Review on LAURA: is it a game changer for unresectable stage III EGFR-mutated non-small-cell lung cancer?

Introduction

Non-small-cell lung cancer (NSCLC) is often diagnosed at stage III, accounting for 20% to 30% of cases. A significant proportion, ranging from 60% to 90%, of these stage III patients present with unresectable tumors (1). For these patients, the treatment standard consists of concurrent chemoradiotherapy (cCRT), followed by durvalumab as consolidation therapy for those who remain progression-free after cCRT (2).

Epidermal growth factor receptor (EGFR) mutations have been identified in up to one-third of patients with unresectable stage III NSCLC undergoing chemoradiotherapy (CRT) (3). Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is recommended for advanced NSCLC harboring EGFR mutations and as an adjuvant treatment for resected EGFR-mutated NSCLC (4). Recent studies have demonstrated its efficacy in unresectable stage III EGFR-mutated NSCLC, where previous therapies, including other EGFR-TKIs, have had limited success (5).

Review

LAURA trial

In the LAURA trial, a phase III, double-blind, placebo-controlled trial, patients with unresectable stage III EGFR (exon 19 deletion or exon 21 L858R mutation)-mutated NSCLC who had not progressed during or after CRT were randomly assigned to receive either osimertinib or a placebo in a 2:1 ratio (6). Treatment continued until disease progression (PD), as assessed by blinded independent central review (BICR), or until discontinuation of the assigned regimen. The primary endpoint was progression-free survival (PFS), also assessed by BICR.

The study enrolled 216 patients, with 143 receiving osimertinib and 73 receiving the placebo. Osimertinib significantly improved PFS compared to the placebo, with a median PFS of 39.1 vs. 5.6 months, respectively. The hazard ratio (HR) for PD or death was 0.16 [95% confidence interval (CI): 0.10–0.24; P<0.001]. Additionally, 74% of patients in the osimertinib group were alive and progression-free at 12 months, compared to 22% in the placebo group. Interim overall survival (OS) data, with a maturity of 20%, showed a 36-month OS rate of 84% in the osimertinib group vs. 74% in the placebo group (HR for death =0.81; 95% CI: 0.42–1.56; P=0.53). In the subgroup analysis of PFS in this trial, the osimertinib group demonstrated significantly better outcomes in both patients aged 65 years and older (HR =0.16; 95% CI: 0.10–0.26) and those younger than 65 years (HR =0.33; 95% CI: 0.19–0.57). Similarly, the osimertinib group showed significantly improved PFS in patients with stage IIIA disease (HR =0.28; 95% CI: 0.15–0.52) and stage IIIB or IIIC disease (HR =0.21; 95% CI: 0.13–0.33). Furthermore, patients with an EGFR exon 19 deletion (HR =0.17; 95% CI: 0.01–0.29) and those with the L858R mutation (HR =0.32; 95% CI: 0.19–0.56) both experienced significantly better outcomes in the osimertinib group.

Regarding safety, grade 3 or higher adverse events (AEs) were reported in 35% of patients receiving osimertinib compared to 12% in the placebo group. Radiation pneumonitis, predominantly of grade 1 to 2 severity, was observed in 48% of the osimertinib group and 38% of the placebo group. Other all-grade AEs included diarrhea (36% vs. 14%) and rash (24% vs. 14%) in the osimertinib and placebo groups, respectively. AEs led to dose interruptions in 80 patients (56%) receiving osimertinib and in 18 patients (25%) receiving placebo. Dose reductions occurred in 12 patients (8%) and 1 patient (1%), respectively, while discontinuations of osimertinib or placebo were observed in 18 patients (13%) and 4 patients (5%), respectively. No new safety concerns were identified during the study. This clinical trial concludes that osimertinib significantly extends PFS in patients with unresectable stage III EGFR-mutated NSCLC compared to placebo, marking it as a highly effective option for this patient population.

