Lung cancer

ALK inhibitor suitable for first line therapy in NSCLC


The ALK inhibitor lorlatinib could be used in first line treatment of ALK-rearranged non-small-cell lung cancer (NSCLC) because of its high efficacy against brain metastases, an Australian-led phase 3 trial has shown.

An interim analysis of the CROWN trial, presented at ESMO Virtual Congress 2020 by Professor Ben Solomon, medical oncologist at the Peter MacCallum Cancer Centre, Melbourne, showed that lorlatinib significantly improved progression-free survival (PFS) compared with crizotinib.

The trail also showed that lorlatinib was highly effective in patients with brain metastases, extending the outcomes benefit already seen with the drug in later-line ALK+ NSCLC, said Professor Solomon.

In the study, 291 newly-diagnosed, previously untreated patients with ALK+ stage IIIB/IV NSCLC were enrolled across 104 study sites in 23 countries, and randomised to receive either lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily).

For the interim analysis, median follow-up for the primary endpoint, progression free survival (PFS) by blinded independent review was 18.3 months for lorlatinib (n=149) and 14.8 months for crizotinib (n=147).

At this cutoff point, the median PFS times were not estimable (NE) for lorlatinib and and 9.3 months for crizotinib. Lorlatinib led to a 72% improvement in PFS compared with crizotinib (hazard ratio [HR] 0.28; p<0.001). The median 12-month PFS rate with lorlatinib was twice that seen with crizotinib (78.1% and 38.7%, respectively).

Lorlatinib was also associated with better overall response rate by independent review, with 113/149 patients (76%) achieving a complete response (CR, n=4) or a partial response (PR, n=109), compared to  85/147 of patients (58%) with crizotinib (0 and 85 patients respectively in CR and PR).

The median duration of response (DOR) among responders receiving lorlatinib was NE, compared with 11.0 months (95% CI 9.0–12.9) for those receiving crizotinib.

Intracranial activity was also high for lorlatinib in the 30 patients who had measurable brain metastases. Fourteen of 17 patients (82%) receiving lorlatinib had a CR (n=12) or a PR (n=2) compared with 3 of 13 (23%) patients (1 CR and 2 PR) receiving crizotinib.

“Of note, lorlatinib also prolonged time to intracranial progression, with a remarkable hazard ration of 0.07,” said Professor Solomon.

There were no new safety signals for lorlatinib in the study, with the incidence of grade 3/4 adverse events (AEs) being higher (72.5%) than crizotinib (55.6%), but most being laboratory abnormalities (mainly lipid abnormalities). Fewer patients receiving lorlatinib, compared with crizotinib, experienced AEs leading to treatment discontinuation (6.7% versus 9.2%).

“So overall I think the results of the Crown study establish that lorlatinib as a highly effective option for first line for ALK-rearranged NSLC,” Dr Solomon concluded.

In August 2020, lorlatinib was listed on PBS as monotherapy for second-line treatment of patients with metastatic (Stage IV) ALK-positive NSCLC who have disease progression following treatment with agents such as crizotinib.

Professor Christine Lovly

In an ESMO discussion session on the trial findings, Professor Christine Lovly of Vanderbilt University said lorlatinib showed promising efficacy and was now one of multiple possible first line options for ALK positive NSCKL, but she cautioned that they were not a cure, as patients would ultimately acquire resistance to ALK TKIs.

With multiple agents available the key questions yet to be answered are which one is likely to be best for first line therapy based on factors such duration of response, brain activity and tolerability, she said.

Another key issue with ALK inhibitors will be to optimise the sequence of therapy with different agents – and a trial is now underway to assess a biomarker-driven protocol.

There are also several trials underway of combination therapy with ALK inhibitors and other agents, though some of these have revealed unacceptable toxicity such as with PD-L! inhibitors, said Professor Lovly.

“So how do we move the needle? We have multiple drugs but we’re still not curing patients. Firstly, I would strongly argue that we need to ensure that all patients have molecular testing for ALK rearrangements and other lung cancer biomarkers. We have wonderful drugs but if we are not testing for the molecular markers then we cannot deploy them,” she said.

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