The recent findings from the LAURA trial mark a pivotal advancement in the therapeutic landscape for patients with locally advanced stage III non-small cell lung cancer (NSCLC). These results provide critical insights into the efficacy and safety of emerging treatment modalities, potentially reshaping clinical practice in this patient cohort. However, the optimal treatment choices for mutation-driven NSCLC remain a topic of ongoing debate.

I would like to begin by examining the discussion held at the Joint ESTRO-IASLC Symposium regarding the role of radiotherapy in EGFR-driven or ALK-driven NSCLC.

 In the EGFR-driven session, presenters Prof. Dirk De Ruysscher and MD. Ph.D Lizza Hendriks explored whether radiotherapy is essential or redundant in this context. Dirk De Ruysscher advocated for the incorporation of radiation therapy in both locally advanced and metastatic disease settings. In the metastatic disease setting, he referenced the TURBO-NSCLC trial, indicating its retrospective nature, which raises concerns regarding potential bias, as reliance on existing data may be limited and less precise. Additionally, he discussed other trials involving locally advanced NSCLC with Icotinib and scenarios of disease oligoprogression.

Conversely, Lizza Hendriks presented arguments against the inclusion of radiation therapy in NSCLC treatment. Her primary concern involved the risk of radiation-induced toxicity and the questionable benefits concerning local control. Nonetheless, by the conclusion of this engaging debate, it was recognized that the potential for reimbursement plays a role in treatment decisions. The integration of radiation therapy, particularly in specific clinical situations alongside targeted kinase inhibitors (TKI), warrants consideration. It is important to note that the biological behavior of EGFR-mutant NSCLC is distinct, and the timing of radiotherapy remains a critical topic for further discussion. The concern of toxicity when combining targeted therapy with radiation is an important topic to investigate in further clinical trials.

New data regarding toxicity in EGFR mutant NSCLC in chemoradiation treatment modality was presented by M.D Terufumi Kato in the Proffered Papers Session „Transformative combined modality treatment strategies“  in the abstract „Osimertinib after chemoradiotherapy in unresectable stage III EGFRm NSCLC: chemoradiotherapy regimens and radiation pneumonitis in LAURA (NCT03521154)“. The main factors associated with RP events (all grades) in the osimertinib arm (multivariate analysis) were: lung V5 <54% vs.≥54%, IMRT vs. 3D conformal technique, stable disease/no evidence of disease progression versus complete response/partial response. In conclusion, radiation pneumonitis was low-grade and manageable.

The key takeaway for clinicians is that the results of the LAURA study regarding EGFR-driven locally advanced non-small cell lung cancer (NSCLC) are influencing current clinical practices, alongside ongoing discussions about reimbursement issues. Radiation pneumonitis is manageable, as previously noted, and RP grade 1 corresponds to asymptomatic clinical presentations. It is important to recognize that the evaluation of radiation pneumonitis severity may have varied during data collection, particularly regarding the assessment of radiological lung abnormalities and the criteria used for diagnosing grade 1 RP. In the context of EGFR-driven metastatic disease, the recommendation is to initiate treatment with a TKI while also evaluating the incorporation of radiation therapy into the management plan.

The discussion on ALK-driven non-small cell lung cancer (NSCLC) and the role of radiotherapy was led by Ph.D Gerard Walls and Anna Wrona. A key takeaway is that radiotherapy is predominantly considered in palliative contexts for ALK-driven NSCLC, with its benefits remaining a subject of debate. We are currently awaiting the results of trial EP08.03-005 HALT, which examines the efficacy of targeted therapy with or without dose-intensified radiotherapy in the setting of oligo-progressive disease in oncogene-addicted lung tumors.

Regarding consolidative treatment for locally advanced NSCLC in patients receiving ALK tyrosine kinase inhibitors (TKIs), the BOUNCE trial has been withdrawn, whereas HORIZON-1 is ongoing, with results pending. For clinical practice, it is essential to emphasize that the standard of care in locally advanced ALK-driven NSCLC consists of radical chemoradiotherapy followed by immunotherapy. In palliative scenarios, such as cases with brain metastases, the preferred approach is to initiate treatment with novel ALK TKIs, reserving radiation for instances of disease progression.

In my opinion, one critical area that has been overlooked in the discussion is leptomeningeal disease in oncogene-driven NSCLC. This condition appears at an elevated frequency among patients with such mutations and is associated with a particularly poor prognosis. The potential role of radiotherapy in managing leptomeningeal spread warrants further exploration in this context.

Rita Steponavičienė

Vilnius University Hospital, Santaros Clinics - National Cancer Center

Radiation therapy Department

Radiation oncologist

Santariškių g. 1, Vilnius

Tel. +370 5 2746453

El. rita.steponaviciene@nvc.santa.lt

President of Lithuanian Society for Radiation Therapy