Yes to adjuvant osimertinib therapy in EGFR-mutated stage IB–IIIA non-small cell lung cancer post resection, but for how long? (ADAURA/NCT02511106)

Introduction

Lung cancer is still the leading cause of cancer mortality worldwide, with the majority of lung cancer being non-small cell lung cancer (NSCLC) in the United States. Approximately a third of NSCLC patients come to us with localized disease amenable to surgery at diagnosis (1,2). In these cases, curative intent surgery is the mainstay of treatment. Following resection, adjuvant cisplatin-based chemotherapy is generally recommended for patients with stage II–IIIA NSCLC and certain high risk patients with IB disease post resection (1,2). Adjuvant chemotherapy is thought to treat micrometastatic disease that is not visible radiographically, prevent spread to distant areas, and thus improve upon the remission rates. Despite this reasoning, recurrence rates or death after surgery remain elevated (varying from 45% to 76% in patients with stage IB to stage III disease, respectively), with or without the use of adjuvant chemotherapy (1).

In NSCLC, epidermal growth factor receptor (EGFR) mutations represent the most common oncogenic driver. Accordingly, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the preferred front-line systemic treatment for patients with metastatic NSCLC harboring activating EGFR mutations (1-4). Given the efficacy of EGFR-TKIs in patients with advanced metastatic disease, further study of their use in the adjuvant setting for resected NSCLC with EGFR mutations was prompted (1).

Use of osimertinib in EGFR mutation-positive NSCLC

Osimertinib is a third-generation EGFR-TKI. Osimertinib inhibits both EGFR-TKI sensitizing (such as exon 19 deletion and exon 21 L858R mutation) as well as the EGFR T790M resistance mutations with potency and selectivity, and is also effective in those with central nervous system (CNS) metastases (1). Osimertinib is currently considered the standard-of-care therapy for previously untreated advanced metastatic NSCLC with EGFR mutation (Ex19del or L858R) as well as the treatment of choice for advanced metastatic NSCLC with acquired EGFR T790M resistance mutations following disease progression on other earlier generation EGFR-TKIs (5,6).

Osimertinib as adjuvant therapy

In 2020, the ADAURA trial, a double-blind, phase 3 trial, assessed the efficacy [disease-free survival (DFS) and overall survival (OS)] and safety of osimertinib in comparison to placebo in patients age 18 years or over (20 years or over in Japan and Taiwan) with completely resected stage IB to IIIA NSCLC with EGFR mutations (Ex19del or L858R) with or without receiving adjuvant chemotherapy (which was per physician and patient choice). Patients were randomly assigned in a 1:1 ratio to be given either osimertinib (80 mg daily) (n=339) or placebo (n=343) until recurrence, up to 3 years of treatment, or meeting a criterion for treatment discontinuation (1).

DFS was significantly longer in patients with stage IB to IIIA EGFR mutation-positive lung cancer who were given adjuvant osimertinib than those who were given placebo. In patients with stage II to IIIA NSCLC, 90% in the osimertinib arm [95% confidence interval (CI): 84–93%] and 44% in the placebo arm (95% CI: 37–51%) were living and without disease at 24 months [overall hazard ratio (HR) for disease recurrence or death 0.17; 99.06% CI: 0.11–0.26; P<0.001]. In the overall population of patients with stage IB to IIIA NSCLC, 89% in the osimertinib arm (95% CI: 85–92%) and 52% in the placebo arm (95% CI: 46–58%) were living and without disease at 24 months (overall HR 0.20; 99.12% CI: 0.14–0.30; P<0.001). Additionally, 98% of the patients in the osimertinib arm (95% CI: 95–99%) and 85% in the placebo arm (95% CI: 80–89%) were living and without CNS disease (overall HR 0.18; 95% CI: 0.10–0.33) at 24 months. This implicates that adjuvant osimertinib reduced CNS recurrence risk among patients with resected NSCLC harboring sensitizing EGFR mutations (1).

