ASCO 2026: unprecedented results in the treatment of advanced non-small cell lung cancer

- The 7-year follow-up results of the CROWN trial, presented at this year's ASCO congress, are among the most important reports in oncology in recent years. They are unprecedented in the history of treatment of disseminated lung cancer, as only a dozen years ago the median survival in these patients was about a year, says Prof. Jacek Jassem of GUMed, a correspondent member of the Polish Academy of Sciences.

- Seven-year follow-up in disseminated lung cancer is a unique situation. In the era of chemotherapy, about 20% of patients survived a year. Today, we're talking about years of progression-free life and controlling the cancer as if it were a chronic disease," adds Prof. Dariusz M. Kowalski, head of the Behavioral Unit of the Lung and Chest Cancer Clinic at the National Cancer Institute in Warsaw, and secretary general of the Polish Lung Cancer Group.

Non-smokers also suffer from this lung cancer

Non-small cell lung cancer (NDRP) with ALK gene rearrangement accounts for about 3-5% of all NDRP cases. The disease more often affects younger people who have never smoked or have smoked little. - The vast majority are never smokers or those who have quit. This is also a younger population, deviating from the 65+ standard, i.e. those who are professionally and family active, reports Prof. Dariusz M. Kowalski.

In this group of patients, brain metastases develop rapidly. - A characteristic clinical feature of this form of cancer is a high propensity for metastasis in the central nervous system, which has been one of the biggest therapeutic challenges for many years, points out Prof. Jacek Jassem. Already at the time of diagnosis, 30% to 40% of patients have metastases to the central nervous system, and during the treatment period the percentage reaches almost 70%, adds Prof. Dariusz Kowalski.

Treatment of non-small cell lung cancer with gene rearrangement ALK

- A dozen years ago, when there were no therapeutic options in the form of immunotherapy or molecularly targeted drugs for specific targets or pathogenic variants, and we had only chemotherapy, the percentage of one-year survival of patients with disseminated stage non-small cell lung cancer did not exceed 20%. Two-year survival was practically non-existent," recalls Prof. Dariusz M. Kowalski.

ALK inhibitors have transformed patient treatment. In 2018, crizotinib entered reimbursement, followed by second-generation ALK inhibitors in 2019. In 2023, the third-generation ALK inhibitor lorlatinib entered reimbursement. - ALK inhibitors have changed the fate of patients, but lorlatinib has taken these effects to an even higher level. We can take the patient to the chronic disease stage, because even in the disseminated stage he lives at least seven years. He takes one pill in the morning and goes to work," says Prof. Dariusz M. Kowalski.

CROWN study

The international CROWN (Phase III) clinical trial was a multi-center study conducted at 104 medical centers in 23 countries around the world. - The Medical University of Gdansk, the University Clinical Center and the Lung and Chest Cancer Clinic of the National Cancer Institute - National Research Institute in Warsaw participated in the CROWN study. We had the opportunity to actively participate in the project, which can already be considered one of the milestones of modern oncology. I am also a co-author of several scientific reports related to this study, so I am very pleased that it has contributed to a radical improvement in the prognosis of patients," says Prof. Jacek Jassem.

Breakthrough results

- That lorlatinib shows an advantage in prolonging progression-free time and other parameters, we have seen at 2, 3 and 5 years. But now we have a 7-year follow-up. And we find that the median progression-free time is still not reached versus 9.1 months for crizotinib," points out Prof. Dariusz M. Kowalski. - The percentage of patients surviving 7 years without disease progression is 55% in the lorlatinib arm versus 3% for crizotinib. And this means that almost 60% of patients have no disease progression after 7 years. This is indeed something amazing," he adds.

The study also showed an 81% reduction in the risk of progression or death compared to crizotinib.

- Lorlatinib is currently the most effective drug in the first-line treatment of patients with advanced ALK-positive lung cancer, which fundamentally changes the patient's perspective. The conversation is no longer solely about short-term cancer control, but also about quality of life, professional activity, mental state or the safety of long-term treatment. In practice, this means a shift from thinking about palliative treatment to long-term disease management," stresses Prof. Jacek Jassem.

Control of brain metastases

Effective control of brain metastases is one of the biggest challenges in the treatment of ALK-positive lung cancer. Lorlatinib is designed to effectively penetrate the blood-brain barrier and combat mutations responsible for the development of resistance to previous ALK inhibitors.

The seven-year analysis showed a 94% reduction in the risk of intracranial progression and no new cases of progression in the brain after the first 30 months of treatment. The median time to intracranial progression for lorlatinib was not reached, and for crizotinib was 16.4 months.

- Interestingly, the treatment is also active in patients who originally had central nervous system metastases. The reduction in the risk of their recurrence or development is 97%. It is noteworthy that the reduction in the risk of central nervous system metastases with lorlatinib is 30 times greater than with crizotinib," stresses Prof. Dariusz M. Kowalski.

The expert points out that lorlatinib has a specific toxicity profile. - It mainly relates to lipid disorders, which we are able to control. There are also such side effects as peripheral edema, weight gain, peripheral neuropathy and, due to its high penetration into the central nervous system, cognitive impairment, he enumerates. Permanent discontinuation of treatment due to therapy-related side effects was reported in 5% and 6% of patients, respectively. - It is still difficult to speak of a cure, since it is not certain that the cancer will not return someday. However, the situation is looking more and more like a chronic disease, in which a patient receiving many years of treatment functions normally professionally, familially and socially, says Prof. Jacek Jassem.