Highlights on lung cancer 1

Prof Dr Christophe Dooms, a respiratory oncologist at the University Hospitals Leuven (Belgium), highlights three significant presentations on mNSCLC from ASCO 2024 relevant to clinical practice.

The first trial, NRG-LU002, is the largest phase II randomised controlled trial in oligometastatic disease, assessing the benefit of adding local consolidative therapy to immune checkpoint inhibitor-based systemic maintenance treatment. All patients received at least four cycles of systemic treatment. If oligometastatic disease occurred, either persistent since baseline or induced through the four-cycle systemic treatment, patients with 3 or fewer distant metastases were randomised to receive either local consolidation treatment (mainly radiation therapy) or continued systemic treatment with immune checkpoint inhibition. The results demonstrated that irradiation of all lesions, whether primary or metastatic, after induction treatment did not increase survival, neither PFS nor OS. More concerning was the higher incidence of adverse events in the experimental arm, including 10% grade 3 pneumonitis. In conclusion, local consolidation treatment with radiation should not be used as a routine clinical treatment in oligo-persistent disease after induction with immune checkpoint-based treatment.

The phase III randomised CROWN study involved previously untreated, advanced ALK-positive NSCLC patients who were randomised to receive lorlatinib 100mg daily versus crizotinib 250mg twice daily. The study investigated the long-term efficacy of PFS in the ITT population. The 5-year interim analysis showed that median PFS was not reached for lorlatinib, resulting in a 5-year PFS of 60% versus 8% for crizotinib. Median intracranial PFS was also not reached for lorlatinib, resulting in a 5-year PFS of 92% versus 21% for crizotinib. Most progressions occurred within the first two years, eventually leading to a plateau at the 5-year follow-up. Lorlatinib was associated with additional toxicity, with 67% experiencing grade 3-5 adverse events versus 39% for crizotinib. Dose reduction within the first 16 weeks of treatment did not impact long-term median PFS or time to intracranial progression. Therefore, early toxicity assessment is important as patients will be exposed to the drug for a long time. In conclusion, while final OS data are still awaited, the durable neuroprotective effect of lorlatinib makes it the first choice for first-line treatment.

The PALOMA3 trial explored the optimal administration of amivantamab, either SC or IV, in refractory EGFR-mutated, advanced NSCLC patients. In this phase 3 randomised controlled trial, patients who had been pretreated with osimertinib in the first line and chemotherapy in the second line were randomised to receive either SC or IV amivantamab plus lazertinib as third-line treatment. Non-inferiority was demonstrated for the primary endpoints, pharmacokinetics and ORR. Interestingly, secondary endpoints favoured SC administration. DoR, PFS, and OS were longer in the SC arm. Median injection time was lower (≤7 minutes vs. 5 hours), and fewer infusion-related reactions (13% vs. 66%) were observed for SC administration versus IV administration. SC administration was also associated with 1.5 times fewer VTE incidents. Therefore, SC administration of amivantamab is preferred in EGFR-mutated metastatic NSCLC because it is more convenient and safer and has the potential to result in an OS benefit.