ADAURA Raises Questions About Optimal Use of Adjuvant EGFR TKIs in NSCLC

Over the past 2 decades, the field of EGFR-mutated non–small cell lung cancer (NSCLC) has grown tremendously, but the influx of data and the recent regulatory approval of adjuvant osimertinib (Tagrisso) have raised several important questions to be addressed to ensure that the optimal treatment approach is utilized.

In a keynote lecture delivered during the 18th Annual Winter Lung Cancer Conference®, Lecia V. Sequist, MD, MPH, director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital and the Landry Family Professor of Medicine at Harvard Medical School, spoke on areas of uncertainty in EGFR-positive NSCLC and shared how she weighs the data available to make informed treatment decisions in practice.¹

PSA: Paradigm for Advanced Disease Might Not Translate to Adjuvant Setting

When EGFR TKIs first emerged, they were successfully being used in patients with metastatic disease. Although it became known that TKIs were more effective than chemotherapy and chemotherapy was better than observation, it prompted the question of whether TKIs are better than observation, according to Sequist.

“The paradigm for advanced-stage disease doesn't necessarily transfer so easily to the edge of insanity because the population is different,” said Sequist. “When you're treating patients with advanced cancer, [all of these patients have] cancer. When you're treating in the adjuvant setting, many people don't have cancer; you don't know who does and who doesn't, because it's microscopic. But you are treating some people who truly don't need treatment.”

The group of patients without residual cancer present magnifies the risks of whatever agent is being administered and could reduce the overall benefit provided to the patient; if a patient is already in a cancer-free state, treatment may result in more harm than value, warned Sequist.

For example, when bevacizumab (Avastin) was added to paclitaxel/carboplatin in patients with recurrent or advanced NSCLC, it was found to have a significant survival benefit over paclitaxel/carboplatin alone (HR, 0.79; P = .003).² However, when the agent was added to adjuvant chemotherapy in patients with resected, early-stage NSCLC, it did not improve overall survival (OS; HR, 0.99; 95% CI, 0.82-1.19; P = .90).³

Adjuvant Chemotherapy Versus EGFR TKI: Is Skipping Chemotherapy Feasible?

To date, 3 studies have been performed in China that have compared the use of adjuvant chemotherapy versus EGFR TKI: the phase 2 EVAN trial (NCT01683175) examining adjuvant erlotinib (Tarceva) versus vinorelbine/cisplatin,⁴ the phase 3 ADJUVANT trial (NCT01405079) examining adjuvant gefitinib (Iressa) versus vinorelbine/cisplatin,⁵ and the phase 3 EVIDENCE trial (NCT02448797) examining adjuvant icotinib (Conmana) versus vinorelbine/cisplatin.⁶

“In the United States, many people feel nervous about just skipping adjuvant chemotherapy since several randomized trials have shown adjuvant chemotherapy to have a survival benefit,” noted Sequist.

All of the trials were similarly designed, with all patients having stage III disease in EVAN, and 65% of patients having stage III disease in the ADJUVANT and EVIDENCE trials. Results from all 3 trials indicated a robust improvement in disease-free survival (DFS) with the TKI over the chemotherapy. The HR for DFS in the EVAN, ADJUVANT, and EVIDENCE trials were 0.27 (95% CI, 0.14-0.53), 0.56 (95% CI, 0.40-0.79), and 0.36 (95% CI, 0.24-0.55), respectively.

However, mature OS data from the largest study of the 3, ADJUVANT, proved to be negative (HR, 0.96; 95% CI, 0.62-1.32). A post-hoc analysis of the trial provided further insight into the duration of which patients received gefitinib. Although patients were supposed to receive 24 months of the agent, some did not due to disease progression or discontinuation for other reasons.

“Patients who stopped before 18 months actually had a lower DFS. This [raises a question] some have wondered about with this adjuvant strategy: Are we actually converting anyone with micrometastatic disease to a disease-free state? In other words, are we curing anybody or are we simply suppressing the disease while they're on the TKI?” questioned Sequist. “This is the ultimate question faced with this strategy and we don't know the answer yet.”

Adding EGFR TKI to Standard of Care: Weighing the Available Data Pre-ADAURA

Several trials have examined the addition of an EGFR TKI to standard-of-care chemotherapy within the past decade, according to Sequist.

Earlier studies conducted by investigators at Memorial Sloan Kettering Cancer Center that have examined the addition of gefitinib or erlotinib to chemotherapy in the adjuvant setting suggested improved recurrence rates and survival compared with chemotherapy alone.^7,8 “The big design flaw here though, is clinical treatment assignment; there was no randomization scheme,” noted Sequist.

The 2 trials that are most heavily discussed are the phase 3 RADIANT (NCT00373425) and the phase 2 SELECT (NCT00567359) trials, according to Sequist.

