Achieving very good PR with lorlatinib and managing AEs in an ALK-positive NSCLC patient with high tumour burden

Presentation, investigations and findings
A 60-year-old female homemaker, never-smoker and never-drinker, with good past health, presented in March 2024 with persistent cough and progres­sively worsening shortness of breath of 3 weeks following COVID-19 infection. Physical examination revealed an en­larged left supraclavicular lymph node (LN) of approximately 2.5 cm. Chest X-ray (CXR) showed a shadow in the left upper lobe (LUL) of the lung.

PET-CT scan in April 2024 revealed a lesion in LUL with lymphangitis carci­nomatosis, multiple LN metastases in the mediastinum and left supraclavicular fossa (SCF), and minor pleural effusion on the left side. The patient also had metas­tases in both liver lobes, abdominal LNs and distant bone metastases. Brain MRI showed a lesion in the left occipital lobe measuring 2.7 cm. (Figure 1A)

Ultrasound-guided biopsy of the left supraclavicular LN confirmed metastatic adenocarcinoma. Immunohistochemistry analysis was equivocal for ALK mutation and negative for EFGR and ROS1 mu­tations. Further fluorescence in-situ hy­bridization analysis was positive for ALK mutation.

Treatment
The patient started lorlatinib 100 mg daily in May 2024. In view of widespread bone metastases, she was also given denosumab 120 mg every 4 weeks sub­cutaneously for prevention of skeletal-related events.

A pretreatment check revealed el­evated levels of total cholesterol (TC; 5.9 mmol/L) and LDL-cholesterol (LDL-C; 3.9 mmol/L). As a result, she was given rosuvastatin 20 mg QD when starting lorlatinib.¹

Very good PR
PET-CT scan in December 2024, 6 months after starting lorlatinib, showed a considerable reduction in size and FDG uptake across the original LUL tumour, with no evidence of lymphangitis carci­nomatosis, while mediastinum, SCF, liver, and bone lesions all became eumetabol­ic, consistent with very good partial re­sponse (PR). There was also no trace of the brain lesion. (Figure 1B)

The latest scan in July 2025 showed an almost complete metabolic response and no evidence of relapse. Last seen in October 2025, 18 months after initiat­ing treatment, the patient was enjoying a good quality of life and did not report any lung cancer symptoms.

Management of AEs
Lipid profile changes
Despite initiating rosuvastatin at base­line, the patient’s TC, triglycerides (TG) and LDL-C began to increase after initi­ating lorlatinib. By late July 2024, 9 weeks after initiating treatment, her TC level was 5.5 mmol/L and TG level was 2.2 mmol/L, at which point ezetimibe 10 mg daily was added as part of lipid management regimen.^1,2

Despite initial decreases after starting ezetimibe, the patient’s TC and TG levels increased dramatically by mid-October 2024 (to 7.5 mmol/L and 16.1 mmol/L, respectively), at which point lorlatinib was withheld for 2 weeks.³ After 2 weeks with­out lorlatinib, the patient’s TC and TG lev­els normalized, but they began to increase again once lorlatinib was reintroduced at the original dose of 100 mg daily, reaching 6.4 mmol/L and 5.5 mmol/L, respectively, in February 2025. At this point, fenofibrate 250 mg daily was added to the lipid man­agement regimen.^2,3 The dose of lorlatinib was reduced to 75 mg daily around the same time to alleviate carpal tunnel syn­drome (CTS) symptoms (described be­low), which also led to a normalization of the patient’s lipid levels.³

Carpal tunnel syndrome and mild irritability
Approximately 4 months after initiat­ing treatment, the patient complained of numbness and weakness in both hands. She reported becoming clumsy with housework. The symptoms were com­patible with CTS, and the patient was referred to a physiotherapist. However, physiotherapy was of limited benefit.

The patient’s CTS eventually became grade 2, and she could no longer hold a spoon or chopsticks and button up gar­ments. She was referred to an orthopae­dic surgeon, who suggested carpal tunnel release surgery, which the patient refused.

The patient also reported very mild moodiness and irritability around the same time.

At this stage, in February 2025, 9 months after commencing treatment, the dose of lorlatinib was reduced to 75 mg daily, which led to prompt improve­ments in the above symptoms.³ Her CTS became grade 1, meaning she regained ability to hold implements and carry out light housework – an outcome the patient was happy with. Her moodiness com­pletely resolved at the same time.

Discussion
Lorlatinib was chosen for this pa­tient with ALK-positive non-small-cell lung cancer (NSCLC) on the basis of the CROWN trial’s results and in view of her very substantial tumour burden.

The CROWN study is an ongoing, international, open-label, randomized phase III trial comparing lorlatinib (n=149) vs crizotinib (n=147) in patients with pre­viously untreated advanced ALK-positive NSCLC.⁴ With a median follow-up for progression-free survival (PFS) of 60.2 and 55.1 months in the respective arms, median PFS by investigator assessment was not reached (NR) with lorlatinib and 9.1 months with crizotinib (hazard ratio [HR], 0.19; 95 percent confidence inter­val [CI], 0.13–0.27).⁴ Lorlatinib’s result represents the longest PFS reported to date with any single-agent molecular tar­geted treatment in advanced NSCLC and across all metastatic solid tumours.⁴

The median time to intracranial pro­gression was NR with lorlatinib and 16.4 months with crizotinib (HR, 0.06; 95 per­cent CI, 0.03–0.12).⁴ At 5 years, the prob­ability of being free of intracranial progres­sion was 92 percent with lorlatinib and 21 percent with crizotinib.⁴ Importantly, for patients with baseline brain metastases, such as ours, the HR for time to intracra­nial progression was 0.03 in favour of lor­latinib (95 percent CI, 0.01–0.13).⁴

In spite of grade 3/4 treatment-related adverse events (AEs) occurring in 66 vs 39 percent of patients in the lor­latinib vs crizotinib arm, the study drugs were discontinued permanently only in 5 and 6 percent of patients, respectively.⁴ At 5-year follow-up, 33 percent of patients in the lorlatinib arm had ≥1 lorlatinib dose reduction; treatment was ongoing in 33 percent of those who had one dose re­duction and in 20 percent of those who had two dose reductions.⁵

Of note, post hoc analyses of patients who had lorlatinib dose reduction within the first 16 weeks suggested that dose reduction did not seem to impact median PFS or time to intracranial progression.⁴

Conclusion
Findings of the CROWN trial, along with our patient’s experience, demon­strate lorlatinib’s unprecedented efficacy in treatment of ALK-positive NSCLC and indicate that dose reductions are helpful in managing AEs without compromising lorlatinib’s benefit.^4,5