "critical to optimal treatment for stage III patients." Nearly one-third of NSCLC patients present with stage III disease, most unresectable; approximately one-third of these have EGFR mutations.

Placebo was a fair comparator. The current standard is durvalumab for 1 year after chemoradiotherapy, but it is generally not used in EGFR-mutant disease because it is ineffective in this setting.

Had controls received durvalumab, they would have needed to wait for progression before safely receiving an EGFR tyrosine kinase inhibitor (TKI), which would not serve their interests.

New lesions developed in 68% of placebo recipients, of which 29% were brain metastases, versus 22% with osimertinib, of which 8% were brain lesions.

Radiation pneumonitis, the most common adverse effect, occurred in 48% with osimertinib and 38% with placebo. Rash, diarrhea, and other known TKI adverse effects were also more common with osimertinib.

Treatment-related grade 3 or worse adverse effects occurred in 13% with osimertinib and 3% with placebo. Overall, 8% of osimertinib recipients developed interstitial lung disease, mostly low grade, although one patient died.

Adverse effects prompted dose interruptions in approximately half of osimertinib recipients and permanent discontinuation in a minority.

Long-Term Treatment and Cost

Treatment continued until progression rather than for a fixed duration as in earlier EGFR TKI studies, raising the uncertain possibility of lifelong therapy.

Treatment until progression acknowledges that unresectable stage III NSCLC is not curable for most patients. A few may not need treatment, however, which matters because the drug costs approximately 180 thousand TL monthly.

In conclusion, osimertinib represents a major advance in unresectable stage III EGFR-mutant NSCLC. LAURA shows substantially prolonged progression-free survival and establishes a new standard. These findings offer considerable hope for better quality of life and broader options. Fewer brain metastases and a favorable overall survival trend further support activity in this group.

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