PACIFIC for unresectable stage III EGFR-mutated NSCLC

One of the controversial aspects of the LAURA trial is that the control arm is not durvalumab maintenance therapy, which is the current standard of care. Previous prospective clinical trials have shown that immune checkpoint inhibitors (ICIs) are poorly effective in EGFR mutation-positive NSCLC. Whether durvalumab maintenance after CRT is effective for EGFR mutation-positive NSCLC is a clinical question. Previously, a phase II trial evaluating pembrolizumab in patients with EGFR-mutated NSCLC and programmed death-ligand 1 (PD-L1) expression was conducted. The interim results of this trial revealed an objective response rate (ORR) of 0% among 10 patients, leading to the study’s early termination due to lack of efficacy (7). Additionally, in a pooled analysis of phase II/III trials that compared ICIs such as nivolumab, pembrolizumab, and atezolizumab with docetaxel as second-line therapy for NSCLC, the HR for OS in patients with EGFR-mutated NSCLC treated with ICIs vs. docetaxel was 1.11 (95% CI: 0.80–1.53; P=0.54). This suggests that ICI monotherapy does not provide a clinical benefit for this patient population (8).

In the PACIFIC trial, a post hoc subgroup analysis of EGFR-mutated NSCLC only was published (9). Among the 713 patients who were randomized, 35 were identified with locally confirmed EGFR-mutated NSCLC (durvalumab, n=24; placebo, n=11). The median follow-up duration for survival in this subgroup was 42.7 months (range, 3.7–74.3 months). The median PFS was 11.2 months (95% CI: 7.3–20.7) in the durvalumab group, compared to 10.9 months [95% CI: 1.9–not evaluable (NE)] in the placebo group, with a HR of 0.91 (95% CI: 0.39–2.13). The median OS was 46.8 months (95% CI: 29.9–NE) for patients receiving durvalumab, vs. 43.0 months (95% CI: 14.9–NE) for those on placebo, resulting in an HR of 1.02 (95% CI: 0.39–2.63). The safety profile of durvalumab was consistent with that observed in the overall study population and aligned with its established safety profile. However, even though these are the results of a prospective study, the small number of patients and the post-hoc analysis require great caution in interpretation. The results of several studies of stage III EGFR mutation-positive NSCLC treated with durvalumab after CRT are summarized in the table (Table 1). Nakamura et al. reported a single institutional retrospective study of durvalumab after CRT for stage III NSCLC with or without EGFR mutation (10). The 3-year OS rates in the wild-type EGFR, and EGFR-mutant groups were 46% (95% CI: 37–55%), and 75% (95% CI: 55–88%), respectively. The OS was significantly higher in the EGFR-mutant group than in the wild-type EGFR group (P=0.002). The 3-year PFS rates in the wild-type EGFR and EGFR-mutant groups were 15% (95% CI: 9–22%) and 8% (95% CI: 2–21%), respectively. No statistically significant difference in the PFS rate was observed either between the wild-type EGFR and EGFR-mutant groups (P=0.439). In a multicenter retrospective study by Riudavets et al., the median PFS of the whole cohort was 17.5 months (95% CI: 13.2–24.9) and the median PFS of the EGFR-mutation group was 8.1 months (95% CI: 5.8–NE) (3). Hellyer et al. reported that in a single-institutional retrospective study, patients in the ERBB2/EGFR cohort had a significantly shorter DFS compared with the EGFR or ERBB2 wildtype cohort (7.5 months vs. not reached, P=0.04) (11). Huang et al. reported that in their single-institutional retrospective study, both EGFR-positive and wild-type patients had numerically improved PFS with durvalumab consolidation compared to cCRT-alone (17.5 vs. 10.9 and 11.8 vs. 6.63 months, respectively; interaction P=0.608) (12). Tsuji et al. reported that in their multi-institutional retrospective study, among the 51 patients who were EGFR positive and 311 who were EGFR negative, 45 (88.2%) from the EGFR-positive group and 247 (79.4%) from the EGFR-negative group received durvalumab following CRT. The median PFS was 23.0 months in the EGFR-positive group and 24.2 months in the EGFR-negative group, with an HR of 1.03 (95% CI: 0.64–1.67) (13). As mentioned above, it has been demonstrated that ICIs have limited efficacy in patients with stage IV EGFR-mutant NSCLC. However, the therapeutic efficacy of durvalumab in EGFR-mutant NSCLC following radiotherapy remains inconclusive.

