CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 23, 2024
Expiration: February 22, 2025
LAURA: Introduction
Zofia Piotrowska, MD:
Patients with advanced NSCLC with classic EGFR mutations such as ex19del and L858R receive first-line osimertinib, an EGFR tyrosine kinase inhibitor (TKI).4 In addition, osimertinib is used in the adjuvant setting after resection for patients with EGFR-mutant NSCLC, based on the results of the phase III ADAURA study, which showed an OS benefit to adjuvant osimertinib over placebo in patients with resected stage IB-IIIA NSCLC (5-year OS: 88% vs 78%; HR: 0.49; 95% CI: 0.34-0.70; P <.001).5 However, there is a gap for unresectable stage III disease, where no data existed for the use of an EGFR TKI until now.
Although the PACIFIC trial provided data on the use of durvalumab for patients with unresectable stage III NSCLC, it included very few patients with EGFR mutations.6 Immunotherapy is generally believed to be less effective for patients with EGFR-mutated NSCLC.7 Consequently, there was skepticism about the role of durvalumab in this setting and hope that a TKI after chemotherapy and radiation could improve outcomes.
LAURA: Osimertinib vs Placebo After Definitive CRT in Unresectable Stage III EGFR-Mutated NSCLC
Zofia Piotrowska, MD:
The LAURA trial addressed this by studying patients with locally advanced unresectable stage IIIA-IIIC NSCLC harboring an EGFR ex19del or L858R mutation.8,9 Enrolled patients (N = 216) completed sequential or concurrent CRT with curative intent. Following completion, if they had no disease progression on repeat scans, they were randomized in a 2:1 ratio to receive either osimertinib 80 mg/day or placebo. Randomization had to occur within 6 weeks of completion of CRT.
A key aspect of this trial is that osimertinib was administered until disease progression or unacceptable toxicity, essentially planning for indefinite use. This contrasts with the ADAURA trial, where osimertinib was given for 3 years in the adjuvant setting.5
The primary endpoint of the LAURA study is PFS, and key secondary endpoints included OS, central nervous system (CNS) PFS, ORR, DoR, and safety.8,9 Of note, patients were monitored with serial brain MRIs to assess CNS outcomes, and crossover was allowed for those who had disease progression on the placebo arm.
LAURA: Patient Disposition
Zofia Piotrowska, MD:
Briefly examining patient disposition, it is important to highlight that there was a high rate of crossover in the study. Among the patients randomized to the placebo arm, 81% crossed over to the osimertinib arm at disease progression.8,9
LAURA: Baseline Characteristics
Zofia Piotrowska, MD:
The 2 arms of this trial were generally balanced. The median age of enrolled patients was approximately 63 years of age and approximately 83% of the trial participants were from Asian countries. Approximately 89% of patients received concurrent CRT and approximately 32% had a partial response to CRT.8,9
LAURA: PFS by Blinded Independent Central Review (Primary Endpoint)
Zofia Piotrowska, MD:
PFS dramatically improved with the addition of osimertinib vs placebo at of 39.1 months vs 5.6 months, respectively (HR: 0.16; 95% CI: 0.10-0.24; P <.001).8,9 This translates to an 84% reduction in the risk of progression, showcasing really dramatic results. PFS also favored osimertinib across all patient subgroups.
LAURA: Response, Overall Survival, and Sites of New Lesions
Zofia Piotrowska, MD:
One of the key characteristics of osimertinib is that it has high CNS activity, and we expect that it may have a CNS protective effect in both the adjuvant setting and in the setting of unresectable, stage III disease. When we look at the patients who developed new lesions within the brain at disease progression, 29% of patients treated with placebo progressed in the brain after CRT vs only 8% of those treated with osimertinib.8,9 This is a key finding and emphasized that CNS protection provided by osimertinib may contribute to its success across various stages of disease.
OS data are immature with 20% data maturity. We did not see statistically significant difference in OS, and we are awaiting longer follow-up.