After the Independent Data Monitoring Committee reviewed the ADAURA trial data, the trial was un-blinded two years earlier than what had been planned due to evidence of an efficacy benefit (1). The interim analysis demonstrated a substantial reduction in the risk of recurrence or death by 83% (overall HR 0.17). The benefit was more significant in more advanced or higher stages of disease (overall HR 0.12 in patients with stage IIIA disease; 0.17 with stage II disease; and 0.39 with stage IB disease) (1,4).

OS results were not mature in time for the 2020 interim analysis, with only 29 deaths (9 in the osimertinib arm and 20 in the placebo arm). Reassuringly, dose modifications and discontinuations of osimertinib occurred at a low frequency and no new safety concerns were noted (1). Overall, the safety profile of adjuvant osimertinib in early stage patients remained consistent with its established safety profile in patients with advanced metastatic NSCLC from the FLAURA and AURA studies (2).

Food and Drug Administration (FDA) approval of osimertinib in the adjuvant setting of surgically resected NSCLC

Based on the DFS data of ADAURA, the FDA gave approval on December 18, 2020 for use of osimertinib in the adjuvant setting in patients with NSCLC tumors that are positive for EGFR exon 19 deletions or exon 21 (L858R) mutations (2).

Although the OS data was not mature at the time, osimertinib received regular FDA approval given the magnitude of benefit in DFS seen in the osimertinib arm and due to the acceptance of DFS as a valid regulatory endpoint. DFS represents direct clinical benefit and the approval of adjuvant therapies for various tumor types such as breast and colorectal cancer have been supported by DFS as a regulatory endpoint (2). The efficacy analyses that remained to be determined for the study were the DFS analysis in the primary efficacy population (stage II–IIIA patients) when the pre-specified 247 DFS events are observed. Similarly, OS analysis will be determined when the pre-specified 94 deaths are observed (2).

Further updates on DFS

In January 2023, further DFS updates from the ADAURA trial were published. The final exploratory DFS analysis reports DFS data with protocol-specified maturity of about 50% and after two additional years of follow up.

Patients with stage II–IIIA NSCLC had a DFS HR of 0.23 (95% CI: 0.18–0.30). At 48 months, 70% (95% CI: 62–76%) of patients were living and without disease on the osimertinib arm while it was 29% (95% CI: 23–35%) for those on placebo. In the overall patient population (stage IB–IIIA disease), the HR for DFS was 0.27 (95% CI: 0.21–0.34). At 48 months, the percentage of patients living and without disease was higher at 73% (95% CI: 67–78%) for osimertinib whereas it was 38% (95% CI: 32–43%) for those on placebo. With these results, osimertinib in the adjuvant setting demonstrates a clinically significant DFS benefit, in keeping with primary data. Moreover, DFS benefit with osimertinib in patients with stage IB–IIIA disease was compatible across all predetermined subgroups which includes patients who were given or not given post operative chemotherapy, age greater than and less than 65, race, smoking history, and disease stage. The safety profile was consistent with the primary analysis (7).

In the Kaplan-Meier curves estimating DFS duration in stage II-IIIA disease and the overall population, there appears to be a shift toward increased DFS event rate from 36 months onward, compared to the initial 36 months (Figure 1). Despite this, the benefit of osimertinib remains clearly sustained as the osimertinib and placebo curves continue to be separated beyond the 3-year treatment period. Herbst et al. argues that this trend indicates that perhaps some patients with high risk of recurrence may benefit from osimertinib given adjuvantly beyond the three years studied in ADAURA (7).

Figure 1 Rate of DFS over time in patients receiving osimertinib versus placebo. (A) DFS rate in patients with stage II to IIIA disease. (B) DFS rate in the overall population (stage IB to IIIA). DFS, disease-free survival.

