ESTRO 2025 - Abstract Book

S162

Invited Speaker

ESTRO 2025

positive NSCLC patients treated with induction crizotinib and the median OS was not assessed in this cohort.Serious adverse events occurred in 44% of ALK -positive patients receiving induction crizotinib (pneumonitis,thromboembolic events,esophagitis) and in29% of ALK -positive patients receiving CRT alone (pneumonia,atrial fibrillation). With the absence of firm data for concurrent ALK TKIs and RT,there is a concern that this strategy may increase thoracic radiotoxicity due to potential radiosensitizing effect in normal tissues.Indeed,the clinicalcase reports using RT combined with next-generation ALK TKIs (alectinib,lorlatinib) showed radiation-induced CNS necrosis.Combining RT with ALK TKIs in locally advanced NSCLC still raises questions concerning i.a. optimal patient selection,RT timing,duration and fractionation.These issues can only be answered by large,well-designedmulti-center clinical trials,withcareful long-term safety analyses,and using best available agents–second and third generation drugs. ALK-positive NSCLCs are characterized by a unique metastatic neurotropism resulting in a particularly high incidence of brain metastases.Intracranial (IC) disease control seems crucial in optimal managing of these patients.Crizotinib,the pioneer ALK TKI,has very limited intracranial activity due to inadequate penetration through blood-brain barrier (BBB).Retrospective analyses proved that CNS-directed RT may improve IC control during systemic crizotinib therapy,at the expense of possible toxicities (i.a. brain radionecrosis,neurocognitive decline,otitis,ocular toxicity),especially when administered concurrently.Next generation ALK inhibitors were designed to cross BBB more efficiently than crizotinib and to achieve higher concentration in the CSF,thus offering a prominent ability to control CNS spread,without the need of RT.The phase III ALEX study (comparing 2 nd generation ALK TKI-alectinib with crizotinib in the first line setting) confirmed excellent IC control reached with alectinib.The 12 months incidence of CNS progression was 9.4% versus 41.4% with alectinib and crizotinib,respectively.Alectinib improved IC disease control with an average PFS of 25.7 months as compared to 10.4 months with crizotinib. Alectinib demonstrated superior IC activity and significantly delayed CNS progression versus crizotinib, irrespective of prior CNS disease or RT.In the phase III CROWN study lorlatinib, the 3 rd generation ALK TKI,resulted in 92% reduction in the rate of IC progression.According to ESMO and NCCN guidelines,forpatients who present with asymptomatic brain metastases at baseline,TKIs with proven IC therapeutic activity should be offered as the primary therapy and the administration of RT might be postponed to avoid potential neurotoxicity. The use ofconsolidation RT in case of oligoprogessive or oligopersistent ALK -positive NSCLC undergoing ALK TKI therapy is already considered a standard clinical practice,supported by ESMO and NCCN guidelines,however based on the data from mainly small,underpowered,poorly standarized phase II trials,where in majority of patients crizotinib (less potent and intracranially inactive inhibitor) was administered.In the phaseIISTOP trial the addition of SABR to ≤5sites of oligoprogression in ia.NSCLC patientsreceiving standard systemic therapy did not translate into PFS and OS benefit.The real benefit from combining ALK TKIs with RT in oligoprogressive or oligopersistent NSCLC still warrantsconfirmation in well-designed trials.

In case ofpoly-progression and an apparent TKI resistance,switching to a novel,more potent inhibitor or recruitment into a dedicated clinical trial is recommended.

5037

Speaker Abstracts When is standard treatment the right choice? Lessons learnt from clinical trials and meta-analyses Pierre Blanchard Radiation Oncology, Gustave Roussy, Villejuif, France

Abstract:

Standard radiation-based treatment options for head and neck (HN) cancer have been extensively studied through large clinical trials and meta-analyses, including MACH-NC, MARCH, MACH-EGFR, and MAC-NPC. These studies have