Adjuvant Osimertinib Induces Promising CNS DFS in Early Stage EGFR-Mutant NSCLC

Masahiro Tsuboi, MD

The phase 3 ADAURA study (NCT02511106) demonstrated that adjuvant osimertinib (Tagrisso) reduced the risk for central nervous system (CNS) death or progression by 82% in resectable patients with early-stage non–small cell lung cancer (NSCLC) who harbor an EGFR mutation. Based on these findings, the FDA granted a Priority Review designation to a supplemental New Drug Application for adjuvant osimertinib as treatment of patients with stage IB/II/IIIA EGFR-mutant NSCLC after a complete resection with curative intent.

Adjuvant treatment with this EGFR tyrosine kinase inhibitor (TKI) induced a clinically meaningful improvement in CNS disease-free survival (DFS) compared with placebo (HR, 0.18; 95% CI, 0.10-0.33; P <.0001), although the median CNS DFS was not reached in the experimental arm compared with 48.2 months in the placebo arm.

Overall, 45 patients had CNS DFS events, including 6 (2%) from the osimertinib arm and 39 (11%) from the placebo arm, and among those who had a recurrence, 4 patients (1%) in the osimertinib arm experienced CNS recurrence compared with 33 (10%) in the placebo arm.

Ten percent to 15% of patients with NSCLC in the United States and Europe, as well as 30% to 40% in Asia, harbor an EGFR mutation, which represent a population of patients that are particularly sensitive to treatment with EGFR TKIs. However, the clinical activity against CNS metastases that has been observed with the third-generation irreversible EGFR TKI osimertinib appear promising.

In an interview with Targeted Oncology, Masahiro Tsuboi, MD, a surgeon at Japan’s National Cancer Center Hospital East, discussed the findings for the ADAURA study, which explored the role of osimertinib as treatment of patients with early-stage EGFR-mutant NSCLC following a complete tumor resection.

TARGETED ONCOLOGY: What is the current standard of care for patients who have stage II or III NSCLC?

Tsuboi: Adjuvant cisplatin-based chemotherapy is recommended in patient with resected stage II-IIIA disease, and it’s recommended for patients with stage IB disease. The 5-year survival rate of the stage IB-IIIA was 36% to 49%. The rate of disease recurrence following the surgery remained high regardless of the chemotherapy use. CNS metastases is a common sight in the standard recurrent in the patient with EGFR mutation-positive NSCLC.

CNS metastases result in poor prognosis, and there remains an unmet need to prevent CNS recurrence in order to improve patient outcomes to control micro metastases. Minimal residual disease after complete resection may introduce the patient’s prognosis. Therefore, the development of adjuvant therapy is essential to improve to the cure rate for the rest of the population.

TARGETED ONCOLOGY: What is rationale behind using adjuvant osimertinib in EGFR-positive NSCLC?

Tsuboi: EGFR TKIs are the standard of care for EGFR mutation-positive NSCLC. In the advanced disease setting, the first-line osimertinib demonstrated superior efficacy in CNS metastases including the 52% reduction in the risk of CNS progression compared with other erlotinib (Tagrisso) or gefitinib (Iressa). The high potency of osimertinib has superior efficacy in the advanced setting and improved the efficacy in the CNS, suggesting that it may be effective in the reduction in the risk of metastatic recurrence in the postoperative adjuvant setting.

TARGETED ONCOLOGY: What results did we see at ASCO earlier this year from the ADAURA study?

Tsuboi: The primary end point was met in the patients with stage II-IIIA disease. An impressive hazard ratio for disease-free survival of 0.17 was observed. There was an 83% reduction in the risk of disease recurrence with osimertinib versus placebo. In the overall population, the patient with the stage IB/II/IIIA disease had a hazard ratio of 0.20, with an 80% reduction in the risk of disease recurrence.

TARGETED ONCOLOGY: Could you discuss the updated findings from ESMO?

Tsuboi: We focus on the recurrence pattern and the burden of the disease, but we especially focused on CNS metastases. Overall, patients treated with osimertinib reported fewer disease recurrence compared with those treated with placebo. Eleven percent of the patients in the osimertinib arm had DFS events versus 46% of the patient in the placebo arm. There were fewer patients with disease recurrence in the osimertinib arm compared with the placebo arm.

CNS metastases are associated with significant morbidity and deterioration in the quality of life. Although CNS recurrence events were reported in 1% of the patient in the osimertinib arm versus 10% of the patient in the in the placebo arm, a clinically meaningful improvement in the CNS DFS was observed with osimertinib, with an impressive hazard ratio of 0.18. An 82% reduction in the risk of the CNS recurrence was observed. At the 18 months, the estimated probability of observing a CNS recurrence of less than 1% with osimertinib versus 9% with a placebo.

TARGETED ONCOLOGY: Where do you feel future research efforts need to be focused in NSCLC?

Tsuboi: Now we have several studies, such as the new ADAURA and LAURA (NCT03521154) trials, which will evaluate the efficacy and safety of the neoadjuvant osimertinib in EGFR-mutant NSCLC and osimertinib following chemoradiotherapy in the stage III unresectable EGFR-mutant NSCLC.

Considering that there are patients who are cured with surgery alone and that adjuvant therapy is not entirely free of toxicity, I [think we] should explore the direction of delivering that adjuvant therapy to those who are more at risk of recurrence.

TARGETED ONCOLOGY: What is your take home message from this research?

Tsuboi: Although there is a limitation that the majority of the DFS and OS are low, given the reality that the patients with early-stage lung cancer missed the chance to be cured once recurrence occurred, I believe that prolonged DFS with adjuvant osimertinib is very useful information for the patient hoping for that cure.

TARGETED ONCOLOGY: Do you have any final thoughts to add in?

Tsuboi: There seems to be a wave of precision medicine in the postoperative care. Using adjuvant therapy aims to control the micrometastases seems to be shifting from the postoperative setting alone to the perioperative treatment. It is important to deliver perioperative treatment to the patient who can be expected to respond to the treatment. The risk-benefit balance should be considered when determining the treatment plan for each patient, considering that some patients may be cured by surgery alone.

Reference

Tsuboi M. Osimertinib adjuvant therapy in patients (pts) with resected EGFR mutated (EGFRm) NSCLC (ADAURA): Central nervous system (CNS) disease recurrence. Presented at: the 2020 ESMO Virtual Congress; September 19-21, 2020. Abstract #LBA1.