Actually standard care of stage 1, stage 2 and 3a disease, cisplatin based chemotherapy is recommended in patients with resectable stage 2 and 3a disease and selected stage 1b patients. But unfortunately surgical outcomes for the early stage non-small cell lung cancer resectable stage 1a is still disappointing. Most of the recurrences are distant metastases. So unmet needs are the rates of the disease recurrence following surgery remain high regarding chemotherapy use.
What methods did you use in this study?
The ADAURA study has evaluated osimertinib as a postoperative adjuvant therapy in patients with complete resected pathological stage 1b, 2 and 3a EGFR mutation positive non-small cell lung cancer. In ADAURA 682 patients were randomised in a one to one ratio to receive osimertinib or placebo. Clinical factors were stage: 1b, 2, 3a; EGFR mutational status: exon 19 or 21; and race: Asian or non-Asian. The primary endpoint was disease free survival for stage 2 and 3a disease and the most superior secondary endpoint was disease free survival for the overall population.
What results did you find?
The primary endpoint of ADAURA was met. In patients with stage 2 and 3a disease an impressive hazard ratio for the disease free survival of 0.17 was observed, equalling to a 83% reduction in the risk of disease recurrence or death for osimertinib versus placebo. In the overall population of patients with stage 1b, 2 and 3a disease, a hazard ratio of 0.20 was observed, equalling to the 80% reduction in the risk of recurrence or death with osimertinib.
Patients who received osimertinib had fewer local and distant metastases than those who received the placebo –11% of patients in the osimertinib arm versus 46% of patients in the placebo arm with a lower incidence of metastatic disease in those patients with recurrence including fewer CNS recurrence events.
Adjuvant osimertinib demonstrated a clear clinically meaningful improvement in CNS disease free survival compared with placebo with a hazard ratio of 0.18 equalling to an 82% reduction in the risk of CNS disease recurrence or death. CNS disease recurrence was less likely with osimertinib compared with placebo with a conditional probability of less than 1% after 18 months with osimertinib.
What are you concluding from these results?
ADAURA has demonstrated that adjuvant osimertinib has a highly statistically significant and clinically meaningful improvement in disease free survival and reduced risk of local and distant metastasis, especially improving CNS disease free survival, in patients with completely resected stage 1b, 2 or 3a EGFR mutation positive non-small cell lung cancer. There seems to be a wave of precision medicine in postoperative care. Although there is a limitation that the majority of both DFS and OS are low, the reality is that the patients with early stage lung cancer may still get a chance to be cured once recurrence occurs. I believe that prolonged DFS with adjuvant osimertinib is very useful information for the patients hoping for a cure.
What do you think will be the clinical implications of this study?
Adjuvant osimertinib is a very useful adjuvant therapy for stage 1b to 3a non-small cell lung cancer with EGFR mutation positive. In clinical practice I think the final decision of whether or not to use adjuvant osimertinib should be made after considering the risk benefit balance, including the financial toxicity in each patient because some patients may be cured by surgery alone.
Future considerations for ADAURA include subsequent treatment, longitudinal assessment of the minimal residual disease and the primary resistance mechanism of the drugs. In my opinion, the patient selection is an important issue considering that there are patients who are cured with surgery alone and that adjuvant therapy is not entirely free of toxicity.
I should explore the direction of delivering adjuvant therapy to those who are more at risk of recurrence using advances in science. I am particularly interested in the ctDNA intervention study.
There are two sister studies for ADAURA, the NeoADAURA and LAURA trials will investigate the efficacy and safety of neoadjuvant osimertinib in EGFR mutation positive resectable non-small cell lung cancer and osimertinib following chemoradiotherapy in stage 3 unresectable EGFR mutation positive non-small cell lung cancer respectively.
Personally, I think it is important to know the cure rate and five year survival after surgery or randomisation – how many patients remain treatment free after adjuvant therapy is completed? The prognosis is also expected to differ depending on the mode of the recurrence and the metastasis, such as whether it is a single tumour, oligo- or micrometastasis, and whether it is a single one or multiple mets. We are awaiting the analysis regarding the sequencing of treatment with great interest.