In the RADIANT trial, 161 patients with completely resected stage IB to IIIA, EGFR-mutated NSCLC were randomized 2:1 to receive treatment with erlotinib or placebo for 2 years. Results showed that the DFS favored erlotinib over placebo (HR, 0.61; 95% CI, 0.38-0.98; P = .039).⁹ “Among that group, we saw a striking DFS advantage, but no OS advantage,” said Sequist. The HR for OS was 1.09 (95% CI, 0.54-2.16).

The single-arm SELECT trial was designed to complement the RADIANT trial, according to Sequist. Here, patients with EGFR-mutant NSCLC were given either erlotinib or standard adjuvant chemotherapy with or without radiotherapy. Results showed a 2-year DFS rate of 88% and a 5-year DFS rate of 56%, although the design flaw was that it was not a randomized trial.¹⁰

ADAURA Makes a Splash in the Adjuvant Setting

The double-blind, placebo-controlled, phase 3 ADAURA trial (NCT02511106) has been a hot topic of discussion since its interim results were presented during the 2020 ASCO Virtual Scientific Program. Data indicated that adjuvant osimertinib significantly improved DFS in patients with stage II/IIIA, EGFR-mutated NSCLC (HR, 0.17; 95% CI, 0.12-0.23; P <.0001).¹¹

The HR for DFS at 2 years was 0.50 (95% CI, 0.25-0.96) in patients with stage IB disease, 0.17 (95% CI, 0.08-0.31) in those with stage II disease, and 0.12 (95% CI, 0.07-0.20) in those with stage IIIA disease. The OS data remain immature, at only 5% maturity.

Based on these findings, the FDA approved adjuvant osimertinib in December 2020 for use as an adjuvant treatment of patients with resected NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations.

Subsequent data from the trial have shown maintained health-related quality of life (QoL) in those who received the EGFR TKI compared with placebo, with no clinically significant differences noted between the arms.¹² “The bottom line from that presentation is that there was a mild decrease in QoL taking osimertinib versus placebo, as you would expect if you're taking something versus nothing,” said Sequist. “But we did not see a clinically meaningful difference in QoL.”

Addressing Concerns Raised by ADAURA

In her presentation, Sequist brought up several questions surrounding the ADAURA data.

Is OS compromised because the study was unblinded early?

Although the results have been unblinded, the investigators and study participants remain blinded. Moreover, crossover before disease progression is not permitted on the study. For these reasons, Sequist does not believe the OS analysis to be compromised.

“One thing to note: At the time of the ASCO presentation, already 55% of patients on the placebo arm had progressed. As such, it is really critical to ensure that these patients with recurrent disease have access to osimertinib,” noted Sequist. “From what I've heard, [the investigators] are trying to ensure that every patient gets it. But that is something we'll all have to keep an eye on, as we see results in the future.”

Does it matter that adjuvant chemotherapy was not mandatory?

Overall, 60% of patients (n = 410/682) received adjuvant chemotherapy on the trial, for a median duration of 4.0 cycles; this was consistent across the arms. Most patients (n = 409/410) received platinum-based chemotherapy; 76% of these patients had stage II/IIIA disease, while 26% had stage IB disease.¹³ Adjuvant chemotherapy was more frequently used in patients under the age of 70 years and those enrolled in Asia; it was not influenced by performance status.

“I think this is reassuring. When I looked at these numbers, I felt that's probably reflective of real-world practice, although it’s hard to know,” said Sequist.

Data presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer showed that adjuvant osimertinib continued to improve DFS, irrespective of prior adjuvant chemotherapy received or disease stage. In the overall patient population, adjuvant osimertinib resulted in an 84% reduction in the risk of disease recurrence or death in patients who had previously received adjuvant chemotherapy (HR, 0.16; 95% CI, 0.10-0.26); the reduction was slightly lower, at 77% (HR, 0.23; 95% CI, 0.13-0.40), in those who had not received chemotherapy.¹⁴

“In the ADAURA trial, not everyone received chemotherapy, but it was actually much higher than [what has been seen in] the real-world [setting],” noted Sequist. “…You can see that the median DFS is worse in the patients who did not receive chemotherapy and my opinion is that this is a therapy with a proven survival benefit. As such, I would [not skip the chemotherapy;] I would try to give chemotherapy first and then osimertinib.”

Does it matter that adjuvant radiation was not permitted?

This concern only applies to the one-third of patients with stage III disease, according to Sequist; it is not a problem for those with stage I or II disease. “The fact that radiation was not allowed is not a fatal flaw. I think the data are still unclear,” said Sequist. “I think the LAURA study will be helpful in [shedding light] on this.”

