Phase III trial results for a new drug targeting advanced lung cancer have just been reported, with some experts calling them “unprecedented” and “off the chart”. The drug is called lorlatinib, and the trial team says it’s setting a “new benchmark for targeted therapies in cancer.” A staggering 60 percent of patients on the drug showed no disease progression after five years – for those taking an existing drug, this was just 8 percent.
“You don’t need a magnifying glass to see the difference between these two drugs,” commented Dr Julie Gralow, chief medical officer of the American Society of Clinical Oncology (ASCO), to the Guardian. “Sixty per cent five-year progression-free survival in non-small cell lung cancer is just unheard of.”
Lorlatinib, also known by its brand name Lorbrena, was developed to target non-small cell lung cancer in which there is a specific genetic mutation involving the ALK gene. Although ALK-positive cancer only accounts for a small fraction of lung cancer diagnoses, it tends to affect younger people and nonsmokers, and can readily spread to the brain in a process called metastasis.
Treating ALK-positive cancer is a challenge. Drugs called tyrosine kinase inhibitors (TKIs), of which lorlatinib is an advanced example, work well initially, but almost all patients will later experience a relapse as their cancer becomes resistant to the drugs.
In this latest, trial, lorlatinib was compared to another TKI called crizotinib. It’s important to note that crizotinib is no longer routinely used in the US, although it is still in use in the UK and elsewhere. Dr Gralow explained to NBC News that the more up-to-date drugs that are used by oncologists in the US had not been approved when the trial originally started, and thus could not be included.
That doesn’t take anything away from the fact that the new results show “the most impressive progression-free survival we’ve ever seen in this population,” Dr Gralow added.
A group of 296 patients with ALK-positive lung cancer were randomly assigned receive treatment with either lorlatinib or crizotinib. The patients were followed up for 5 years to track their progress.
As well as the unprecedented progression-free survival outcomes, only four patients taking lorlatinib developed lesions on their brains, suggesting that the cancer was spreading there. For those who were already showing signs of brain metastasis when the trial started, lorlatinib decreased the probability of their brain disease continuing to worsen by 83 percent. In the crizotinib group, every patient with brain metastases experienced disease progression during the trial.
The second-generation TKIs – the ones that are too new to have been included in this trial – have led to significant improvements over crizotinib when it comes to treating brain metastases, but the authors note the prognosis for these patients remains poor. With lorlatinib, we could be looking at another big leap forward.
“Lorlatinib is the only ALK TKI that has reported five-year progression-free survival, and even after this time, the majority of patients continue to have their disease controlled, including control of disease in the brain,” lead author Dr Benjamin Solomon told the Guardian.
All drugs can cause side effects, and the potential side effects of chemotherapy are often among people’s biggest fears when they’re diagnosed with cancer. A majority of patients taking lorlatinib, 77 percent, did experience some adverse effects, with the most common being swelling, high cholesterol, and elevated lipid levels – these are known issues with other anticancer drugs, and may be tackled with cholesterol-lowering medications.
Sometimes chemotherapy side effects can be mitigated by reducing the dose or pausing treatment for a while.
Because of adverse effects, the study authors report that 62 percent of patients took a temporary break from lorlatinib treatment and 11 percent stopped it completely. Crizotinib, too, caused side-effects, with 48 percent of patients taking a break and 11 percent permanently coming off the drug.
Importantly, though, the authors report that reducing the dose of lorlatinib early in treatment did not seem to have a negative impact on outcomes.
Overall, the authors conclude that the results represent “the longest [progression-free survival] ever reported with any single-agent molecular targeted treatment not only in advanced [non-small cell lung cancer] but across all metastatic solid tumors.”
Lung cancer is the leading cause of cancer death worldwide. Lorlatinib may only be suitable for a small fraction of cases – those with the ALK mutation – but for eligible patients, this new generation of drugs could be genuinely changing the game.
The study is published in the Journal of Clinical Oncology.
