Scientifically Speaking | Lorlatinib: A game-changer in lung cancer therapy

The drug has shown impressive results in extending progression-free survival, due to its ability to penetrate the blood-brain barrier and treat brain metastases

Lung cancer is responsible for more deaths worldwide than any other type of cancer. This disease is especially hard to beat because it’s often detected late. In India, lung cancer is a major public health concern made worse by limited access to treatments and high exposure to risk factors like smoking and pollution.

Lung cancer rates have been rising, particularly in urban and northeastern regions, largely driven by higher smoking rates and significant air pollution. (Pexels)

Lung cancer rates have been rising, particularly in urban and northeastern regions, largely driven by higher smoking rates and significant air pollution. Second-hand smoke exposure from cigarettes and bidis is another major concern, significantly increasing lung cancer risk. Policies banning smoking in public places have been effective in reducing exposure. However, enforcement varies, and the challenge remains ongoing.

Beyond smoking, India’s predominant form of tobacco use is smokeless tobacco, leading to higher risks of many other cancers. However, exposure to biomass fuels for cooking in rural areas is also a major risk factor for lung cancer. The smoke from these fuels releases carcinogenic pollutants like benzene and polycyclic aromatic hydrocarbons, further compounding the problem.

Tobacco smoking is a primary risk factor, with smokers being about 20 times more likely to develop lung cancer than nonsmokers. Notably, there are also cases of lung cancer among non-smokers, likely due to genetic factors and environmental issues like air pollution. My own grandmother, who was not a smoker, but consumed paan with tobacco for most of her life, succumbed to lung cancer in her seventies.

Cancer is fundamentally a genetic and evolutionary disease. It arises from genetic mutations that cause uncontrolled cell growth, and lung cancer is particularly challenging due to its genetic complexity and its tendency to spread to the brain. Lung cancer can be divided into small-cell lung cancer and non-small-cell lung cancer based on the appearance of the cancer cells under a microscope. Non-small cell lung cancer makes up about 85% of all cases.

One type of non-small cell lung cancer involves mutations in the anaplastic lymphoma kinase (ALK) gene, which drives cancer growth. Traditional treatments like chemotherapy and radiation have not been very effective in treating it, especially in advanced stages. This cancer tends to occur in younger patients who are nonsmokers. It’s particularly deadly and adept at spreading to the brain.

About a quarter of patients develop brain metastasis within the first two years of being diagnosed. This has led to a search for more targeted treatments.

Lorlatinib (available globally, including in India) is a targeted therapy designed to inhibit the activity of the ALK protein. The ALK gene can fuse with other genes to create a hybrid gene that produces a protein promoting cancer cell growth. By inhibiting this protein, lorlatinib can halt the growth and spread of cancer cells.

What makes lorlatinib particularly special is its ability to cross the blood-brain barrier, which many drugs cannot do effectively. This allows it to target and treat brain metastases. This discovery could change the landscape of lung cancer treatment.

The cancer study led by Dr. Benjamin Solomon and his team, was presented at the American Society of Clinical Oncology Annual Meeting in Chicago on Friday. Detailed results were published in the Journal of Clinical Oncology. They represent a real breakthrough.

Let me walk through some of the details. The study involved nearly 300 patients with ALK-positive non-small cell lung cancer. They were randomly assigned to receive either lorlatinib or a different drug that used to be the standard of care earlier, crizotinib. After five years, more than half the patients on lorlatinib were still living without their cancer worsening. In contrast, for those on crizotinib, the median progression-free survival was only around nine months. This is a big deal. By this metric, lorlatinib is the best-performing single treatment reported for any advanced non-small cell lung cancer and across all metastatic solid tumours.

While lorlatinib did show higher rates of side effects like high cholesterol, weight gain, and high blood pressure compared to crizotinib, these were manageable with appropriate medical care. The significant benefits of lorlatinib far outweigh these side effects, offering much better overall survival rates and quality of life.

Cancer treatments have come a long way since my grandmother’s fatal encounter nearly two decades ago. Now targeted therapies focus on specific genetic changes that drive cancer growth in different patients. Lorlatinib, a drug available in India, showcases the potential of targeted therapies to offer longer survival and better quality of life.

Commenting on these results, Dr. Jessica Lin of Massachusetts General Hospital and Harvard Medical School, said that 5-year outcomes reported in the study have “raised the bar” not only for lung cancer but also in terms of what targeted therapies in general may be able to achieve. As targeted therapies continue to evolve, the future of cancer treatment looks increasingly promising for sufferers of this dreaded ailment.

Anirban Mahapatra is a scientist and author, most recently of the popular science book, When The Drugs Don’t Work: The Hidden Pandemic That Could End Medicine. The views expressed are personal.