If decades and decades of research have shown anything, it is that there is no magic bullet to knock it down. The scientific community knows with increasing certainty that the success of the fight against the most aggressive tumors involves attacking to prevent, at all costs, the escape of some tumor cells that allow the disease to progress. Two new independent investigations delve into this strategy in the context of liver cancer and confirm that combining two targeted therapies with a traditional intervention that cuts off the tumor’s nutritional pathways slows the progression of the disease. The two studies, both phase III trials, evaluate different combinations of drugs, but with a common strategy: attacking the tumor from different fronts to maximize effectiveness.
One of the investigations, called LEAP-012, has consisted of a three-way therapeutic approach against an intermediate-stage tumor that, although it has not spread to other parts of the body, has a size that already makes its removal impossible: the unresectable non-metastatic hepatocellular carcinoma. In a clinical trial, researchers from the Idibaps-Clínic of Barcelona have shown that adding lenvatinib (a molecular therapy) and pembrolizumab to traditional chemoembolization (blocking the blood supply to the tumor) improves progression-free survival. That is, the time the patient spends alive without tumor progression. The results of the clinical trial, the scientists admit, are modest—progression-free survival goes from 10 months with chemoembolization alone to 14.6 with the three-pronged shot—but they mark a turning point in a type of which no therapeutic innovations had been achieved for two decades. Nearly half a thousand patients have participated in the research.
In the other study (EMERALD-1), led by the Clínica Universidad de Navarra (CUN), the researchers also tested a three-way strategy in inoperable liver cancer: in a trial with 616 patients, they added conventional chemoembolization to a combination of durvalumab (an immunotherapy) and bevacizumab (a drug that blocks the growth of blood vessels) and found that it also slowed the progression of the disease: the combination of the two targeted therapies delayed cancer progression by 6.8 months compared to those study participants who received placebo.
Every year, around 6,000 cases of cirrhosis occur in Spain. In the vast majority of situations (90%), patients have previous cirrhosis due to hepatitis B or C, either due to alcohol abuse or associated with metabolic diseases. Josep Maria Llovet, who is a professor of Medicine and Hepatology at the University of Barcelona and ICREA professor at Idibaps, points out that 30% of tumors are diagnosed in the initial stages and the therapeutic approach is usually the removal of the cancerous mass, the liver transplant or radioembolization (microwaves that eliminate the tumor when it is small). But there are other cases in which the cancer is already more advanced, he points out: “Between 40% and 50% of tumors are detected in advanced stages, when there is an invasion of the blood vessels or nodes or there is spread with metastasis. But there are another 25% of tumors that are detected in intermediate stages and chemoembolization is the standard treatment.” The new therapeutic approaches that have just been tested are aimed at the latter.
“After 20 years with a mechanical treatment, in which we prevented the nutrition of the tumor by blocking the nutritional artery and released regional chemotherapy [en la zona]we began to have a combined treatment with systemic therapy,” explains Llovet, who is the international principal investigator of the LEAP-012 study. Precisely, the same Idibaps-Clínic group was the one that designed chemoembolization two decades ago, the standard treatment since then.
This intervention was a breakthrough in clinical practice, but his and these patients continued to have, in the medium term, a poor prognosis. The new approach described in the trial published in The Lancet It is a step forward for a group of patients who “urgently” needed better therapeutic results, according to Llovet: “With the standard treatment we achieved a survival of about 25 months, but after eight months, the tumor progressed. With this new treatment, progression-free survival is 15 months and we globally reduced the probability of progression by 34% in more than a third of patients. “These results are expected to change clinical practice in 25% of patients with this cancer worldwide.”
Triple action
The Idibaps team’s new strategy involves shooting three tumor targets at the same time. On the one hand, with chemoembolization, the tumor is starved by blocking the nutrient artery, the highway through which the nutrients enter that allow it to grow, and chemotherapy is released in the same cancerous mass to annihilate the malignant cells more efficiently. . Then, with lenvatinib, which is a multikinase inhibitor, the pathways that allow the tumor to revascularize (develop blood vessels) are blocked, which helps stop the progression of tumor cells. And finally, with pembrolizumab, they lift the tumor to the immune system to avoid being attacked.
“75% of treated patients achieve an objective response [una reducción de al menos el 30% del diámetro del tumor]. Before, with chemoembolization alone, it was 50% of the patients,” explains Llovet. The impact on overall survival, the authors admit, showed a trend that is not yet statistically significant, but they call for studying the results when there is greater follow-up of the patients included in the study. So far they were followed for about 26 months.
In the case of the EMERALD-1 trial, its authors assure that the risk of disease progression or death decreased by 23%, although they admit that the study is still ongoing to be able to analyze the overall survival of the patients in the future. Bruno Sangro, director of Hepatology at the CUN and lead author of the study, explained in a statement that the results of his research represent “an important advance” for a group of patients for whom “there had been no progress in more of 20 years” and adds that “it is a realistic therapeutic alternative for those who cannot undergo surgery.”
These synergies between various therapeutic approaches also follow the scientific path of advancing precision drugs, such as immunotherapy or molecular therapy, to increasingly earlier stages of the disease. Regarding the Idibaps study, María José Safont, spokesperson for the Spanish Society of Medical Oncology (SEOM) and oncologist at the Valencia General University Hospital Consortium, assures that this new therapeutic approach “represents a significant innovation in trying to improve results in a patient population with limited therapeutic options.
Safont, who was not involved in this research, puts into perspective the five-month improvement in progression-free survival achieved by one of the new drug combinations: “It is a clinically relevant advance in the context of hepatocellular carcinoma, since it is It is a disease with a generally unfavorable prognosis. This increase in survival leads to a delay in tumor progression and can improve patients’ quality of life. Although a difference of five months may seem modest a priori, in oncology it represents a significant advance, especially in diseases with limited therapeutic options.”
