EGFR inhibitor impressed in ADAURA trial, but more data needed to see gains in stage IA-IB disease

Patients with early-stage EGFR-positive NSCLC had high recurrence rates, and more than 35% of patients with early- and late-stage disease achieved cure without adjuvant osimertinib, begging the question: How universally applicable are the findings from the ADAURA trial in a real-world setting?

In the Singapore-based study of patients with stage IA to IIIA NSCLC, all of whom underwent curative surgery, 41.4% (n=299/723) had cancer recurrence at a median follow-up of 46 months, according to Daniel S. W. Tan, PhD, of the National Cancer Centre Singapore, and co-authors.

In addition, disease-free survival (DFS) came in at:

  • Stage IA: 81.0% two-year DFS (95% CI 74.0%-86.3%).
  • Stage IB: 78.4% two-year DFS (95% CI 68.2%-85.6%).
  • Stage III: 57.1% two-year DFS (95% CI 43.7%-68.4%).
  • Stage IIIA: 46.6% two-year DFS (95% CI 34.7%-57.7%).
  • Stage IB through IIIA: Overall five-year DFS 37.2% (95% CI 30.1%-44.3%).

“The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib,” Tan’s group wrote in JAMA Network Open. “While an early snapshot of recurrence data has been published for ADAURA… clinicopathologic and genomic factors associated with early recurrence and long-term cure for resected EGFR-positive NSCLC remain unknown.”

In a 2021 International Association for the Study of Lung Cancer ILCN Multidisciplinary Forum, Tan stressed that “one of the challenges now with the use of osimertinib is really the unknown factor of some of the resistance mechanism as well as the extent to which they are actionable…I think there’s a lot more to be learned about the drivers of resistance beyond mutations.”

Those “early snapshot” ADAURA results were presented at the 2020 European Society for Medical Oncology (ESMO) virtual meeting, and published in the New England Journal of Medicine (NEJM). In short, the trial showed that patients with stage IB to IIIA EGFR-mutated NSCLC experienced a DFS that was significantly longer if they got osimertinib versus placebo.

Trial investigator Roy S. Herbst, MD, PhD, of Yale University in New Haven, Connecticut, highlighted to VJOncology that the study “really shows that not only do we improve disease-free survival, but we also improve morbidity because we keep patients from developing metastasis in such sensitive sites as the brain. This is very important and right now the ADAURA study will continue on to look at the other important secondary endpoints including survival.”

In particular, the data on central nervous system (CNS) recurrence from ADAURA was “highly anticipated,” according to Sanjay Popat, MBBS, PhD, of the Royal Marsden NHS Foundation Trust in London. ADAURA “did report a huge reduction in the incidence of CNS progression from 10% in the placebo arm down to 1% in the osimertinib arm, and that is also coupled [with] a huge reduction in the distant relapse rate afforded with ongoing systemic osimertinib therapy.” Popat told VJOncology at the ESMO meeting. “One thing that we have to bear in mind is that [ADAURA] patients did not have to have mandatory brain MRIs to go into the study.”

And that was also a limitation of the current retrospective study; not all patients had baseline PET/CT and brain MRI staging, which could have led to understaging. Also, the study was done at a single site with predominantly Asian patients, genomic data was limited, and the findings require outside validation.

But the fact remains that in the current study, “a significant number of patients remain disease-free at 5-years without osimertinib,” according to Tan’s group, so will the results have an impact on how and when lung cancer specialists will work osimertinib into their preferred EGFR-mutated NSCLC treatment regimen?

The FDA certainly made their position clear when they green lighted the agent in December 2020 as adjuvant therapy in patients with stage IB to IIIA resection NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by the cobas EGFR Mutation Test.

The research from Tan’s group “is especially timely and relevant,” because “many researchers still await mature overall survival data from this landmark study [ADAURA]” noted Christopher D’Avella, MD, of the University of Pennsylvania, and J. Nicholas Bodor, MD, PhD, of the Fox Chase Cancer Center, both in Philadelphia, in an invited commentary accompanying the study.

They pointed out that patients with stage IA NSCLC were not included in ADAURA, so are not eligible for osimertinib, according to the FDA. Yet Tan and co-authors “found similar DFS for patients with stage IA (81%) and IB (78%) NSCLC in the EGFR-positive cohort,” and that “[e]ven among patients with very early-stage disease, nearly 20% of patients still experience early recurrence or death,” wrote D’Avella and Bodor.

They reiterated that 37% of current overall cohort with stage IB to IIIA NSCLC achieved a 5-year DFS and were deemed cured without adjuvant osimertinib. While “[m]any oncologists admit a greater enthusiasm for offering [adjuvant osimertinib] to patients with stage II to IIIA disease,” they also “acknowledge the need for more nuanced discussions regarding the risks and benefits in stage I disease.”

