Adjuvant Osimertinib Possesses Potential to Revolutionize NSCLC Treatment, But Longer Follow-Up Needed

Heather A. Wakelee, MD

The disease-free survival (DFS) benefit observed with the third-generation EGFR TKI osimertinib (Tagrisso) as an adjuvant treatment in patients with EGFR-mutant non–small cell lung cancer (NSCLC) in the phase 3 ADAURA trial is striking, said Heather A. Wakelee, MD, in a presentation during the virtual 21st Annual International Lung Cancer Congress^®, a program by Physician’s Education Resource^® (PER^®).¹

However, longer follow-up will determine whether the data are sufficient enough to change practice for the adjuvant setting of NSCLC, specifically for patients with EGFR mutations, according to Wakelee. 

“This is a very striking, early separation [of curves]; we can argue whether or not that was expected,” said Wakelee, a professor of medicine (oncology) at Stanford University/Stanford Cancer Institute. “I would say ‘yes’—we were fully expecting to see a DFS benefit, based on what we have observed in earlier trials with other EGFR TKIs. When you look at the separation here, [the DFS benefit] is much more striking. In earlier trials, [the hazard ratio (HR)] ranged from .5 to .6. Here, we are dealing with a HR of less than .2. I don’t think any of us are going to say that this DFS benefit is anything other than statistically significantly different." 

To date, the status of adjuvant treatment for patients with NSCLC has been found to be equivalent to neoadjuvant chemotherapy; both approaches translate to a survival benefit for patients. However, clinical trial findings have been mixed. 

The use of adjuvant chemotherapy was explored in an analysis conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) and NSCLC Meta-Analysis Collaborative Group. The analysis, which evaluated 5 trials comprising 4584 patients with NSCLC, showed that this approach led to a modest overall survival (OS) benefit (HR, 0.89; 95% CI, 0.82-0.96; P = .005) and an OS benefit at 5 years of 5%.² The OS improvement was more pronounced in patients with stage II/III disease (HR, 0.83; 95% CI, 0.73-0.95) compared with stage IB (HR, 0.93; 95% CI, 0.78-1.10) or stage IA disease (HR, 1.40; 95% CI, 0.95-2.06).

Furthermore, updated individual data of adjuvant chemotherapy in patients on or after January 1, 1965, included 34 trials comprising 8447 patients and showed a HR of 0.86 for OS (95% CI, 0.81-0.92; P <.0001).³ The absolute benefit at 5 years with this treatment was 4%. 

Other adjuvant chemotherapy trials highlighted the modest recurrence-free survival (RFS) benefit achieved with various regimens. For example, in the JIPANG trial, the investigator-assessed median RFS was 37.3 months with vinorelbine/cisplatin versus 38.9 months with pemetrexed/cisplatin at a median follow-up of 45.2 months (HR, 0.98; 95% CI, 0.81-1.20; one-sided log-rank P = .474; two-sided log-rank P = .948).⁴ The 24-month RFS rate was 60.7% and 58.3%, respectively, and the respective 36-month RFS rates were 50.2% and 51.1%.

OS served as a secondary end point of the trial. The median OS was not reached in either arm (HR, 0.98; 95% CI, 0.71-1.35; one-sided log-rank P = .434; two-sided log-rank P = .868). Additionally, the 24-month OS rates were 91.8% and 92.5% with vinorelbine/cisplatin and pemetrexed/cisplatin and the 36-month OS rates were 83.5% and 87.2%, respectively. 

Erlotinib (Tarceva) was also examined as an adjuvant treatment in patients with resected I to IIIA disease that was either EGFR-positive or amplified by fluorescence in situ hybridization in the RADIANT trial. Patients were randomized 2:1 to receive erlotinib at 150 mg orally once daily for 2 years or placebo for 2 years. No statistically significant difference in DFS was observed; the median DFS was 50.5 months for erlotinib and 48.2 months for placebo (HR, 0.90; 95% CI, 0.74-1.10; P = .324).⁵ 

Among 161 patients (16.5%) in the EGFR-mutant–positive subgroup, DFS favored erlotinib at a median 46.4 months versus 28.5 months (HR, 0.61; 95% CI, 0.38-0.98; P = .039), but this was not determined to be statistically significant due to the hierarchical testing procedure. Also, in the EGFR-mutant–positive group, the median OS was not reached in either arm (HR, 1.09; 95% CI, 0.54-2.16; P = .815). Overall, the HR for DFS and OS were 0.90 and 1.13, respectively. 

Moreover, the ADJUVANT CTONG 1104 trial, which evaluated adjuvant gefitinib (Iressa) versus vinorelbine plus cisplatin, showed a DFS benefit with the EGFR TKI in patients with stage II to IIIA (N1-N2) disease. Here, the median DFS was 28.7 months with gefitinib and 18.0 months for vinorelbine plus cisplatin (HR, 0.60; 95% CI, 0.42-0.87; P = .005); the 3-year DFS rate was 34% versus 27%.⁶ However, gefitinib was not found to result in an improvement in OS; in the intent-to-treat population, the median OS was 75.5 months and 62.8 months with gefitinib and vinorelbine/cisplatin, respectively (HR, 0.92; 95% CI, 0.62-1.36; P = .674). 

