"Lorviqua has suggested new long-term trt standard for ALK-positive NSCLC"

The risk of disease progression 81%↓-PFS at 7-year mark 55%

Efficacy maintained after dose reductions

"Lorviqua," a treatment for ALK-positive non-small cell lung cancer (NSCLC), has demonstrated long-term effectiveness in inhibiting disease progression in a 7-year long-term follow-up analysis, establishing a new treatment standard in ALK-targeted therapy.  

Notably, Lorviqua reduced the risk of disease progression or death by 81% compared to conventional therapy. It achieved long-term suppression of central nervous system (CNS) metastasis, which is the most significant clinical challenge in ALK-positive lung cancer. Analysis suggests that this drug is leading a paradigm shift in treatment.

Professor Ji-Youn Han of the National Cancer Center

On June 30, Pfizer Pharmaceuticals Korea hosted a press conference at the Conrad Seoul Hotel in Yeouido to showcase the clinical value of Lorviqua (lorlatinib). Pfizer recently announced the 7-year follow-up results from the global Phase 3 CROWN study, confirming the long-term efficacy of Lorviqua.  

ALK-positive NSCLC is a rare oncogenic driver mutation in NSCLC, accounting for approximately 3% to 5% of all NSCLC cases. It frequently occurs in a relatively younger patients and exhibits a high incidence of brain metastasis during the disease course; thus, long-term disease control and the suppression of CNS metastasis are considered critical determinants of clinical outcomes.  

In fact, the development of ALK-targeted therapies has evolved continuously to address these specific unmet medical needs.

The first-generation ALK inhibitor, 'Xalkori (crizotinib),' established the foundation for treating ALK-positive lung cancer but faced limitations in sufficiently suppressing CNS metastasis due to restricted blood-brain barrier (BBB) penetration. Subsequently, second-generation ALK inhibitors such as 'Alecensa (alectinib)' and 'Alunbrig (brigatinib)' emerged, improving intracranial control. However, the development of therapeutic agents to achieve more potent ALK inhibition and overcome resistance mechanisms continued.  

Lorviqua is a third-generation ALK inhibitor designed to overcome these limitations. Unlike existing drugs, it incorporates a macrocyclic structure engineered to bind more selectively and potently to the ALK protein, and it is characterized by its ability to effectively penetrate the blood-brain barrier (BBB) to maintain high intra-CNS drug concentrations.  

Professor Ji-Youn Han of the National Cancer Center explained, "Because brain metastasis is highly prevalent in ALK-positive lung cancer, how effectively an agent crosses the BBB to control intracranial disease is the linchpin of long-term therapy. Lorviqua is a drug specifically developed to address this requirement."

The CROWN study is a global, randomized, open-label Phase 3 clinical trial comparing Lorviqua versus Xalkori in 296 treatment-naive patients with advanced ALK-positive NSCLC.  

At 7-year follow-up, the median progression-free survival (PFS) in the Lorviqua group was not reached (NR), compared with 9.1 months in the Xalkori group. The PFS rates at 7 years were 55% and 3%, respectively.  

The risk of disease progression or death was reduced by 81% compared to Xalkori (HR 0.19). The risk reduction efficacy previously validated in the 5-year follow-up has been sustained seamlessly through the period of 7-year.

Notably, among the patients who were free of disease progression at 24 months after treatment initiated, 79% maintained their progression-free status at the 7-year mark. This indicates that a vast majority of patients who maintain therapeutic efficacy during the first 2 years go on to achieve durable, long-term disease control.  

Professor Han evaluated, "An HR of 0.19 in advanced lung cancer is an unprecedented level of benefit," and added, "It is highly significant that a degree of risk reduction typically observed only in the adjuvant targeted therapy setting for early-stage lung cancer has been sustained long-term in the advanced-stage setting."

Professor Han added, "It is also noteworthy that most patients who did not progress within the first two years maintained durable long-term disease control thereafter".

In this updated analysis, the intracranial control efficacy was reconfirmed as a foundational mechanism supporting Lorviqua's prolonged systemic PFS.

No new intracranial progression events were reported in the Lorviqua group after 30 months of treatment. The median time to intracranial progression was also not reached with Lorviqua, compared to 16.4 months in the Xalkori group. 

Furthermore, durable CNS disease control was consistently maintained over the long term, both in patients with baseline brain metastases and in those without.  

Professor Han explained, "The primary reason for the sustained PFS in this long-term follow-up ultimately is the continuous protection of the CNS," and added, "This can be interpreted as the effective suppression of brain metastases in highly ALK-dependent patients, translating into remarkable long-term survival and disease control outcomes."

The safety profile was consistent with the previously reported 5-year follow-up results. All-cause Grade 3 or 4 adverse events occurred in 77% of the Lorviqua group and 57% of the Xalkori group; however, permanent treatment discontinuations due to treatment-related adverse events (TRAEs) remained low at 5% and 6%, respectively. No new permanent treatment-related discontinuations were observed in the Lorviqua group after the first 26 months of therapy.  

An additional analysis on dose reductions was also presented. Patients who underwent dose reductions due to adverse events successfully maintained both systemic PFS and intracranial disease control, providing robust evidence that dose adjustments during toxicity management do not compromise long-term therapeutic efficacy.

However, overall survival (OS) data have not yet reached the protocol-specified analysis endpoints, and further follow-up is ongoing. The industry anticipates that since these outcomes have re-confirmed Lorviqua's long-term disease-modifying capabilities, significant focus will remain on the upcoming definitive OS datasets.