ADAURA: redefining the role of target therapy in resectable lung adenocarcinoma

Introduction

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers (LCs) (1). The prevalence of lung adenocarcinoma (LUAD) has decreased significantly, mainly because of a decrease in the magnitude of tobacco exposure, which has occurred to a greater extent in high-income countries (2). In addition, the implementation of LC screening selected in populations by age and smoking habits increased the proportion of patients with LC in the early stages. Risk model-based eligibility for LC screening has been shown to outperform the traditional criteria, identifying more high-risk individuals with improved sensitivity and considerable mortality benefits (1). These issues have an impact now and will further enhance the proportion of patients diagnosed with early-stage LUADs with target alterations. LC with epidermal growth factor receptor mutations (EGFRm) occurs almost exclusively in LUAD and usually affects younger people, with less cardiovascular comorbidity, and consequently, longer life expectancy at diagnosis. There is no difference in stage-specific disease-free survival (DFS) between patients with EGFRm LUADs and those with wildtype EGFR, but recurrence risk plateaued at 8 to 9 years in the former vs. 5 to 6 years in the latter (3).

Adjuvant treatment with osimertinib has revolutionized the management of early stage LC showing benefits in DFS, adequate tolerance profile, maintaining quality of life, and recently benefit in overall survival (OS) (4-6). We will discuss here the OS results of the ADAURA study, try to put these results in the context of clinical practice and highlight some questions that the results have raised (Figure 1).

Figure 1 Includes the points of most significant controversy surrounding the ADAURA trial. TKIs, tyrosine kinase inhibitors; MRD, minimal residual disease.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the standard of care for patients with advanced NSCLC harboring Ex19del or L858R EGFR mutations (called common EGFR mutations) (4). However, its role in early disease has been in doubt for decades. Multiple studies have been conducted with first-generation EGFR-TKIs as adjuvant therapy, mainly in the Asian population and with different designs (Phase II and III trials; EGFR-TKIs vs. chemotherapy; EGFR-TKIs vs. observation; 1 or 2 years of duration) showing improved DFS but lack of apparent OS benefit (7-9).

In the EVAN trial, patients treated with adjuvant erlotinib had a 2-year DFS rate of 81.4% versus 44.6% in patients who received chemotherapy (relative risk, 1.823; 95% CI: 1.19–2.78; P=0.0054) (10). The ADJUVANT/CTONG1104, a larger (N=222) phase III trial, reported that patients who received adjuvant gefitinib had a significantly longer DFS rate than those who received chemotherapy in the intention-to-treat population. Specifically, those who received gefitinib had a DFS of 30.8 months compared with 19.8 months for patients in the chemotherapy arm [hazard ratio (HR), 0.56; 95% CI: 0.40–0.79; P=0.001]. Further, the DFS was higher at 3 years (39.6% vs. 32.5%), although this benefit did not translate to an OS advantage (HR, 0.92; P=0.674), even considering that nearly 50% of patients in the chemotherapy arm did not receive EGFR-TKIs at progression (11). Recently, the EVIDENCE trial showed that icotinib impacted the DFS (47 vs. 22.1 months for placebo; HR 0.36, 95% CI: 0.24–0.55; P<0.0001). The 3-year DFS was 63.9% (95% CI: 51.8–73.7) in the icotinib group and 32.5% (95% CI: 21.3–44.2) in the chemotherapy group, and still immature OS showed an HR of 0.91 (95% CI: 0.42–1.94) and a more significant benefit for those who received the TKI for more than 18 months (12). Importantly, these trials have demonstrated the heterogeneity of the tumoral genomic landscape, with some genetic features (such as TP53 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC) predicting EGFR-TKIs benefit and others indicating chemotherapy advantage (13,14).

In early-stage EGFRm NSCLC, primary surgery is the standard of care; however, unmet needs persist in this patient population, given that the risk of mortality after five years of R0 surgery has been estimated between 26% (pT2aN0M0) and 53% (pT4N0M0) (15). Neoadjuvant or adjuvant chemotherapy has been shown to improve 5-year OS by only about 5% (16,17). Some of these studies allowed the recruitment of a small population of patients with driver mutations (e.g., EGFRm) and unknown EGFR status. The role of immunotherapy in patients with EGFRm NSCLC is still an area of debate. Indeed, there is concern that patients who received immunotherapy followed by EGFR-TKIs could have a significant risk of developing toxicity (mainly pneumonitis). For now, this select population does not seem to be the one that derives the most benefit from chemoimmunotherapy; on the contrary, there is an increase in toxicity (18,19).