LAURA: Treatment Exposure and Safety Overview
Zofia Piotrowska, MD:
The safety profile for osimertinib in the LAURA trial was as expected. Eight percent of patients in the osimertinib arm required dose reduction, and 13% of patients discontinued because of an AE.8,9
LAURA: Most Common Any-Cause Adverse Events
Zofia Piotrowska, MD:
Here, radiation pneumonitis was grouped separately from interstitial lung disease (ILD) or other pneumonitis. Radiation pneumonitis was fairly common in both arms, at 48% in the osimertinib arm and 38% in the placebo arm, with the majority of these being grade 1/2.8,9
ILD occurred in 8% of patients in the osimertinib compared with 1% in the placebo arm. It is important to note that distinguishing between drug-related pneumonitis and radiation pneumonitis is not always straightforward. Sometimes we can see differences in the pattern of where pneumonitis occurs, but we must remain vigilant for any new respiratory findings or CT scan findings being suggestive of pneumonitis in these patients, as this can be a serious complication.
Other AEs were consistent with what is expected for osimertinib, which we are accustomed to seeing in other settings.
LAURA: Clinical Implications
Zofia Piotrowska, MD:
This study also received a standing ovation at the plenary session at ASCO 2024. I believe this will be immediately practice-changing for our patients. I anticipate that osimertinib will become a new standard of care for patients with unresectable stage III EGFR-mutated NSCLC after completion of CRT.
A key point is that we can only implement this strategy if we test all our patients for EGFR mutations. EGFR testing should happen across all stages of disease to identify patients who may benefit from osimertinib as adjuvant therapy, as consolidation with osimertinib after CR, or as treatment in the advanced disease setting. Of importance, this will also help us avoid giving durvalumab to patients who will not benefit, while preventing increased AEs when trying to introduce osimertinib at the time of disease progression.
I hope osimertinib will receive FDA approval as consolidation therapy for unresectable, stage III EGFR-mutated NSCLC soon.
Natasha Leighl, MD, MMSc, FRCPC, FASCO:
I was excited about the results from the LAURA study, which show that osimertinib significantly improves PFS outcomes and reduced the number of new brain lesions when compared with placebo in patients with EGFR-mutated NSCLC.8,9 This patient population does not traditionally do well with CRT alone and they do not benefit from the addition of consolidation durvalumab.6
Although the OS data from LAURA are not mature yet, the results are anticipated to be similar to previous studies such as ADAURA, which showed a significant decrease in intracranial progression and translated into improved survival rates.8-10
In LAURA, 81% of patients from the placebo group have crossed over to osimertinib at disease progression, a notably higher proportion compared to ADAURA and FLAURA2, where crossover rates in the placebo groups in these studies ranged from 40% to 50%.8,9,11,12 I think despite the high crossover rates in LAURA, we are going to see an overall impact of osimertinib treatment, albeit the benefit may be attenuated.
Historically, we have been hesitant about relying solely on PFS as a primary endpoint for determining practice change, but together with the decreased intracranial progression, I think these data support osimertinib as the new standard of care for unresectable, stage III EGFR-mutated NSCLC.
In LAURA, there was a higher incidence of radiation pneumonitis (48% in osimertinib arm vs 38% in the placebo arm), and ILD (8% vs 1%, respectively), but the majority of these AEs were grade 1/2, with 1 fatality because of ILD in the osimertinib arm.8,9 This safety profile of osimertinib shows that patient selection and careful monitoring is important, as well as considering modifications to minimizing radiation exposure in susceptible patients in induction therapy. With osimertinib now being the standard treatment for stage IB-IV EGFR-mutated NSCLC, these safety considerations are important. As a note, we are still awaiting the results of ADAURA2, which aims to show the efficacy of adjuvant osimertinib in completely resected stage IA EGFR-mutant NSCLC.11
Looking ahead, the focus remains on enhancing treatment strategies and improving outcomes for patients with NSCLC. CRT alone is inadequate, and other approaches such as TKI induction should be explored. We will also need to re-evaluate if chemotherapy or radiation is necessary. It will also be important to consider treatment duration, in LAURA treatment was indefinite until disease progression, but it is possible that some patients would only need a fixed duration of therapy (eg, 3 years), and others may not need osimertinib treatment after CRT.
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