Proffered paper session: metastatic NSCLC

The proffered paper session on metastatic non-small cell lung cancer (NSCLC) at ESMO 2024 focussed on three main topics: immune checkpoint inhibitor (ICI) combinations, the management of EGFR-mutant NSCLC after progression on osimertinib and the search for a fourth generation of ALK inhibitors. To guide us through these presentations we consulted Prof Dr Johan Vansteenkiste, thoracic oncologist at the University Hospitals Leuven in Belgium. 

In the phase II GALAXIES Lung-201 study, the combination of dostarlimab and the anti-TIGIT agent belrestotug was compared to dostarlimab alone as first line treatment for patients with advanced NSCLC and a PD-L1 expression >50%.1 While dostarlimab induced an objective response (ORR) in 37.5% of patients, the ORR with the combination ranged from 63.3% to 76.7%, depending on the dose of belrestotug that was used.1 As could be expected, the addition of the anti-TIGIT agent did increase the incidence of immune-related adverse events (AEs), but in general these events were manageable. 

A second ICI-combination study (RELATIVITY-104) compared the combination of nivolumab with the anti-LAG3 agent relatlimab and platinum doublet chemotherapy (PDCT) to nivolumab + PDCT as first line treatment for patients with metastatic NSCLC. In the overall study population, no significant difference in progression-free survival (PFS) or ORR was observed between both treatment arms. However, in patients with PD-L1 expression (≥1%), nivolumab plus relatlimab and PDCT did induce a significant benefit in PFS compared to nivolumab-PDCT with a median PFS of 9.8 and 6.1 months, respectively (HR[95%CI]: 0.63[0.45-0.88]). Also in terms of ORR a significant benefit was seen with nivolumab-relatlimab-PDCT vs. nivolumab-PDCT in patients with PD-L1 expression (53.2% vs. 40.8%).2

For patients with EGFR-mutant NSCLC who progressed on osimertinib, the phase III MARIPOSA-2 study previously demonstrated a superior PFS with the combination of amivantamab and chemotherapy over chemotherapy alone, with a favorable trend for a longer OS. During ESMO 2024, updated results of this trial were presented with a 75% maturity for OS. After a median follow-up of 18.1 months, the OS continued to be numerically better with amivantamab-chemotherapy than with chemotherapy alone, with a median OS of 17.7 and 15.3 months, respectively (HR[95%CI]: 0.73[0.54–0.99]; p= 0.039). Given the stringent threshold for significance in this interim analysis, this difference did not yet reach statistical significance. However, with an absolute difference in OS rate of 10% at 18 months (50% vs. 40%) we can expect that a significant OS benefit will be demonstrated in the final OS analysis.3

A final presentation of this session evaluated the potential of the 4th generation ALK inhibitor NVL-655 in a cohort of heavily pretreated, ALK-fusion positive, metastatic NSCLC patients.4 The 133 patients enrolled in the phase I/II ALKOVE-1 trial received a median of 3 prior anticancer therapies, including at least two 2nd generation ALK inhibitors or lorlatinib. Despite the heavy pretreatment of patients in this study, NVL-655 still induced an ORR of 38%. Responses to this agent also proved to be durable, with a median response duration of 14 months. These impressive data mark NVL-655 as an important agent to watch in the years to come.