LAURA vs. PACIFIC in EGFR-mutant stage III NSCLC

This multi-institutional, international retrospective study, conducted across 24 institutions, examined outcomes in patients with stage III EGFR-mutated NSCLC who underwent cCRT followed by consolidation therapy with either osimertinib, durvalumab, or observation (14). Out of 136 patients included, 56 received durvalumab, 33 were treated with osimertinib, and 47 were observed without additional treatment. Baseline characteristics were well-matched across all three groups. With a median follow-up of 46 months, the median treatment duration was not reached for the osimertinib group, while it was 5.5 months for those on durvalumab. After adjusting for variables such as nodal status, disease stage, and age, patients receiving osimertinib demonstrated significantly longer 24-month PFS compared to those receiving durvalumab or undergoing observation (osimertinib: 86%, durvalumab: 30%, observation: 27%; P<0.001). No significant PFS difference was observed between the durvalumab and observation groups. OS rates across the groups did not show significant differences, likely due to the limited follow-up period. AEs occurred in 52% of patients on osimertinib and 48% on durvalumab. Among patients who progressed after durvalumab, 82% received subsequent EGFR-TKIs, with 38% experiencing treatment-related AEs. The findings suggest that osimertinib as consolidation therapy significantly improves PFS compared to durvalumab or observation, without unexpected safety issues. Aredo et al. performed a multi-institutional retrospective study focusing on patients with unresectable stage III EGFR-mutated NSCLC to compare PFS between patients who received CRT followed by durvalumab and those who did not (15). Of the 37 patients analyzed, 13 began durvalumab treatment at a median of 20 days post-CRT. Only two patients completed the full 12 months of durvalumab, while five discontinued due to PD and another five due to immune-related AEs (irAEs). Among the 24 patients who did not receive durvalumab, 16 completed CRT alone, and eight were treated with CRT combined with either induction or consolidation EGFR-TKIs. The median PFS was 10.3 months for those treated with CRT followed by durvalumab, compared to 6.9 months for CRT alone (P=0.993). Notably, patients receiving CRT plus EGFR-TKI had a significantly longer median PFS of 26.1 months compared to those treated with CRT and durvalumab or CRT alone (P=0.023). Six patients who progressed on durvalumab subsequently initiated EGFR-TKIs, with one experiencing grade 4 pneumonitis on osimertinib. The study concluded that consolidation durvalumab did not confer a PFS benefit in EGFR-mutated NSCLC and was associated with a high incidence of irAEs. Furthermore, initiating osimertinib after durvalumab may increase the risk of irAEs.

While the comparative efficacy of osimertinib vs. durvalumab as maintenance therapy following CRT for locally advanced EGFR mutation-positive NSCLC has been explored only in a limited number of retrospective studies, and no definitive conclusions can be drawn, this area of research holds promise for informing future clinical trials of molecular targeted therapies and immunotherapies. However, even in upcoming studies comparing molecular-targeted therapies with ICIs, interpreting the results may prove challenging due to factors such as treatment duration and endpoint selection.

How long is appropriate to continue osimertinib after CRT?

In the LAURA trial, the primary endpoint of PFS yielded positive results. However, a significant challenge we face in clinical practice is determining the appropriate duration of osimertinib treatment. While the ADAURA study administered adjuvant osimertinib for 3 years, the LAURA study was designed to continue treatment until PD or the onset of AEs (4,6). Herbst et al. demonstrated a substantial drop in DFS rates between 36 and 48 months, which was more pronounced than the decline observed between 24 and 36 months (16). Similarly, the LAURA study suggests that PFS may drop between 36 and 48 months, implying a need for at least 4 years of treatment. However, defining the optimal duration of anticancer therapy post-curative treatment poses a significant challenge for clinicians, patients, and healthcare economics.

