Adult patients with advanced stage Alk + non-small cell cancer now have one more option: lorlatinib, approved under reimbursement regime for the monotherapy treatment of patients who, after treatment with alectinib or ceritinib as first-line therapy or crizotinib and at least one other anti-Alk Tki have had disease progression. Pfizer communicates this in a note. The new drug is a third generation tyrosine kinase (Tki) inhibitor, specifically designed to overcome the blood brain barrier and therefore act in the brain, as well as to be active even in patients previously treated with which secondary resistance mutations have developed. .
Lung cancer is one of the most common cancers, in Italy it is the third most frequent in men and the second in women, and causes a higher number of deaths than any other form of cancer. Thanks to scientific research, however, in recent years it has been possible to identify numerous molecular alterations which are the basis of its development and which can represent therapeutic targets. These include the alteration of the Alk gene (Anaplastic Lymphoma Kinase) – a rearrangement due to the fusion of two gene fragments – present in 5-7% of patients with non-small cell lung cancer (Nsclc), with a greater incidence in younger ones (under 50) preferentially – but not exclusively – non-smokers. In the presence of the alteration, a mutated protein is produced that promotes tumor growth and metastasization of neoplastic cells.
“In the last twenty years, there have been many scientific advances and research progresses in the diagnosis and treatment of non-small cell lung cancer with the identification of new action targets and specific drugs. Despite this, there is still a strong need for solutions, especially to deal effectively with the disease at the time of progression and in particular when it affects the brain compartment. The availability of lorlatinib is therefore absolutely positive news – comments Silvia Novello, professor of medical oncology at the Department of Oncology of the University of Turin and president of Walce Onlus – because it allows us to treat patients with Alk rearrangement, for which it was it is urgent to find a solution for an adequate approach to the disease in its course “.
The inhibitors of the Alk tyrosine kinase – explains the note – are a class of drugs capable of blocking the action of the mutated protein, demonstrating efficacy in the treatment of tumors that present this molecular alteration. However, the majority of patients treated with first generation Tki undergo disease progression due to the development of secondary mutations. Although second generation molecules have been developed precisely to overcome the resistance problem, other resistance mutations inevitably lead to further disease progression, especially in the central nervous system.
“The development of resistance and the progression of the disease in the central nervous system remain unsolved problems – explains Cesare Gridelli, director of the Department of Onco-hematology, hospital company ‘SG Moscati’, Avellino – in the management of the disease despite the clinical benefit derived from use of second generation tyrosine kinase inhibitors. The data for lorlatinib show significant and lasting responses in patients with Alk-positive Nsclc, many of whom had brain metastases and a history of failure with previous Alk Tki. The drug demonstrated high efficacy, recording tumor regressions in about 50% of pretreated translocated Alk patients “.
The ability to reach the brain allows lorlatinib to act on brain metastases and make them regress. “Unfortunately, about half of Alk-positive patients develop brain metastases during their illness – underlines Federico Cappuzzo, director of Uoc Medical Oncology 2 National Cancer Institute ‘Regina Elena’ in Rome – To have a drug available that has an action on brain even higher than that exerted in other organs is an element of great importance because very often brain metastases are associated with symptoms and disabilities that lead to a significant worsening of the quality of life. The drug is also well tolerated, with adverse events generally well manageable “.
The multicenter Phase 1/2 study (B7461001) involved 139 patients previously treated with one or more Tki Alk, 67% of whom had brain metastases at enrollment. The results – Pfizer highlights – show an overall objective response to treatment of 42.9% for patients treated with one or more Alk Tki, with an intracranial response rate of 66.7%, and 39.6% for treated patients. with two or more Alk Tki, with a 52.1% Ic4 response rate.
“After being pioneers in the development of target drugs for the treatment of Alk-positive non-small cell lung cancer, we are proud in Pfizer to be able to make lorlatinib available in Italy today, a new and effective therapeutic option that offers patients with this pathology, progressing from previous therapies, the opportunity to continue a therapeutic path based on precision medicine, with a positive impact on the quality of their life “, concludes Alberto Stanzione, Oncology Director of Pfizer in Italy.