More evidence supports osimertinib for EGFR-mutated NSCLC

Safety data from the phase III ADAURA study support osimertinib as an effective adjuvant therapy for resectable, stage IB–IIIA EGFR-mutated non–small-cell lung cancer (NSCLC), says an expert.

In this exploratory analysis of long-term safety data from ADAURA, median actual exposure for osimertinib was similar to median total exposure and was 10 months longer than placebo (35.4 months vs 25.1 months), indicating the little impact of dose interruptions,” reported Dr Thomas John from the Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, at ESMO Asia 2022. 

Interstitial lung disease (ILD) was reported in 11 patients in the osimertinib arm (all Grade 1 or 2 and reversible) and the most frequently reported in patients from Japan (n=6). All were reported to have recovered.

QTc prolongation and cardiac effects were reported in both the osimertinib and placebo arms, with the majority of events either Grade 1 or 2 and resolved by data cut-off. The majority of adverse events (AEs) occurred within the first 12 months. Three years of treatment did not result in late emergent AEs.

“Combined with significant efficacy benefit, these safety data are consistent with the known profile of osimertinib and support 3 years of treatment with osimertinib in the adjuvant setting,” John told oncologists attending ESMO Asia 2022.

Osimertinib is a third-generation CNS-active EGFR-TKI* approved for previously untreated EGFR-mutated NSCLC.

Longer DFS with osimertinib

Efficacy findings from ADAURA showed a significant disease-free survival (DFS) benefit with adjuvant osimertinib vs placebo in patients with completely resected, EGFR-mutated stage IB–IIIA NSCLC. “The DFS benefit with osimertinib was observed across all predefined subgroups, including Asian and non-Asian patients,” said John.

The study included 682 patients randomly assigned to receive osimertinib  80 mg once daily (n=339) or placebo (n=343) for 3 years. DFS among patients with stage II–IIIA disease (by investigator assessment) was the primary endpoint.  Important secondary endpoints included DFS in the overall population of patients with stage 1B–IIIA disease (classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer [AJCC]), overall survival, and safety. Patients were treated until disease recurrence, treatment completion, or fulfilment of a criterion for discontinuation.

At 24 months, there was a significant improvement in DFS with osimertinib among patients with stage II–IIIA disease (overall hazard ratio [HR] for disease recurrence or death, 0.17; p<0.001) and in the overall cohort (overall HR for disease recurrence or death, 0.20; p<0.001). [N Engl J Med 2020; 383:1711-1723]

Updated analysis, with an additional 2 years of follow-up,  showed osimertinib was associated with a 73-percent reduction in the risk of disease recurrence or death (HR, 0.27) in those with stage IB–IIIA NSCLC, and a 77-percent reduction in the risk of recurrence or death (HR, 0.23) among patients with stage II–IIIA disease. DFS improvement was observed irrespective of prior adjuvant chemotherapy or disease stage. [Ann Oncol 2022;33(suppl 7):S808-S869; ESMO 2022, abstract LBA47]

“The updated data reinforce adjuvant osimertinib as the standard of care (SoC) for patients with EGFR-mutated, stage IB–IIIA NSCLC after complete tumour resection, with or without adjuvant chemotherapy,” said Dr Masahiro Tsuboi from the National Cancer Center Hospital East in Kashiwa, Japan at ESMO 2022.

Navigating the complexity of NSCLC

In a separate symposium at ESMO Asia 2022, Dr Solange Peters from Lausanne University Hospital, Lausanne, Switzerland said 30–60 percent of patients with resected NSCLC relapse despite adjuvant chemotherapy.

“There is a need for personalized (neo)adjuvant treatment options to help improve outcomes in these patients,” she emphasized. “Currently, there are ongoing phase III trials investigating immune checkpoint inhibitors in the neoadjuvant and adjuvant setting, demonstrating that systemic therapies for resectable NSCLC are evolving.”

Dr Solange Peters

John, for his part, said the current SoC for patients with oncogene-driven tumours is targeted therapy (except for those with KRAS, BRAF, or MET mutations). “But this may change to involve antibody-drug conjugates (ADCs) and chemotherapy combinations in those with poor prognostic tumours.”

In patients with non-oncogene-driven tumours, PD-(L) 1 ± CTLA-4 inhibition remains the SoC. However, there remains a need for improved treatment, he emphasized.  “The addition of chemotherapy and/or ADCs may change the current treatment paradigms, particularly in those with low tumour mutation burden or co-mutations with KEAP1, STK11, and KRAS genes. Novel bispecific antibodies and BiTEs** also offer promise as novel immunotherapeutics.”

“One size does not fit all in NSCL anymore,” commented John. “Management is becoming more nuanced and personalized.”

Dr Puey Ling Chia from the Department of Medical Oncology, Tan Tock Seng Hospital, Singapore, added that resistance mechanisms are crucial to understanding the next strategy beyond first-line therapy for advanced NSCLC. “Always consider rebiopsy post progression to help guide second and third-line treatment options,” she added.

From left, session chair Dr Wong Seng Weng from the Cancer Center (Singapore Medical Group), Dr Solange Peters, Dr Thomas John, and Dr Puey Ling Chia during the panel discussion and Q&A that followed the presentations.