The ADAURA trial, however, has had the most recent readout in this setting. In the international, randomized, placebo-controlled, double-blind, phase 3 study, 682 patients with primary nonsquamous stage IB to IIIA NSCLC harboring EGFR mutations, with exon 19 deletions or L858R mutations, were randomized 1:1 to receive 80 mg of osimertinib once daily or once-daily placebo. 

Interim results showed that adjuvant treatment with osimertinib led to a 83% reduction in the risk of disease recurrence or death in patients with stage II to IIIA EGFR-mutant NSCLC (HR, 0.17; 95% CI, 0.12-0.23; P <.0001).⁷ At 33% maturity, the median DFS was not reached (95% CI, 38.8—not calculable [NC]) with osimertinib compared with 20.4 months (95% CI, 16.6-24.5) with placebo.

Additionally, in patients with stage IB to IIIA disease, which was the overall study population, osimertinib demonstrated a 79% reduction in the risk of disease recurrence or death (HR, 0.21; 95% CI, 0.16-0.28; P <.0001).

Moreover, when looking at the overall population of patients with stage IB to IIIA disease, the median DFS was also not reached with osimertinib (95% CI, NC—NC) and was 28.1 months (95% CI, 22.1-35.8) with placebo at 29% maturity.

In the stage II to IIIA population, the DFS rates at 1, 2, and 3 years were 97%, 90%, and 80% with osimertinib, respectively; these rates were 61%, 44%, and 28%, respectively, with placebo.

In the overall population, osimertinib led to DFS rates at 1, 2, and 3 years of 97%, 89%, and 79% with osimertinib, respectively. In the placebo arm, these rates were 69%, 53%, and 41% with placebo. The DFS benefit with osimertinib was also observed in subgroups across the entire population, regardless of race, stage of disease, and type of EGFR aberration.

While OS data are immature, early survival findings showed that the median OS was not reached in both arms, with a 60% reduction in the risk of death (HR, 0.40; 95% CI, 0.18-0.90).

Osimertinib was well tolerated with a safety profile that was consistent with prior findings. The most frequent adverse effects included diarrhea, paronychia, and dry skin, although the majority of these were of grade 1/2 in severity. Grade 3/4 AEs were low.

Interstitial lung disease was reported in 3% of patients on osimertinib; additionally, QTc prolongation was reported in 7% of patients in the osimertinib arm versus 1% of patients on placebo arm.

“We will see how [ADAURA] pans out over time; it’s still too early to make too much of this. However, one has to wonder: Are we going to be in a similar situation to what we have seen in the other trials, where there is a striking DFS benefit that prolongs recurrence, but it does not necessarily translate to an OS benefit?” Wakelee asked. “[This means] that perhaps we are not curing patients, we are just delaying when the disease recurs. The benefit of that then is something to discuss. There clearly is a benefit to delaying recurrence of disease, but it’s different then when we are actually potentially curing patients, as we have been shown to do with chemotherapy—although [it has been in] a small subset.”

Beyond chemotherapy and TKIs, immunotherapy is also being explored in the adjuvant setting of NSCLC in a number of ongoing studies, including: 

• ALCHEMIST/ANVIL (NCT02595944): Phase 3 study of nivolumab (Opdivo) versus observation in patients with stage IB to IIIA NSCLC given after adjuvant chemotherapy and/or radiation
• IMpower010 (NCT02486718): Phase 3 study of atezolizumab (Tecentriq) versus placebo in patients with stage IB to IIIA NSCLC given after adjuvant chemotherapy
• MEDI4736 (NCT02273375): Phase 3 trial of durvalumab versus placebo in patients with stage IB to IIIA given after adjuvant chemotherapy
• KEYNOTE-091 (NCT02504372): Phase 3 study of pembrolizumab (Keytruda) in patients with stage IB to IIIA NSCLC given after adjuvant chemotherapy 

“We are waiting for the results of these trials; it is unclear when we will have readout, but hopefully we’ll see data fairly soon,” concluded Wakelee. [These trials] may also be practice-changing, but we haven’t seen any of these results yet.”

References:

1. Wakelee HA. Current status of adjuant therapy for NSCLC. Presented at: 21st Annual International Lung Cancer Congress^®; July 23-25, 2020; Virtual.
2. Pignon J-P, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. doi:10.1200/JCO.2007.13.9030
3. NSCLC Meta-analyses Collaborative Group; Arriagada R, Auperin A, Burdett S, et al. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet. 2010;375(9722):1267-77. doi:10.1016/S0140-6736(10)60059-1
4. Kenmotsu H, Yamamoto N, Yamanaka T, et al. Randomized phase III study of pemetrexed/cisplatin (pem/cis) versus vinorelbine /cisplatin (vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (ns-NSCLC): The JIPANG study. J Clin Oncol. 2019;37(15):8501-8501. doi: 10.1200/JCO.2019.37.15_suppl.8501.
5. 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
6. Wu Y-L, Zhong W, Wang Q, et al. Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): a randomized, phase III trial (CTONG 1104). J Clin Oncol. 2017;35(suppl; abstr 8500). doi:10.1200/JCO.2017.35.15_suppl.8500
7. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5