Evidence from other cancers may provide insights. For example, a randomized phase III trial in patients with high-risk localized gastrointestinal stromal tumors (GISTs) showed that administering adjuvant imatinib for 3 years after surgery significantly improved recurrence-free survival (RFS) and OS compared to 1 year of treatment. Five- and 10-year RFS were 71.4% and 52.5% in the 36-month group, vs. 53.0% and 41.8% in the 12-month group (HR =0.66; 95% CI: 0.49–0.87; P=0.003). Similarly, 5- and 10-year OS rates were higher in the 36-month group (92.0% and 79.0%) compared to the 12-month group (85.5% and 65.3%) (HR =0.55; 95% CI: 0.37–0.83; P=0.004) (17). In contrast, a phase III trial comparing 2 vs. 1 year of adjuvant trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer found no superiority in DFS for the longer treatment duration (HR =0.99; 95% CI: 0.85–1.14; P=0.86), with more frequent grade 3–4 AEs and decreased left ventricular ejection fraction in the 2-year group (18). Various clinical trials have investigated optimal treatment durations, and a meta-analysis indicated that while shorter durations of adjuvant trastuzumab were non-inferior to 1 year for DFS in HER2-positive breast cancer, shorter treatment came with a 3.9% increase in absolute risk for 5-year DFS (19).

The question of whether osimertinib as an adjuvant therapy after CRT offers curative potential or simply delays recurrence remains unanswered. At present, it is reasonable to continue osimertinib until PD, in accordance with the protocol of the LAURA trial. Several clinical trials have commenced to evaluate the role of circulating tumor DNA (ctDNA) monitoring in predicting recurrence and prognosis following curative treatment (20). In the future, these trials may allow for the prediction of the optimal duration of adjuvant chemotherapy, and the results are awaited.

AEs associated with osimertinib, with a focus on interstitial lung disease (ILD)

A primary concern with osimertinib treatment is the risk of pneumonitis, particularly when administered following thoracic radiotherapy. Although the LAURA trial did not show a significant difference in the incidence or severity of pneumonitis between the osimertinib and placebo groups, real-world data suggest that the frequency of pneumonitis might be higher in clinical practice (6). Additionally, a Japanese multicenter cohort study (n=452) investigating first-line osimertinib reported drug-related pneumonitis (DRP) in 18% of patients, with grade 3 or higher DRP occurring in 4.6% (21). In the ADAURA trial, ILD was observed in 11 patients (3%) in the osimertinib group, with no cases reported in the placebo group. Although the LAURA trial showed favorable PFS outcomes in the Asian subgroup, the higher incidence of EGFR-TKI induced pneumonitis in Asian populations suggests that careful monitoring is essential during osimertinib treatment.

Conclusions

The LAURA trial is a significant addition to the standard treatment options, but several critical issues remain for discussion. Similar to the ADAURA trial, where the debate over adjuvant osimertinib persisted until a significant OS benefit was demonstrated, the OS data for the LAURA trial are still immature, and further results are eagerly awaited. Identifying which patients are most likely to benefit from osimertinib maintenance therapy, determining when it might be appropriate to discontinue treatment, and establishing the optimal treatment duration are essential considerations for both patient outcomes and healthcare economics. The identification and validation of biomarkers are crucial for guiding these decisions. Further clinical trials are necessary to explore and refine these aspects, with careful attention to optimizing treatment protocols in the context of maintenance therapy following curative-intent treatment.

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-24-167/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-167/coif). K.N. has received honoraria fees for lectures from AstraZeneca, Bristol-Myers, Ono Pharmaceutical, Chugai Pharmaceutical Co., Taiho Pharmaceutical, and MSD. S.W. has received grants from Boehringer Ingelheim and Nippon Kayaku, and honoraria fees for lectures from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol-Myers, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo, Kyowa Kirin, Takeda Pharmaceutical, Nippon Kayaku, Merck, Celltrion, and Taiho Pharmaceutical. T.K. has received grants from Nobelpharma, Boehringer Ingelheim, Taiho Pharmaceutical, KYORIN Pharmaceutical, Shionogi, Chugai Pharma, Asahi Kasei, Daiichi Sankyo, Nippon Kayaku, and Teijin Pharma, consulting fees from AN2 Therapeutics, honoraria for speakers bureaus from Viatris, Astellas Pharma, Insmed, Boehringer Ingelheim, Terumo, Eli Lilly, AstraZeneca, Daiichi Sankyo, KYORIN Pharmaceutical, Novartis, Merck, Bristol-Myers, NIPRO, Eisai, Ono Pharmaceutical, Chugai Pharma, GSK, Sumitomo Pharma, Kyowa Kirin, MSD, Sanofi, Shionogi, Meiji Seika Pharma, and Taiho Pharmaceutical; participated on the Advisory Board for Janssen Pharmaceutical; and received drugs from Nobelpharma. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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