The phase 3 LAURA trial (NCT03521154) will evaluate the safety and efficacy of osimertinib as maintenance therapy in patients with locally advanced, unresectable, EGFR-mutated, stage III NSCLC without progressive disease during or following platinum-based chemoradiation.¹⁵

The control arm may have performed poorly. What does that mean?

To address this question, Sequist turned back to the EVAN, ADJUVANT, and EVIDENCE trials as a comparison for ADAURA, likening those in the chemotherapy arms of the 3 trials to those in the placebo arm for ADAURA. The 2-year DFS rates appear to be almost identical, according to Sequist, although more patients with stage III disease were enrolled to the Chinese studies compared with ADAURA, added Sequist.

“It's possible that the control arm did a little bit of an underperformance but not extremely,” said Sequist. “This will be an important thing to watch as the study matures. It also underlines the importance of ensuring that those who do recur on the control arm have access to osimertinib.”

Central nervous system (CNS) imaging was required, but CT or MRI could have been used. Did that impact anything?

The argument that has been made, according to Sequist, is if many patients had CNS metastases that were too small to detected on CT with contrast, then the study is being turned into more of a randomized control study of patients with stage IV disease where treatment with osimertinib would favor placebo.

In ADAURA, patients received CNS imaging, but it was up to local standards regarding whether a CT would be done or an MRI. At the time of the ASCO presentation on the data, the breakdown was not available, but additional findings were revealed at the 2020 World Conference on Lung Cancer. About half of the patients got an MRI, while the other half got a CT scan, noted Sequist.

“It was a little bit more skewed toward having a higher proportion of CT scans in the placebo arm. Is this enough to say that the placebo arm had many more patients with stage IV disease and brain metastases that were not there on CT, but if you had only done an MRI, they were there? I don't know, I still think that this whole argument is a little bit hard to swallow,” said Sequist. “But I know there is a high rate of CNS relapse for these patients and having a drug that gets into the CNS is important.”

Can this trial change practice without the OS data available?

“My take is that I would prescribe this for patients, now. And I have. I am awaiting the OS data with great interest,” concluded Sequist. “In the next 5 to 10 years, while we're waiting, future trials in this space should build upon the framework.”

References

1. Sequist LV. EGFR TKIs in the adjuvant setting. Presented at: 18th Annual Winter Lung Cancer Conference; February 5-7, 2021; Virtual.

2. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550. doi:10.1056/NEJMoa061884

3. Wakelee HA, Dahlberg SE, Keller SM, et al. Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2017;18(12): 1610-1623. doi:10.1016/S1470-2045(17)30691-5

4. Ye D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation–positive non–small–cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med. 2018;6(11):863-873. doi:10.1016/S2213-2600(18)30277-7

5. Wu Y-L, Zhong W, Wang Q, et al. CTONG1104: adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation–final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial. J Clin Oncol. 2020;38(suppl 15):9005. doi:10.1200/JCO.2020.38.15_suppl.9005

6. Zhou C. Icotinib versus chemotherapy as adjuvant treatment for stage II-IIA EGFR-mutant NSCLC (EVIDENCE): a randomized, open-label, phase 3 study. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. https://bit.ly/3twMVkI.

7. Janjigian YY, Park BJ, Zakowski MF, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol. 2011;6(3):569-575. doi:10.1097/JTO.0b013e318202bffe

8. D’Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol. 2012;7(12):1815-1822. doi:10.1097/JTO.0b013e31826bb7b2

9. Kelly K, Altorki NK, Eberhardt WEE, et al. Adjuvant erlotinib versus placebo in patients with stage IB-IIIA non–small­–cell lung cancer (RADIANT): a randomized, double-blind, phase III trial. J Clin Oncol. 2015;33(34):4007-4014. doi:10.1200/JCO.2015.61.8918

10. Pennell NA, Neal JW, Chaft JE, et al. SELECT: a phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor–mutant non–small–cell lung cancer. J Clin Oncol. 2019;37(2):97-104. doi:10.1200/JCO.18.00131

11. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 15):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5

12. Majem M, Goldman JW, John T, et al. Patient-reported outcomes from ADAURA: osimertinib as adjuvant therapy in patients with resected EGFR mutated (EGFRm) NSCLC. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Accessed February 6, 2021. Abstract OA06.03. https://bit.ly/3aePvTN

13. Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. N Eng J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

14. Tagrisso extended disease-free survival regardless of prior adjuvant chemotherapy in early-stage EGFR-mutated lung cancer. News release. AstraZeneca. January 29, 2021. Accessed February 6, 2021. http://bit.ly/3oEix4t.

15. Lu S, Casarini I, Kato T, et al. LAURA: osimertinib maintenance following definitive chemoradiation therapy (CRT) in patients (pts) with unresectable stage III epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC). Ann Oncol. 2020;31(suppl 6):S1385. doi:10.1016/j.annonc.2020.10.367