JAMA Oncology Hearing different perspectives in the face of ADAURA study with stunning data

Article source: Medicine Rubik's Cube Med

Author: Arale

New anti-tumor drugs represented by EGFR-TKIs and immune checkpoint inhibitors (ICIs), after achieving great success in advanced NSCLC, will advance their exploration to perioperative treatment
.

Among them, the ADAURA study, with its amazing data, ignited the enthusiasm of TKI in the adjuvant treatment of NSCLC, and published the research results in the top journal "New England Journal of Medicine" in September 2020

A brief review of the ADAURA study[1]

A brief review of the ADAURA study[1]

The ADAURA study is a double-blind, phase III clinical trial.
A total of 682 patients with stage IB-IIIA, EGFR mutation-positive NSCLC after complete tumor resection were enrolled and randomly divided into two groups according to 1:1, respectively receiving osimertinib or placebo for 3 years
.

The primary endpoint was DFS in patients with stage II-IIIA; secondary endpoints included DFS, OS, and safety in the overall population (IB-IIIA)

The results showed that at 24 months, among patients with stage II-IIIA NSCLC, the DFS rates in the osimertinib group and placebo group were 90% and 44%, respectively (HR=0.
17, P<0.
001)
.

In the whole population, the DFS rates in the osimertinib group and placebo group were 89% and 52%, respectively (HR=0.

DFS of osimertinib and placebo in patients with stage II-IIIA NSCLC
.

Image from: N Engl J Med.

Based on this result, osimertinib was approved by the US FDA and NMPA for the post-operative adjuvant treatment of EGFR-mutated NSCLC, and it was the first adjuvant targeted therapy for NSCLC recommended by the NCCN guidelines
.

However, after the results of the ADAURA study were published, different views emerged one after another.
The discussion points focused on two points: 1.
Can DFS be translated into OS benefits? 2.
Possible overtreatment
.

The editor chose the opinion article (Why Not Adore ADAURA?) [2] published in JAMA Oncology in May 2021 as a representative, and organized the content to share with you
.

The authors of this article are Professor Howard Jack West from the City of Hope Comprehensive Cancer Center in the United States and Professor Bishal Gyawali from the Department of Oncology at Queen's University in Canada
.

By extension, Professor Bishal Gyawali can be regarded as a frequent visitor in the field of tumor reviews, including JAMA Intern Med, Nat Rev Clin Oncol, Mayo Clin Proc and other famous journals
.

In fact, this is not the first time that Professor Bishal Gyawali has commented on ADAURA research

Discussion point 1: Is improving DFS enough?

Discussion point 1: Is improving DFS enough?

Rational adjuvant therapy can improve the long-term survival of patients with early-stage NSCLC
.

After several prospective randomized trials and demonstrated OS benefit, chemotherapy became the standard regimen for adjuvant treatment of stage II-IIIA NSCLC

However, DFS should not be a standard measure, especially if treatment involves clinically meaningful adverse effects and costs
.

Compared with advanced disease, adjuvant therapy has a higher treatment burden and clear adverse effects, while the potential survival benefit awaits long-term evaluation

In the CTONG ADJUVANT study (gefitinib vs chemotherapy) and the OPTIMAL study (erlotinib vs chemotherapy), although there was a significant benefit on the surrogate endpoint, it did not translate into an OS benefit
.

Therefore, the significant benefit of DFS in the ADAURA study does not represent a benefit of OS

Discussion point 2: Characteristics of the included population

Discussion point 2: Characteristics of the included population

Notably, prior to randomization, patients were not required to have received adjuvant chemotherapy, and in fact 45% of enrolled patients had not received adjuvant chemotherapy
.
In addition, patients with resected stage IIIA N2-positive nodes need not have received adjuvant radiotherapy, although there is evidence that adjuvant radiotherapy can benefit these patients
.
Exact tumor staging details have not been published, and high recurrence rates may accompany if standardized mediastinal staging, positron emission tomography (PET), and computed tomography (CT) are not performed
.

Discussion point 3: Potential overtreatment

Discussion point 3: Potential overtreatment

It took 3 years to assess the long-term benefit of this study, suggesting that osimertinib may be suppressing rather than curing patients
.
In addition, long-term use of osimertinib may lead to acquired resistance and affect overall survival
.
To answer this question, a comparison is still needed: adjuvant osimertinib vs osimertinib after relapse
.

We also need to consider the socioeconomic costs of this strategy
.
In the United States, the annual cost of treatment per patient will exceed $200,000, which is an economic burden, especially in patients with a low risk of recurrence (eg, stage IB)
.
Subgroup analysis showed that the HR of this group of patients was relatively insignificant (DFS HR=0.
50), most of these patients were cured, and the social cost of overtreatment was high
.
Of course, the premise of discussing the economic cost effect is that the ADAURA study needs to show a clear and statistically significant OS benefit
.

Author's sharp summary

Author's sharp summary

The ADAURA study has not yet provided the data we expect to see
.
Clinical trials are designed to truly address critical clinical questions
.
Alternatively, this responsibility can also be placed on the pharmaceutical companies involved in the design of clinical trials to maximize sales, rather than helping patients as we hope
.

Osimertinib sales data.
Data from: NextPharma database

Written at the end: In terms of targeted drugs, in addition to the ADAURA study, almetinib, icotinib, and alectinib are all conducting adjuvant treatment studies for NSCLC
.
In terms of ICIs, Merck announced on January 10 that the Keynote-091 study (pembrolizumab as postoperative adjuvant therapy for stage IB-IIIA NSCLC) achieved the primary endpoint of DFS
.
Nivolumab, atezolizumab, durvalumab, and canakinumab are also in clinical trials for adjuvant therapy
.
The discussion points raised in this JAMA Oncology article may apply to them as well
.

Write at the end:

references

1.
Yi-Long Wu, et al.
N Engl J Med.
2020; 383(18): 1711-1723.

2.
Howard Jack West, Bishal Gyawali.
JAMA Oncol.
2021; 7(5): 677-678.

3.
Bishal Gyawali, Howard Jack West.
J Clin Oncol.
2021;39(3): 175-177.