Dr Nieva on the Rationale for Comparing ALK Inhibitors in ALK+ NSCLC

“Many of the [oncologists] in the room thought the best approach was to use lorlatinib because it’s the most powerful drug, but use it as a reduced dose. Others felt that it needs to be an individualized decision that the patient makes after a discussion of risks and benefits.”

Jorge Nieva, MD, an associate professor of clinical medicine at the Keck School of Medicine of the University of Southern California, discussed key clinical implications from matched-adjusted indirect comparison (MAIC) data evaluating the efficacy and safety of crizotinib (Xalkori) vs alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena) in patients with ALK-positive non–small cell lung cancer (NSCLC).

ALK-positive NSCLC is a relatively rare molecular subtype, and consequently, there is a limited number of large-scale randomized clinical trials directly comparing the full range of approved ALK inhibitors, Nieva began. Most available data stem from studies in which individual agents have been evaluated against crizotinib, a first-generation ALK inhibitor, serving as a common comparator across multiple trials, he explained. This has enabled the application of MAICs as a method for formally assessing the comparative efficacy of newer agents, despite the absence of direct head-to-head trials, he noted. MAIC methodology involves statistical adjustment of patient-level data to account for differences in baseline characteristics—like age, sex distribution, race, and key prognostic indicators—between trial populations, he said. When performed appropriately, this method allows for more reliable cross-trial comparisons by harmonizing patient demographics, enabling a more accurate assessment of treatment effect size relative to a common comparator, he emphasized.

Although all next-generation ALK inhibitors have shown efficacy benefits over crizotinib, in MAICs between these ALK inhibitors, lorlatinib appears to provide the greatest incremental improvement in PFS compared with alectinib and brigatinib, as reflected by its hazard ratio in indirect comparisons. However, this enhanced efficacy is counterbalanced by a higher incidence of treatment-related adverse effects, particularly neurocognitive toxicities, he cautioned. These may manifest as alterations in mood, personality, memory, or general cognitive function and can significantly impair a patient’s quality of life, he stated.

As discussed during the 2025 Bridging the Gaps in Lung Cancer meeting, the therapeutic choice between ALK inhibitors should involve a nuanced, individualized approach, Nieva emphasized. Although many oncologists advocate for the use of lorlatinib as first-line therapy due to its potent central nervous system activity and robust efficacy profile, some recommend initiating treatment at a reduced dose to mitigate toxicity, he added. Others emphasize shared decision-making, incorporating a comprehensive discussion of benefits and risks with the patient to determine the most appropriate therapeutic course, Nieva concluded.