Neoadjuvant targeted therapy has multiple preclinical advantages and offers a unique window of opportunity to carry out translational studies to identify drug-tolerant persistent cells (DTPC) and overcome their resistance mechanisms. Recent clinical trials in this setting have shown somewhat disappointing response rates, and it remains to be defined whether the outcomes evaluated in early disease studies (pathological complete response, major pathologic response, and event free survival) will impact OS (20-22).

ADAURA trial

The early unblinding of results from the phase 3 ADAURA clinical trial (NCT02511106) evaluating osimertinib, a third-generation EGFR-TKI, was met with much noise by the oncology community, primarily because of the details of the interim results. Specifically, this analysis showed an 83% reduction in the risk of disease recurrence or death (HR 0.17; 99.06% CI: 0.11–0.26), with the most significant benefit observed in patients with more advanced stages of the disease. Among patients with stage IIIA disease, the HR was 0.12 (95% CI: 0.07–0.20); among those with stage II disease, it was 0.17 (95% CI: 0.08–0.31); and among those with stage IB disease, it was 0.39 (95% CI: 0.18–0.76). The prognosis of patients who received placebo was poor, with a DFS probability of 28% at 3 years among patients with stage II to IIIA disease (5).

Safety, and health-related quality of life, critical secondary endpoints, also has been reported (23,24). In terms of safety and tolerability, adjuvant treatment with Osimertinib is safe and well tolerated. Only 13% of patients had to discontinue treatment due to intolerance and there was no deterioration in quality-of-life measures compared to placebo (6).

Recently, Tsuboi et al. reported that among patients with stage II to IIIA disease, osimertinib reduced the risk of death by 51% (HR 0.49, 95% CI: 0.33–0.73; P=0.0004), with 85% of patients in the osimertinib arm surviving for 5 years compared with 73% of patients in the placebo arm. Similarly, adjuvant osimertinib appears to alter the course of the disease, with radical reductions in distant recurrence, including central nervous system (CNS) recurrence (2% vs. 11%) (17). In addition, 66% and 41% of the patients in the osimertinib and placebo arms, respectively, completed the planned treatment duration of 3 years. Consistent with the DFS findings, fewer patients in the osimertinib arm (22%) received subsequent anticancer treatment than those in the placebo arm (54%) (5). Since OS has historically been considered the gold standard efficacy endpoint for randomized adjuvant clinical trials, this is a significant achievement that will help broaden treatment access for patients, considering the importance of globalizing molecular testing for EGFRm.

How can we incorporate ADAURA into clinical practice?

PET/CT, brain MRI, and mediastinal staging are standards for LC diagnostic evaluation; unfortunately, in clinical practice, there are some difficulties in performing these evaluations in a timely manner. Unexpectedly, the rigorous staging was also quite variable in ADAURA and other similar adjuvant trials, with less than 25% of patients undergoing PET/CT and brain MRI (11). Therefore, it is difficult to differentiate real DFS and OS improvements in patients with minimal residual disease (MRD) from those with residual or metastatic disease undetected by conventional imaging. The predominant surgery in both ADAURA and other adjuvant studies and retrospective series is lobectomy (>95%), so it is difficult to define the role of sublobar surgery in this scenario, especially considering the greater probability of a lepidic pattern in EGFRm tumors (13).

