A retrospective analysis of lorlatinib therapy in patients with ALK-rearranged non-small cell lung cancer (NSCLC) has demonstrated impressive clinical outcomes, with a median progression-free survival (PFS) of 21.8 months and median overall survival (OS) of 70.1 months.
The study, conducted at I.P. Pavlov Medical University in St. Petersburg, Russia, included 35 patients with ALK-rearranged NSCLC who received lorlatinib between March 2017 and December 2019. The median follow-up time was 17.5 months, with data collection ending in June 2020.
Efficacy Results
Lorlatinib demonstrated robust clinical activity with an objective tumor response observed in 15 of 35 patients (43%), while disease control was achieved in 33 of 35 cases (94%). Notably, among the 27 patients who presented with intracranial metastases, 22 (81%) showed objective response for brain metastatic lesions.
The median PFS of 21.8 months significantly exceeds that reported in most previous lorlatinib trials, which typically ranged from 6.9 to 9.6 months in heavily pretreated patients. This difference may be attributed to several factors, including the study population having less extensive prior treatment with ALK inhibitors compared to earlier trials.
"The strikingly higher PFS observed in our study compared to majority of similar investigations may be related to distinct pretreatment history and patient selection," the researchers noted.
Patient Characteristics and Treatment History
The mean age of patients was 46.7 ± 2.3 years (range: 24–80 years). Most patients (31/35, 89%) had received prior ALK-targeted therapy, with 26 patients having received one previous tyrosine kinase inhibitor (TKI) and 5 patients having received two TKIs. Four patients were TKI-naïve.
Among those with prior TKI exposure, 12 had received crizotinib only, 14 had received ceritinib only, and 5 had received crizotinib plus another TKI. Fifteen patients had also received prior chemotherapy.
Dose reduction of lorlatinib to 75 mg (n = 4) or 50 mg (n = 8) was required in 12 out of 35 cases due to drug toxicity.
ALK Variant Analysis
The study included molecular analysis of ALK translocation variants in 28 patients. The most common variants were EML4ex13/ALKex20 (V.1) in 13 patients, EML4ex6/ALKex20 (V.3) in 8 patients, and EML4ex20/ALKex20 (V.2) in 4 patients. Two patients had rare variants, while 8 patients had unknown ALK rearrangement types.
Interestingly, patients with common ALK translocation variants (V1, V2, or V3) had numerically higher PFS (23.7 months) compared to subjects with rare ALK variants (5.6 months) or unknown type of ALK rearrangement (13.1 months), although this difference did not reach statistical significance.
Safety Profile and Correlation with Efficacy
Adverse events were observed in 31 of 35 patients (89%), with hypercholesterolemia (20 cases) and edema (13 cases) being the most frequent. Other reported adverse events included weight gain, peripheral neuropathy, psychosis, hypercreatinemia, and pleuritis.
One of the most striking findings was that patients who experienced no adverse events had significantly worse outcomes compared to those who did experience side effects. The PFS in patients without adverse events was only 1.1 months versus 23.7 months in those with adverse events (p < 0.0001). Similarly, OS was 10.5 months versus not reached, respectively (p < 0.0001).
"Our data may potentially call to consider an adjustment of lorlatinib dosage in patients with poor tumor response and complete lack of the toxicity of the drug," the researchers suggested, hypothesizing that some patients may have ultra-rapid drug metabolism affecting treatment efficacy.
Brain Metastases Outcomes
The study revealed that patients with brain metastases had higher PFS compared to subjects without CNS involvement (23.5 months vs. 11.1 months). This finding is particularly relevant given lorlatinib's known efficacy in penetrating the blood-brain barrier.
Of the 17 patients who initially benefited from lorlatinib but later progressed, 14 experienced systemic progression with enlargement of multiple metastatic lesions. Three patients had oligometastatic progressive disease in the brain (n = 2) or lung (n = 1).
Comparison to Other ALK Inhibitor Studies
These findings add to the growing body of evidence supporting the efficacy of ALK inhibitors in NSCLC. A complementary real-world study from Alberta, Canada, analyzing outcomes in 92 patients with ALK-rearranged NSCLC treated with either crizotinib or alectinib, reported a median OS of 48.5 months and median PFS of 17.0 months.
The Canadian study also demonstrated that patients with ALK-mutant NSCLC who received ALK TKIs had significantly longer median OS compared to matched patients with ALK-wildtype NSCLC treated with cytotoxic chemotherapy (46.8 versus 14.2 months, p < 0.001).
Clinical Implications
The impressive 70.1-month overall survival observed in the lorlatinib study represents a significant advancement in NSCLC management. As the researchers noted, "ALK-driven NSCLCs have high life expectancy, thanks to the availability of multiple treatment options."
The findings suggest that lorlatinib may be particularly effective in patients with brain metastases and those who have received limited prior ALK-targeted therapy. The correlation between adverse events and efficacy also raises important considerations for dosing strategies.
A recent phase 3 randomized trial comparing lorlatinib and crizotinib in the first-line setting has led to the approval of lorlatinib for first-line NSCLC treatment. However, the researchers note that "the experience of treatment of ALK-rearranged NSCLC after the failure of lorlatinib is very limited for the time being," highlighting the need for further research on optimal sequencing of ALK-specific agents.
As more data emerges on the use of lorlatinib and other next-generation ALK inhibitors, clinicians will be better equipped to develop personalized treatment strategies for patients with ALK-rearranged NSCLC, potentially leading to further improvements in survival outcomes for this patient population.
