For the First Time, a Targeted Drug Provides a Survival Benefit in Postoperative Adjuvant Lung Cancer Treatment

Among our patients diagnosed with the most common main subtype of lung cancer, non-small cell lung cancer (KHDAK), only 30% are suitable for surgery. Even if the tumor has been completely removed surgically, the likelihood of recurrence is high in these patients (50% in stage 1 and > 70% in stage III). With the adjuvant (postoperative preventive) chemotherapy regimens used as standard treatment, the contribution we provide to patients' 5-year overall survival is approximately 5%, which is relatively low.

Osimertinib (Tagrisso) targets the EGFR mutation and is a third-generation tyrosine kinase inhibitor (TKİ) taken orally as a pill. Research to date has confirmed that it is the most effective option against the EGFR mutation. Today, in metastatic (stage 4) EGFR-positive patients, it has surpassed first-generation EGFR-TKI drugs with its survival contribution in first-line treatment, received FDA approval and entered clinical use. This raised the question, "Is osimertinib also effective in earlier-stage lung cancers?"

The ADAURA study

The ADAURA study, which demonstrated the efficacy of osimertinib in the adjuvant treatment of non-small cell lung cancer, was a study that made its mark on ASCO 2020.

• The phase III clinical trial ADAURA enrolled patients with surgically treated stage IB, II or IIIA EGFR-mutant (exon 19 deletion or L858 mutant) nonsquamous non-small cell lung cancer (KHDAK).
• The study, which included a total of 682 patients, compared Osimertinib 80 mg with a placebo group in terms of disease-free survival, overall survival, safety and quality-of-life scores.
• Patients were included regardless of whether they had received adjuvant chemotherapy. The duration of adjuvant treatment was planned as 3 years.
• The distribution of patients by stage IB/II/III was 31%, 35% and 34%.
• Of these patients, 45% had not received adjuvant chemotherapy.
• In patients with stage II and IIIA disease, median disease-free survival was not reached in the osimertinib group because the disease had not recurred in more than half of those receiving it, while it was 20.4 months in the placebo arm. In the full patient group, median disease-free survival was not reached in the osimertinib arm, while it was 28.1 months in the placebo arm.
• The phase III ADAURA study showed that osimertinib reduced the likelihood of disease recurrence or cancer-related death by 83% in the adjuvant treatment of stage II and IIIA EGFR-mutant KHDAK.
• In addition, in patients with stage IB-IIIA disease, osimertinib reduced the likelihood of disease recurrence or cancer-related death by 79%.

The disease-free survival benefit of osimertinib was found to be effective in all subgroups, regardless of race, sex, stage, smoking, whether adjuvant chemotherapy had been received and EGFR mutation type.

The study's two-year overall survival data were 100% with osimertinib and 93% with placebo. However, median overall survival was not reached in either arm.

Looking at safety and adverse-effect data, median osimertinib use was 22.3 months, while placebo use was 18.4 months. The most common adverse effects were diarrhea, paronychia / inflammation around the nails and dry skin. All these adverse effects were grade 1-2 (mild).

Grade 3-4 (serious) adverse effects included:

• Interstitial lung disease in 3% of patients receiving osimertinib (10 patients),
• ECG changes and QT prolongation were observed in 7% of the osimertinib arm (22 patients) and 1% of the placebo arm (4 patients).
• No deaths associated with osimertinib use were observed.

Conclusion & Comment

Overall survival data, brain metastasis rates, quality-of-life scores and additional molecular analyses from this study will be evaluated during the ongoing follow-up. Questions about the study include surgical differences between the patient groups and the characteristics of patients who did not receive adjuvant chemotherapy. The point open to criticism here is the duration of adjuvant osimertinib use. I think its 3-year use will be discussed in the period ahead. Another likely topic of debate is that if metastasis develops in these patients, there is no effective tyrosine kinase inhibitor or chemotherapy regimen to use, at least at present. This is the first study to demonstrate a statistically and clinically meaningful contribution from a targeted treatment in EGFR-mutant KHDAK. The study shows that osimertinib is effective in early-stage disease as it is in metastatic patients. Although the benefit was more pronounced in stage III patients, it was observed in all subgroups.

The current results of the ADAURA study indicate that osimertinib will become standard adjuvant treatment after surgery for patients with EGFR-mutant KHDAK who have a high risk of postoperative recurrence.

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