In regard to disease recurrence, fewer patients with stage IB–IIIA disease had recurrence of disease with osimertinib than with placebo [93/339 (27%) vs. 205/343 (60%)]. CNS DFS was higher with osimertinib in patients with stage II–IIIA (HR 0.24; 95% CI: 0.14–0.42) as well as in the overall population (HR 0.36; 95% CI: 0.23–0.57). Interestingly, CNS recurrences in the osimertinib arm mostly emerged after treatment completion. Additionally, only three of 18 patients in the osimertinib arm with stage II–IIIA disease had CNS disease as their initial site of recurrence while on therapy, in contrast to 29 of 32 patients in the placebo arm, further suggesting CNS DFS benefit with osimertinib (7).

Skepticism of ADAURA

Despite these results from the ADAURA study, there was skepticism regarding whether osimertinib brings true clinical benefit to patients with EGFR-mutated stage IB to IIIA NSCLC that had been resected. The argument stems from lack of data supporting a correlation between DFS and OS in targeted agents such as oral gefitinib and erlotinib. The phase 3 CTONG1104 trial, randomized patients with surgically-resected stage II through IIIA NSCLC harboring EGFR-mutations into either gefitinib or cisplatin-based chemotherapy. The median DFS among patients receiving gefitinib was found to be significantly longer; however, this significant advantage of gefitinib given adjuvantly did not convert into prolonged OS upon further follow-up. At the time of initial FDA approval, some argued that without understanding the OS data, the goal of adjuvant treatment—which would be to eliminate micrometastatic disease, thus improving upon the cure rates and ultimately provide OS benefit—is not addressed through the preliminary data of the ADAURA study (8). Furthermore, confirming the true clinical benefit of osimertinib prior to its routine use as standard adjuvant therapy in EGFR-mutant NSCLC is crucial given its substantial costs of on average $608 per tablet in the United States, as well as adverse effects (AEs) that can impact patient quality of life (QOL) (8).

OS of ADAURA trial

In June 2023, the long-awaited OS updates from ADAURA were finally presented. In patients with stage II to IIIA NSCLC, the OS at 5 years were 85% (95% CI: 79–89%) in the osimertinib arm and 73% (95% CI: 66–78%) in the placebo arm (for an overall HR for death 0.49, 95.03% CI: 0.33–0.73; P<0.001). In the overall population (stage IB to IIIA NSCLC), the OS rates at 5 years were 88% (95% CI: 83–91%) in the osimertinib arm and 78% (95% CI: 73–82%) in the placebo arm (for an overall HR for death 0.49, 95.03% CI: 0.34–0.70; P<0.001). Additionally, the OS benefit with osimertinib given adjuvantly was consistent across the subgroups, including disease stage (HR for death in patients with stage IB, II, and IIIA were 0.44, 0.63, and 0.37, respectively) and those who were or were not given post operative chemotherapy (HR for death 0.49 and 0.47, respectively), for the overall population and for those with stage II to IIIA NSCLC (9).

These results of the ADAURA trial demonstrate that adjuvant osimertinib allowed for significant OS benefit over placebo in completely resected, EGFR-mutant, stage IB to IIIA NSCLC.

The real question—duration of adjuvant osimertinib therapy

Given now the positive OS data, it is difficult to argue against the use of osimertinib in the post operative setting for patients with resected stage IB to IIIA NSCLC with EGFR-mutations. However, an important question yet to be answered may be the optimal treatment duration of adjuvant osimertinib. The ADAURA trial assesses adjuvant osimertinib treatment over the span of three years. Perhaps the most critical point from the Herbst JCO paper was the fact that it showed a large DFS rate drop from 36 to 48 months, much more than from 24 to 36 months (7). Hence, the question may be, was three years of adjuvant osimertinib enough? We know from 20 years of breast cancer literature that the longer the adjuvant hormonal blockade the better the DFS (10,11). Furthermore, most of the CNS relapses in the osimertinib arm emerged after treatment with osimertinib had been completed (7,9). Thus, for better OS and DFS, including the CNS, perhaps additional therapy beyond three years may be what is necessary.

While it would likely be beneficial for some patients to receive a longer duration of adjuvant osimertinib, the exact adjuvant treatment duration remains unclear.

