Overall survival of ADAURA: game, set, and match?

Three years after its first publication, the ADAURA study (1) has released its last findings, and they are up to expectations.

As a great cause of death, non-small-cell lung cancer (NSCLC) is a major health problem and searchers are always on the breach to find ways to fight it. One of these ways is the epidermal growth factor receptor (EGFR) pathway whose involvement in NSCLC was discovered nearly twenty years ago (2). Since then, the development and applications of tyrosine kinase inhibitors (TKIs) arose with three drug generations, providing great prognostic improvements for eligible patients. With their validation for advanced and metastatic disease (3), their use at curable stage was naturally explored and many trials were conducted in adjuvant and neo-adjuvant settings. While showing increased disease-free survival (DFS), almost all studies failed to find overall survival (OS) improvement, and even meta-analyses couldn’t assess a positive effect (4).

Then came ADAURA, the biggest cohort of resected, EGFR-mutant NSCLC: 682 patients in a phase 3, double-blind, placebo-controlled, randomized, international trial. Investigators enrolled patients above 18 years old, World Health Organization (WHO) status 0–1, with primary non-squamous NSCLC, stage IB–IIIA, and confirmed EGFR mutation (Ex19del or L858R). Patients were randomized either to osimertinib group or placebo group for 3 years or until recurrence or death. Primary outcome was DFS at 2 years within II–IIIA patients [intention-to-treat (ITT) population] and secondary outcomes included OS and DFS within IB–IIIA patients (overall population), along with health-related quality of life (QoL) and safety. Adjuvant chemotherapy was allowed but not mandatory. Their results were impressive: 80% risk reduction of recurrence after 2 years and 82% risk reduction of central nervous system recurrence, enough to unblind their trial early and include osimertinib in international guidelines as adjuvant therapy (5). Safety and QoL were very acceptable (6). Yet, OS data were immature, and we had to wait for these crucial results which were finally reported to the American Society of Clinical Oncology this year.

As a reflection of DFS, the impact on OS is tremendous: the hazard ratio (HR) for death is 0.49; P<0.001, with results consistent within all subgroup analyses (7). Authors also report a decrease in the use of subsequent treatment by three (HR 0.29, median not reached in osimertinib group) and good safety profile (8). We note that 95% confidence intervals for stage IB and II subgroups did not exclude the value 1, meaning statistical significance was reached only for stage IIIA subgroup. This may be due to smaller group numbers but may also support the theory of a lower impact on early stages. In the original publication, the impact on DFS was growing with the stage (DFS HR IB, II, IIIA 0.39, 0.17, 0.12, respectively) (1). This is an important point because ADAURA used the seventh tumor, node, metastasis (TNM) edition, with IB tumors of at least 4 cm, which are now classified as stage II in the eighth TNM. However, international guidelines recommend osimertinib to be used for eighth TNM IB tumors, even though this patient group was not evaluated (9,10). We can also note that the use of chemotherapy does not affect the survival, comforting the feeling of a weaker impact of chemotherapy compared to new targeted therapies. Nevertheless, such result should be considered with care because the ADAURA trial was not designed for this question. Finally, authors also report that subsequent treatment was not monitored and osimertinib was allowed in open-label for placebo group, potentially improving the survival of this group and thus lessening the difference in survival. ADAURA is a well-designed trial, with few biases and enough statistical power to avoid misinterpretation. These results confirm osimertinib as a first-line adjuvant therapy to be recommended for eligible patients after surgery.

We will now try to see beyond the results. As a reminder, osimertinib overcomes the T790M mutation, which provide resistance for almost all other TKI and is very common, mostly acquired after treatment and clonal selection (11). This may leave the drug’s effect undisputed for a longer time since the residual disease cannot use it main gateway to return and must find alternative resistance pathways. Yet those pathways exist and once osimertinib resistance is acquired, treatment remaining options are few or remain experimental (12). Question should then be addressed about the potential interest of sequential targeted therapies, as reported in renal cell carcinoma for example (13). The point would be to delay osimertinib resistance by using first an older generation TKI and keep osimertinib for T790M-mutations. This could be relevant, for example in early stages IB where the osimertinib effect seems to be smaller. Nevertheless, this suppose an equivalent efficacy of other TKIs in de novo EGFR-mutations, which is not widely supported (14), as osimertinib seems to provide better results, maybe because of its T790M overcoming, once again. Also, previous adjuvant studies using other TKIs did not show any benefit on OS (15-19). Finally, such a sequential targeted therapy should probably be monitored by frequent T790M searching, considering that this mutation remains the main resistance mechanism. Altogether, to answer this question, an option could be a trial comparing adjuvant osimertinib first versus a sequential therapy with 1^st or 2^nd generation TKI followed by osimertinib at relapse or after the first finding of T790M, based on very sensitive testing of circulating tumor DNA (20). Furthermore, EGFR-mutations are numerous and each one may produce a different level of drug-response for one or another molecule (21): in ADAURA original publication, subgroup analyses showed a lower effect in patients with L858R mutation compared to del-19 (DFS HR 0.31 vs. 0.12), and consistent data were reported in EVAN, ADJUVANT and EVIDENCE trials (16,18,22). Although this subgroup analysis was not reported in the final ADAURA report, this may encourage a more precise drug-response monitoring according to presenting mutations, hopefully resulting in enhanced personalized adjuvant strategies.

In conclusion, ADAURA is a landmark in the use of TKI in adjuvant setting, yet some afterthought is needed to fully exploit all our available tools in the purpose of giving our patients individualized drug assignment and tailored treatment plans.

Acknowledgments

Funding: None

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-19/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-19/coif). AT has made boards for Astrazeneca to discuss problems of ctDNA in prostate cancer and detection of variants in HRR (Homologous Recombination Repair) genes. Astrazeneca also financed 2 meetings per year for somatic molecular biologists in France (JEPO and GFCO). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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