D’Avella and Bodor aren’t the only one with questions about how expansive the application of osimertinib should be in these patients. In a 2021 NEJM letter to the editor, Jianxing He, MD, of the National Center for Respiratory Medicine in Guangzhou, China, and co-authors asked if “chemotherapy is necessary when osimertinib is used as adjuvant therapy in patients with [EGFR] mutation-positive resected stage IB, II, or IIIA [NSCLC]. Some previous studies involving Asian patients with NSCLC—half of whom had EGFR mutation-positive NSCLC—suggested that survival was shorter among patients who received adjuvant chemotherapy than among those who did not,” referencing the 2014 ICAN trial.

Herbst and colleagues replied that “the use of adjuvant chemotherapy was determined according to physician and patient choice before randomization,” but that a “benefit of osimertinib with respect to disease-free survival was observed with or without the previous use of chemotherapy (hazard ratio for disease recurrence or death, 0.16 and 0.23, respectively).”

Tan and co-authors conducted the study from early January 2010 to the end of June 2018 (ADAURA ran from 2015 to 2019), with 723 patients (50.6% women; median age 64; >80% Chinese ethnicity) with stage IA to IIIA NSCLC per the American Joint Committee on Cancer 7.

Of those 723 patients, 41.4% had stage IA NSCLC, 21.4% were stage IB, 19.5% were IIB, and 17.3% were stage IIIA. Also, 389 had EGFR-positive NSCLC (48.6% with exon 19 deletions; 38% with exon 21 L858R mutations) and 334 had wild-type EGFR NSCLC. The authors explained that patients with EGFR-positive NSCLC met the following versus those with wild-type disease:

  • More likely to be women: 31.7% versus 64.5%.
  • More like to be never smokers: 36.2% versus 81.5%.

In the 2019 consensus statement from the Asian Thoracic Research Oncology Group, Tan and colleagues noted that “The prevalence of these oncogenes [EGFR] and smoking prevalence makes NSCLC found in Asian patients intrinsically distinct from that found in Caucasian patients.”

For the current study, “[c]linicopathological information, treatment data (including adjuvant chemotherapy), and survival data were collated through retrospective manual electronic health record review of our institution’s database,” Tan’s group wrote. More than 90% of all the patients received no adjuvant radiotherapy, while over 75% did not get adjuvant platinum doublet therapy.

The authors reported that the median time to recurrence was 16 months, and that there was no statistically significant difference in two-year DFS for EGFR-positive and wild-type EGFR NSCLC at 70.2% (95% CI 65.3% to 74.5%] versus 67.6% (95% CI 62.2% to 72.4%, P=0.70), respectively.

In terms of the sites of disease at recurrence, 16.4% of patients with EGFR-positive disease experienced locoregional recurence versus 16.8% of those with wild-type disease. Other areas of recurrence were lungs (10.5% vs 12.0%, respectively), and intracranial (9.5% vs 6.6%, respectively). The latter was the most common metastases, according to Tan and co-authors.

However, patients with EGFR-positive NSCLC had significantly better five-year overall survival at 77.7% (95% CI 72.4% to 82.1%) versus 66.6% (95% CI 60.5% to 72.0%, P=0.004) for wild-type disease, they wrote.

The authors conducted a univariable and multivariable analyses and pinpointed that the clinicopathological features were tied to recurrence:

  • Wild-type EGFR NSCLC: Higher stage; lymphovascular invasion.
  • EGFR-positive NSCLC: Higher stage; nonacinar and nonlepidic adenocarcinoma subtype; sublobar resection; positive resection margins; lymphovascular invasion.

They also found that “[a]djuvant radiation therapy was associated with recurrence on multivariate but not univariate analysis, likely owing to small numbers…receiving adjuvant platinum doublet chemotherapy and adjuvant radiotherapy were associated with recurrence in univariable analysis… [but]… were not significant on multivariable analysis, likely owing to adjustment for stage.”

D’Avella and Bodor noted that the authors conducted an 85-patient exploratory analyses of EGFR-positive NSCLC with “whole-exome and transcriptome sequencing data integrated with histopathological information,” and identified “alterations in RHPN2, CTNNB1, and micropapillary subtype to be associated with increased risk of recurrence, while loss of RB1 was associated with decreased risk.”

They also noted that post-ADAURA, many patients undergo such testing right after resection so “whole-genome sequencing may be a plausible strategy and readily adaptable to assess for molecular risk-signatures in such patients with early-stage cancer in the future.”

  1. Recurrence rates were high in resected EGFR-positive non-small cell lung cancer (NSCLC) and more than one-third of patients with stage IB through IIIA disease were cured without adjuvant osimertinib.

  2. Patients with wild-type EGFR NSCLC with higher stage and lymphovascular invasion had a higher recurrence risk, as did patients with EGFR-positive NSCLC at higher stage; with nonacinar and nonlepidic adenocarcinoma subtype; with sublobar resection; and with positive resection margins, as well as lymphovascular invasion.

Shalmali Pal, Contributing Writer, BreakingMED™

This work was supported by grants from the Singapore National Medical Research Council and the NMRC Clinician-Scientist Award

Saw disclosed no relevant relationships.

D’Avelia and Bodor declared no relevant relationships.

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Topic ID: 78,24,730,24,192,65,925