European Society for Medical Oncology Congress

European Society for Medical Oncology Congress

Perspective from Christine M. Lovly, MD, PhD
Source:

Solomon B, et al. Abstract LBA2. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.

Disclosures: Pfizer supported the study. Solomon reports consultant/advisory roles with Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Pfizer and Roche-Genentech. Please see the abstract for all other researchers’ relevant financial disclosures.
September 23, 2020
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Lorlatinib ‘highly effective’ as first-line therapy for ALK-positive NSCLC

Perspective from Christine M. Lovly, MD, PhD
Source:

Solomon B, et al. Abstract LBA2. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.

Disclosures: Pfizer supported the study. Solomon reports consultant/advisory roles with Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Pfizer and Roche-Genentech. Please see the abstract for all other researchers’ relevant financial disclosures.
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Lorlatinib appeared superior to crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer, according to an interim analysis of the randomized phase 3 CROWN study presented at ESMO Virtual Congress 2020.

Patients assigned lorlatinib (Lorbrena, Pfizer) achieved longer PFS and were more likely to achieve objective or cranial response. Lorlatinib also was associated with improvements in patient-reported quality of life, results showed.

Lorlatinib appeared superior to crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer.
Lorlatinib appeared superior to crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer.

ALK rearrangements are found in about 3% to 5% of NSCLCs and result in sensitivity to ALK tyrosine kinase inhibitors. However, acquired resistance to treatment and disease progression, particularly in the brain, remain problematic,” Benjamin Solomon, MBBS, PhD, FRACP, consultant medical oncologist at Peter MacCallum Cancer Center in Australia, said during his presentation.

Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK inhibitor approved for patients previously treated with ALK TKIs.

The open-label, multicenter CROWN study compared lorlatinib with the ALK inhibitor crizotinib (Xalkori; Pfizer, EMD Serono) as first-line treatment for advanced ALK-positive NSCLC. All 296 patients had stage IIIB to stage IV disease and ECOG performance status of 0 to 2.

Solomon and colleagues randomly assigned patients to 100 mg lorlatinib once daily (n = 149) or 250 mg crizotinib twice daily (n = 147). Investigators stratified patients based upon presence of central nervous system metastases and ethnicity.

PFS as measured by blinded independent central review per RECIST v1.1 served as the primary endpoint. Secondary endpoints included PFS by investigator review, objective response rate by investigator and blinded independent central review, intracranial response rate, OS, safety and quality of life as assessed by the EORTC quality-of-life questionnaire.

Five patients in the crizotinib group did not receive treatment but were included in the intention-to-treat-population.

At data cutoff, researchers observed 133 PFS events.

Median duration of follow-up for PFS was 18.3 months with lorlatinib and 14.8 months with crizotinib.

Results showed lorlatinib significantly improved PFS compared with crizotinib by blinded independent central review (median, not estimable vs. 9.3 months; HR = 0.28; 95% CI, 0.19-0.41), with 1-year PFS rates of 78% (95% CI, 70-84) vs. 39% (95% CI, 30-48).

Investigator-assessed PFS also showed benefit with lorlatinib (median, not estimable vs. 9.1 months; HR = 0.21; 95% CI, 0.14-0.31). One-year PFS rates were 80% (95% CI, 73-86) vs. 35% (95% CI, 27-43).

“The benefit of lorlatinib over crizotinib was consistently observed across all prespecified subgroups. The HR for PFS was 0.2 among patients with brain metastases vs. 0.32 among those without brain metastases,” Solomon said.

Moreover, ORR by blinded independent central review was significantly higher with lorlatinib (76% vs. 58%). Median duration of response was not reached with lorlatinib vs. 11 months (95% CI, 9-12.9) with crizotinib.

Confirmed intracranial ORR by blinded independent central review of MRI scans was significantly higher with lorlatinib among patients with measurable and immeasurable brain metastases at baseline (66% vs. 20%; OR = 8.41; 95% CI, 2.59-27.23), as well as among those with measurable brain metastases (82% vs. 23%; OR = 16.83; 95% CI, 1.95-163.23).

Lorlatinib appeared superior to crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer.
Benjamin Solomon

“The intracranial complete response rate to lorlatinib in patients with measurable brain metastases was a remarkable 71%, and the time to progression was improved with a remarkable HR of 0.07 that was highly statistically significant,” Solomon said. “These data indicate the ability of lorlatinib not only to delay progression of existing brain metastases, but also to prevent the development of new brain metastases in patients with ALK-positive NSCLC.”

Although OS data were immature at the time of data cutoff for the interim analysis, the HR for OS was 0.72 (95% CI, 0.41-1.25) in favor of lorlatinib.

A higher percentage of lorlatinib-treated patients experienced grade 3 to grade 4 adverse events that required treatment discontinuation (73% vs. 56%). The most common grade 3 to grade 4 adverse events among lorlatinib-treated patients included asymptomatic elevations of cholesterol and triglycerides, Solomon said.

Patient-reported outcomes showed significantly greater improvement in baseline global quality of life among patients treated with lorlatinib.

“Compared with crizotinib, lorlatinib significantly improved PFS, resulted in higher overall intracranial response rates and improved global quality of life in first-line, treatment-naive, ALK-positive NSCLC,” Solomon said. “Notably, lorlatinib showed substantial intracranial activity, including high responses rates and longer time to intracranial progression. These results of the CROWN study support the use of lorlatinib as a highly effective first-line therapy for [this population of patients].”