Osimertinib in Unresectable Stage 3 Lung Cancer – A Standing Ovation at ASCO 2024

Osimertinib (Tagrisso) is moving toward approval for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) at all stages .

A third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib is a targeted cancer drug already indicated for metastatic disease and for adjuvant use in early-stage EGFR-mutant NSCLC.

A Standing Ovation

ASCO 2024 annual meeting featured the AstraZeneca-funded phase 3 LAURA trial , whose results are expected to lead to approval in another setting: unresectable stage III disease.

The presenting principal investigator, lung cancer specialist Dr. Suresh S. Ramalingam of Emory University in Atlanta, received a standing ovation. Oncology specialists described the results as "extraordinary."

Unresectable stage III non-small cell lung cancer is a stage in which cancer has spread within the lung and to surrounding lymph nodes but cannot be completely removed surgically. Because of the extent of spread, surgery is generally not possible, and treatment options are usually limited to other approaches such as chemotherapy and radiotherapy.

Before This Study

Before this study, durvalumab was the standard treatment after chemoradiotherapy for unresectable EGFR-mutant stage III non-small cell lung cancer (NSCLC). It was used as immunotherapy for 1 year after chemoradiotherapy. However, durvalumab is known to have limited activity in EGFR-mutant disease and is generally not used in these patients. Osimertinib is therefore considered a potentially more effective option for this group.

The Importance of LAURA – A New Era in Unresectable Stage III EGFR-Positive NSCLC

We can summarize the NADINA study in 3 key points:

1. A Dramatic Increase in Progression-Free Survival:

The LAURA trial showed that, in patients with unresectable stage III EGFR-positive non-small cell lung cancer (NSCLC), osimertinib increased median progression-free survival compared with placebo by 33.5 months , to 39.1 months (39.1 months versus 5.6 months). This represents an 84% reduction in the risk of cancer progression or death. The dramatic increase substantially improves patients' quality of life and survival.

2. A New Standard of Care for EGFR-Mutant Patients:

The results indicate that osimertinib will become the new standard of care after chemoradiotherapy for EGFR-mutant stage III NSCLC. Given durvalumab's limited activity in EGFR-mutant disease, osimertinib offers a more effective treatment option for this group, bringing a major change to treatment protocols.

3. Fewer Brain Metastases:

Osimertinib significantly reduced the development of new lesions during the study, particularly brain metastases . Brain metastases developed in 29% of placebo patients, compared with only 8% of those receiving osimertinib. This finding substantially improves quality of life and highlights osimertinib's protective effect against brain metastases.

Study Details

The trial 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 between the arms, with a largely even distribution across stage III subtypes.

Patients were staged by biopsy or CT and MRI to confirm the absence of brain metastases. Follow-up imaging was repeated at regular intervals.

Progression-free survival at 12 months, assessed by blinded independent central review, was 74% with osimertinib and 22% with placebo. At 24 months, the rates were 65% and 13%, respectively.

The progression-free survival benefit persisted across many subgroups but was statistically significant only among Asian participants, who made up more than 80% of both arms.

Although the data remain immature, osimertinib also shows a trend toward improved overall survival. This trend is difficult to interpret because 81% of placebo patients crossed over to osimertinib after progression. Mature overall survival results are expected within 2 years.

Commentary

Based on these results, it can be said that osimertinib "will become the new standard of care after definitive chemoradiotherapy in this patient group".

EGFR mutation testing has now become "critical to providing optimal treatment for stage III patients." Nearly one third of patients with NSCLC present with stage III disease, and most are inoperable. Approximately one third of these patients have EGFR mutations.

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

If control patients had received durvalumab, they would have had to wait for progression before an EGFR tyrosine kinase inhibitor (TKI) could be given safely, which would not have been in their best interests.

68% of placebo patients developed new lesions during the study, of which 29% were brain metastases. New lesions developed in 22% of osimertinib patients, of which 8% were brain lesions.

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

Treatment-related grade 3 or worse adverse events occurred in 13% of osimertinib patients and 3% of placebo patients. Overall, 8% of osimertinib patients developed interstitial lung disease; most cases were low grade, but one person died.

Side effects led approximately half of the patients to interrupt osimertinib dosing, and a minority discontinued it.

Long-Term Treatment and Cost

Patients received osimertinib until progression rather than for a limited duration as in previous EGFR TKI trials. This approach raises the possibility of lifelong treatment, although that remains uncertain.

Treatment until progression acknowledges that unresectable stage III NSCLC cannot be cured in most patients. However, a small number may not need treatment, which matters because the drug costs approximately 180 thousand TL per month.

In conclusion, osimertinib represents an important advance in treating unresectable stage III EGFR-mutant NSCLC. The LAURA results show that it substantially prolongs progression-free survival in these patients and may be regarded as the new standard of care. These findings offer considerable hope for improving quality of life and expanding treatment options. Fewer brain metastases and the trend toward improved overall survival further support osimertinib's activity in this patient group.