Lorlatinib Demonstrates Promise for ALK-Rearranged Patients With NSCLC

Benjamin Solomon, MBBS, PhD

The third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib (Lorena) appears to be an encouraging new treatment option for patients with ALK-positive non–small cell lung cancer (NSCLC) following results from the phase 3 CROWN study. This study demonstrated a significant improvement in progression-free survival (PFS), as well as higher overall and intracranial response rates, compared with crizotinib (Xalkori) in ALK-positive NSCLC.

The median PFS was not estimable (NE) at the time of data cut-off for lorlatinib (NE; 95% CI, NE-NE) compared with 9.3 months with crizotinib (95% CI, 7.6-11.1), resulting in a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.19-0.41; 1-sided P <.001).

The highly potent, brain-penetrant agent received its approval in November 2018, for the treatment of patients with ALK-positive NSCLC who have progressed on 1 or more ALK TKIs, which must include crizotinib. More recently in December 2020, the FDA accepted a supplemental New Drug Application for lorlatinib and granted it a priority review as a potential frontline therapy for patients with ALK-positive NSCLC.

In an interview with Targeted Oncology, Benjamin Solomon, MBBS, PhD, consultant medical oncologist, professor, group leader, Molecular Therapeutics and Biomarkers Laboratory, Research Division, Peter MacCallum Cancer Center, discussed the findings from the CROWN study that compared lorlatinib with crizotinib as treatment of patients with ALK-positive NSCLC.

TARGETED ONCOLOGY: What options are currently available to treat these patients with ALK-positive lung cancer?

Solomon: ALK-rearranged lung cancers account for about 5% of NSCLCs. They tend to occur in younger patients and in patients who have never smoked, but they can be found across the spectrum of clinical scenarios, so current guidelines recommend testing all newly diagnosed adenocarcinoma patients for ALKrearrangements. One thing that we've learned is that these tumors are very sensitive to treatment without TKIs, and first-line treatment without TKIs has been established as a standard of care, firstly with crizotinib, a first-generation ALK inhibitor, and more recently with second-generation ALK inhibitors.

TARGETED ONCOLOGY: What was the rationale to evaluate these agents head-to-head in the treatment of patients with ALK-positive NSCLC?

Solomon: Although ALK-rearranged lung cancers are sensitive to TKIs, resistance is a major problem, and patients progress on treatment without TKIs, and progression in the brain can be a particular problem. Lorlatinib is a highly potent brain penetrant ALK TKI. It's what we call the third-generation ALK TKI. It's already received approval in patients who have progressed on prior ALK TKIs. The aim of the study was to evaluate lorlatinib in the first-line setting in previously untreated patients with ALK-rearranged lung cancer.

TARGETED ONCOLOGY: How was the study designed?

Solomon: The CROWN study is a randomized phase 3 study comparing lorlatinib to crizotinib in previously untreated ALK-rearranged lung cancer. The study included eligible patients with previously untreated ALK-positive NSCLC who were randomized to treatment either with lorlatinib 100 mg daily or crizotinib 250 milligrams twice daily. Stratification was based on the presence of brain metastases and ethnicity, and the primary end point of the study was PFS by blinded independent central review.

TARGETED ONCOLOGY: What were the findings in terms of efficacy?

Solomon: The key findings with respect to efficacy, the study made its primary end point. Lorlatinib significantly prolonged PFS by blinded independent central review compared with crizotinib. The hazard ratio was 0.28, which was highly statistically significant, and the median PFS with lorlatinib has not been reached compared with 9.3 months for crizotinib. The 12-month PFS rate was 78% with lorlatinib compared to 39% with crizotinib. We also looked at a number of secondary end points in this study in these interim results of this analysis. PFS by investigator report was also positive for their hazard ratio of 0.21. The response rate was improved with lorlatinib at 76% compared to 58%, and that difference was significant.

One important finding of this study was evidence of intracranial activity with lorlatinib, so every patient on the study had baseline MRIs and serial assessment of disease in the brain with MRI scans, which was centrally reviewed. The intracranial objective response rate by independent review in patients with measurable brain metastases was 82% with lorlatinib compared to 23% with crizotinib, with an intracranial complete response rate of 71%. We also looked at time to intracranial progression, and the hazard ratio for time to intracranial progression was 0.07, which is a remarkable result. This speaks to the ability of lorlatinib, not only to delay progression of existing brain metastases, but to potentially prevent the formation of new brain metastases.

TARGETED ONCOLOGY: How did the toxicity profiles of these agents compare with each another?

Solomon: Lorlatinib has quite a distinct toxicity profile to ALK inhibitors, and it's very important that as clinicians treating patients with lorlatinib, we understand the toxicity profile and how to manage these toxicities. What we saw is that grade 3/4 toxicities were more frequent with lorlatinib with crizotinib at 72% compared with 56%, but in terms of adverse events (AEs) leading to actual discontinuation of therapy, these were pretty similar, 7% for lorlatinib compared to 9% with crizotinib. The toxicities that we saw with lorlatinib in this study were similar to that which have been reported from the previous phase 1 and 2 studies. The most common AEs were asymptomatic elevations of cholesterol and triglycerides, which were quite easily managed with statins, but there are also other AEs, such as edema, a reversible peripheral neuropathy, and some cognitive effects, which are a distinct feature of lorlatinib. There were some toxicities that were seen that were more frequent with crizotinib, and these included gastrointestinal side effects such as nausea, diarrhea, and constipation as well as elevation of alanine transaminase and aspartate aminotransferase.

TARGETED ONCOLOGY: What are the clinical implications of these findings?

Solomon: The study shows that lorlatinib is a highly effective first-line treatment option for newly diagnosed patients with ALK-rearranged lung cancer. The activity in the brain is pretty remarkable, and we know that brain metastases are a devastating event for patients with lung cancer. The study clearly establishes lorlatinib as a new option for first-line treatment of ALK-rearranged lung cancer.

TARGETED ONCOLOGY: Are there any next steps planned for this study?

Solomon: It'll be important to get additional long-term follow-up. For example, the overall survival data are not mature, there being fewer than 20% of survival events. It'll also be important to try to understand mechanisms of resistance to lorlatinib to work out how we can provide even further benefits for patients with ALK-rearranged lung cancer, but it's clear that ALK inhibitors such as lorlatinib have transformed outcomes for this patient population.