Recently, the cytotoxic effects of EGFR-TKIs have been questioned. However, data from other trials using these drugs as the only adjuvant intervention, as well as the subgroup of patients with ADAURA who did not receive CT and derived benefit in OS, help clarify the role of osimertinib as a cytotoxic therapy. Nevertheless, it is premature to preclude any additional benefits of adjuvant chemotherapy. Further, follow-up is required, given the higher risk of late relapse than in EGFR wild-type tumors. Additional translational research is warranted to establish which mutational profile benefits more than one strategy (osimertinib monotherapy) or a combination approach, such addition of chemotherapy, considering the frequency of co-mutation in TP53, MUC16, FAM104B, KMT5A, some, particularly TP53, and RB1 are associated with poor DFS independent of disease stage (25). On the other hand, there is a benefit in OS with adjuvant treatment with osimertinib independent of the type of EGFRm documented (Exon 19 or exon 21 L858R deletion), however the magnitude of the benefit in the exon 21 L858R mutation is lower, a situation similar to that observed in advanced disease. Again, it is necessary to establish whether complementary therapies will be required in this type of mutation. It is also essential to stratify patients according to MRD status and prospective kinetics to better define the role of adjuvant therapy. Measurement of cell-free DNA by liquid biopsy can estimate MRD, however improved techniques are required to allow for improved sensitivity. Key genetic and proteomic markers were collected prospectively and sequentially in the ADAURA trial; knowing these results is still a need.

The optimal duration of adjuvant therapy remains controversial and requires further investigation. The median treatment exposure was 35.8 months (range, 0–38 months) in the osimertinib group, and 66% completed the planned treatment duration of 3 years (5). In this heterogeneous disease, a fixed period of adjuvant therapy duration could represent over treatment for some patients and under treatment for some others considering the narrowing of PFS curves at 2 and 3 years after treatment completion (24). Longer follow up is essential to understand the long-term benefits, including whether patients are cured or merely have a delay in relapse.

Tailoring adjuvant therapy represents an area of interest (26). Selection of patients who are more prone to benefit from adjuvant EGFR-TKI would be extremely important. Molecular profiling and monitoring of MRD may determine being eligible for adjuvant therapy and the optimal treatment length; particularly longitudinal undetectable MRD defines a potentially cured population, representing a negative predictive value of 96.8% and a negligible benefit of adjuvant therapy; however brain-only recurrence could represent a caveat, being less commonly detected by MRD (20%) (27).

Understanding clinical utility of adjuvant osimertinib in different stages is critical for clinicians to make informed treatment decisions. Patients with stage IA–B LC have a lower relapse risk and noteworthy that these patients may have an important rate of circulating tumor DNA (ctDNA) positivity in the preoperative setting, but a high ctDNA clearing rate of nearly 80%. Some patients with tumors between 3.1–4 cm were also included in the ADAURA trial; although the study did report DFS for this subgroup, it will be important to evaluate the DFS and OS benefit in this subgroup (28).

Discussion and conclusions

Soon, the NeoADAURA (NCT04351555; neoadjuvant osimertinib in resectable stage II to IIIB (N2 disease), ADAURA-2 study (NCT05120349; adjuvant osimertinib in patients with stage IA disease), and TARGET (NCT05526755; 5-year adjuvant osimertinib in stage II to IIIB disease) trials will define the additional role of osimertinib in other populations of interest. Future adjuvant trials should advance our knowledge and not just replicate the results of ADAURA.

For patients with relapse after completion of the adjuvant therapy, there is no consensus about the optimal treatment (29). Osimertinib resistance mechanisms are quite variable and include EGFR dependent/independent alterations and small-cell LC transformation; these mechanisms are well characterized at least in advanced disease (30). Defining tumoral biology at relapse represents an important tool for assisting therapeutic decisions. Osimertinib retreatment, newer therapies, chemotherapy with or without immune checkpoint inhibitors and antiangiogenic therapy represent options and future platform clinical trials explore treatments to overcome acquired resistance. Future possibilities include the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. The SAVANNAH trial combined osimertinib with savolitinib, and the ORCHARD study investigated osimertinib in combination with savolitinib, gefitinib, or necitumumab. On the other hand, it is necessary to know the mutational profile of patients who recur after adjuvant treatment with osimertinib. This will make it possible to establish a specific or progression-guided therapy. Liquid biopsy or tissue biopsy will be tools to be used for this purpose.

Remaining to be elucidated is the effect of adjuvant EGFR-TKIs in patients with very early disease, especially for some patients with high-risk features and a higher probability of relapse in which adjuvant chemotherapy may still have a role (31). Nevertheless, patients with early-stage NSCLC and uncommon EGFRm are small yet growing subgroups not included in adjuvant trials in which novel compounds or chemoimmunotherapy could still be an option.