To answer these questions, there remain ongoing studies that will further determine the long-term benefits and toxicities of adjuvant osimertinib. Importantly, one of the largest barriers to long-term adjuvant osimertinib treatment may be its cost at $608 per tablet or more than $18,000 a month in the United States (8). It will be crucial to consider this significant financial burden while determining the optimal duration of therapy. Another aspect to consider is the impact of prolonged osimertinib use on the QOL of patients. There is a risk of toxicity that comes with treatment with osimertinib. ADAURA reported AEs of any cause in 98% (n=330) of patients in the osimertinib group and 90% (n=309) in the placebo group. The most common AEs noted and considered to be causally related to osimertinib were diarrhea (40%), paronychia (25%) and dry skin (22%), while for the placebo group they were reported in 14%, 1%, and 5% of patients, respectively. Although AEs with grade 3 or higher were reported only in about 23% and 14% patients in the osimertinib and placebo groups, respectively (12), AEs such as day-to day episodes of diarrhea, paronychia, pruritus, or nausea of lower grades can still be distressing long-term, and may reduce the QOL of patients at the individual level, although a recent QOL publication from the ADAURA study has concluded that there were no statistically significant differences in time to deterioration for the SF-36 (short form-36) physical and mental component summaries between the use of osimertinib and placebo (12). Importantly, the AURA3 trial, which assessed patient-reported symptoms while treated with osimertinib or chemotherapy in advanced NSCLC, showed overall greater improvement rate of lung cancer-specific symptom burden, such as dyspnea, fatigue, and appetite loss, compared to chemotherapy. They argue that improvement of such symptoms aids in physical and role functioning and thus improved overall QOL (13). While it is possible that symptoms caused from cancer may be alleviated by further therapy in the advanced metastatic setting, we must be cognizant of the fact that in the adjuvant setting, the majority of the tumor burden has been presumed eradicated. Thus, we must be mindful of not causing further harm with further treatment that may be potentially unnecessary in some patients.

Other ongoing studies include trials that will further evaluate the efficacy and safety of osimertinib as adjuvant therapy for resected EGFR-mutant stage IA NSCLC (ADAURA2/NCT05120349); as 5-year adjuvant therapy in EGFR-mutant stage II–IIIB NSCLC (TARGET/NCT05526755); and as maintenance therapy post chemoradiation in unresectable EGFR-mutant stage III NSCLC (LAURA/NCT03521154). Interestingly, the LAURA study which allowed patients with unresectable EGFR-mutated NSCLC post-chemoradiation to receive osimertinib until progression, announced its “overwhelming efficacy benefit” in a recent press release and may provide insight into the benefits of prolonged therapy until progression (14).

Conclusion

In summary, the ADAURA trial demonstrated significant DFS as well as OS benefit over placebo which supports the use of adjuvant osimertinib therapy in patients with resected, EGFR-mutated stage IB–IIIA NSCLC. There remain questions regarding optimal duration of adjuvant osimertinib therapy, with evidence of possible benefit with longer duration of adjuvant osimertinib beyond three years.

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-24-27/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-27/coif). S.H.I.O. was a speaker for Merck, Roche/Genentech, Astra Zeneca, Takeda/ARIAD and Pfizer and has received advisory fees from Roche/Genentech, Astra Zeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc., Spectrum, Daiichi Sankyo, Jassen/JNJ, and X-Covery; reports stock/stock options from MBrace Therapeutics and Turning Point Therapeutics Inc. (until February 28, 2019); also on the DSMB of Turning Point Therapeutics Inc. (until February 28, 2019), Elevation Oncology. M.N. was on the advisory board of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly and Company, Bayer, Regeneron, BMS and Genentech; consultant for Caris Life Sciences (virtual tumor board); speaker for Blueprint Medicines, Janssen, Mirati and Takeda; and reports travel support from AnHeart Therapeutics, stock/stock options from MBrace Therapeutics. The other author has 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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