The controversy has become more complex, considering the cost-effectiveness of the adjuvant osimertinib. In American Society of Clinical Oncology 2023, Muthusamy et al. demonstrated that using adjuvant osimertinib resulted in a gain in DFS of 35.4% at 5 years, but with a significant financial cost of approximately $450,000 per eligible patient (32). However, the cost-effectiveness modeling of adjuvant osimertinib for the Canadian healthcare system favored TKI treatment over active surveillance (33). The ADAURA trial also opened the perspective toward studies in patients with ALK alterations, such as ALINA (NCT03456076), ALNEO (NCT05015010), HORIZON-01 (NCT05170204), and ALCHEMIST (NCT02194738), or in other populations such as NAUTIKA1 (NCT04302025). Recently, the ALINA trial, a randomized, active-controlled, multicenter, open-label trial evaluating the efficacy and safety of first-line adjuvant alectinib (600 mg/d for two years) compared with four cycles of platinum-based chemotherapy in patients with Completely resected stage IB to IIIA ALK-positive NSCLC included 257 patients stratified by disease (II vs. IIIA) as well as by race (Asian vs. non-Asian). Like ADAURA, the primary outcome was DFS, and the secondary outcome was OS. The baseline characteristics were balanced between the two arms; most patients were never smokers who had undergone a lobectomy, and 54% and 50% of the cases had stage IIIA disease and node-positive disease at baseline, respectively (34). Following the results described for EGFR-positive disease, ALINA demonstrated that after a median follow-up of 27.9 months, the median of DFS for alectinib was not reached, while it was 44.4 months for chemotherapy. Additionally, the 3-year DFS rate was 88.3% vs. 53.3%, respectively. When outcomes were analyzed according to disease stage, alectinib improved disease-free survival by 79% in stage IB, 76% in stage II, and 75% in stage IIIA disease. Brain recurrences were reported in 4 patients in the alectinib arm vs. 14 in the chemotherapy arm, and the 2-year rate of CNS DFS was 98.4% vs. 85.8%, respectively (at three years, the rate was 95.5% vs. 79.7%, respectively) (34). These data support the evolution of research around targeted adjuvant therapy for some NSCLC subpopulations.

Finally, the fact that patients in the placebo group had not received osimertinib treatment after recurrence could reduce the magnitude of the OS benefit observed in the ADAURA study. Real-life studies in this setting could help define the real OS benefit of adjuvant osimertinib therapy as well as the stratification of the population following molecular factors that allow optimizing the risk characterization. In this sense, Liu et al. presented comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, including five predictive biomarkers (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC) integrated by Multiple-gene INdex to evaluate the relative benefit of various adjuvant therapies using the MINERVA score, which categorizes patients into three subgroups with relative DFS and OS benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups) (14).

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-23-17/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-17/coif). J.A.Z. reports grants or contracts from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Bristol-Myers Squibb; payment or honoraria from Astra Zeneca, Merck Sharp & Dohme, Bristol Myers Squibb, and Pfizer; payment for expert testimony from AstraZeneca, Bristol-Myers Squibb, Pfizer; support for attending meetings and/or travel from Adium Pharma, AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Eli Lilly; receipt of equipment or other services from AstraZeneca, Pfizer, Roche. L.R. reports grants or contracts from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Conquer Cancer Foundation; payment or honoraria from Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Eli Lilly; payment for expert testimony from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis; support for attending meetings and/or travel from Merck Serono, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis. O.A. reports grants from Astra Zeneca, Boehringer Ingelheim, and Roche; consulting fees from Pfizer, Lilly, Merck, Bristol-Myers Squibb, Astra Zeneca, Boehringer Ingelheim, and Roche. A.F.C. reports grants or contracts from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Foundation Medicine, Roche Diagnostics, Termo Fisher, Broad Institute, Amgen, Flatiron Health, Teva Pharma, Rochem Biocare, Bayer, INQBox and The Foundation for Clinical and Applied Cancer Research – FICMAC; payment or honoraria from EISAI, Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research – FICMAC; payment for expert testimony from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Foundation Medicine, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research – FICMAC; support for attending meetings and/or travel from Merck Serono, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, and Foundation for Clinical and Applied Cancer Research – FICMAC; participation on the Data Safety Monitoring Board or Advisory Board of Roche, Merck Sharp & Dohme; receipt of equipment or other services from Roche, Roche diagnostics, Rochem Biocare. The authors have no other conflicts of interest to declare.

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