2024-07-21 00:33:59
A drug that binds lymphocytes with malignant cells to destroy them is improving the effect of immunotherapy in small cell tumors.
There is a lung cancer that grows aggressively, quickly and very aggressively. It is a small cell tumor (or microcytic), a disease that expands rapidly and, when it appears, is often very advanced, with metastases in other organs and a very poor prognosis. Its biology is so violent that science has not guided it for decades, with little more than chemotherapy to fight the first fight, but without many weapons to defend itself when it reappears. However, that journey through a kind of medical desert has come to an end. Step by step, with mixed but steady results, a new generation of drugs has begun to open the gap of fire in this catastrophic tumor.
The scientists did not plan the financial work or leave it alone, but they believe that the new star of treatment for small cells is promising. Above all, in the tumor present in 70% of cases are found in very advanced stages and whose five-year survival does not exceed 5%. In this context, and after decades without strong positive results for new drugs, the first immunotherapy, which arrived five years ago with moderate results, is a game changer. Since then, tests of new drug combinations, researches with promising applications and, in particular, the access of a new drug that unites lymphocytes with tumor cells to facilitate their destruction, have opened the way and hope for increasing survival in this complex tumor.
Throughout the year 2024, approximately 33,000 cases of lung cancer will be diagnosed in Spain, according to estimates by the Spanish Society of Medical Oncology. Of them, around 15% will be microcytic, a tumor that is highly linked to smoking, typical of smokers. “It is the most aggressive tumor, with the ability to multiply. It is usually diagnosed in advanced stages and can go to the liver or brain [con metástasis en esos órganos]. Also, when it starts, the patient is very symptomatic. It is a tumor that puts patients on edge,” explained Ernest Nadal, director of the Thoracic Tumors Program at the Catalan Institute of Oncology.
At this point, treatment options are limited. As we have seen of late, the possibility of surgery to remove the tumor is “anecdotal,” admits Luis Paz-Ares, head of the Medical Oncology service at Hospital 12 de Octubre in Madrid. Chemotherapy and radiotherapy are the most common tools, but they are far from being ineffective: “The prognosis is not good because although it is sensitive to chemotherapy and radiotherapy, this sensitivity is temporary and the tumor becomes more active,” he explained.
Attempts to incorporate innovative strategies that have already been used in other types of lung cancer, finding molecular targets to attack or formulas to reactivate the immune system, have also not borne fruit. The nature and environment of the tumor cells themselves work against it, the oncologist from 12 de Octubre explains: “It does not have the goals of therapy. There are no aberrations or mutations in the oncogenes that initiate the disease. And, in addition, you have a very compromised immune system and the immune system tends to be less effective.”
Orphan disease
As a result of smoking, the tumor has many changes, but none have been found in any of the important genes involved in the spread of cancer. And if that is not enough, tumor cells have the ability to evade the immune system: they separate themselves and prevent the lymphocytes, which are part of the immune system, to recognize and kill them. “The first step is chemotherapy. If nothing is done, within weeks, we may lose the patient. The fraction of long rest is very small. So, as it is such an orphan disease, any progress is hopeful,” Nadal reflected.
The first light came five years ago with the introduction of the first immunotherapy in combination with traditional chemotherapy. This means, in the words of Margarita Majem, an oncologist at Sant Pau Hospital in Barcelona, ”a small improvement”, but nothing compared to the effect of the immune system on non-small cell lung cancer. -small and other types of tumors. . Paz-Ares admits: “It’s a bit of an advantage. “Three or five-year survival has gone from being between 2% and 5% to reaching 12% or 15%.” Survival increased in understanding, but, at least, it broke the unfortunate forces of the last 30 years, in which 60 materials were tested in 40 tests and all were negative.
After that turning point, other therapies have been shown to be effective in treating this complex tumor. Last year, phase II research was presented with a new drug, tarlatamab, an antibody that acts as an intermediary, putting lymphocytes in contact with tumor cells so that these natural hosts recognize them and destroy them. “We’re starting to understand how to intervene in the immune system and that’s what happened with tarlatamab,” explained Paz-Ares, lead author of this study. The molecule is a bispecific antibody with two parts: one binds to the lymphocyte and the other binds to a protein in the membrane of the tumor cells, and presents them so that the immune system recognizes and kills these malignant cells.
According to the study, 40% of the patients responded — the tumor decreased. And the median survival mark is 14 months. “With more follow-up, we found that the median survival was more than 18 months. We think there will be an effect on survival,” Paz-Ares predicted. The US Food and Drug Administration (FDA) has already approved this treatment.
Beware of hope
Tarlatamab is the most promising treatment so far, but it is not without risks. It can be side effects, such as neurotoxicity (examination, behavior change) or cytokine release syndrome, the most worrying: when the immune system is released, the lymphocytes begin to release substances, such as cytokines, and a species is generated that , if not treated in time, can lead to multiple organ failure and death. Paz-Ares explains that cytokine storm occurs in 50% of cases, but less than 5% are severe symptoms.
Enriqueta Felip, head of Thoracic Tumors and Head and Neck Cancer at the Vall d’Hebron Institut d’Oncologia (VHIO), assures, however, that it is “an appropriate drug.” “The toxicity, which has been a concern for a while, is controllable. We see long lasting responses and it is very useful in this situation,” he added. Majem agrees, but calls for caution: “We’ve found it to work well and open the door to a promising new therapy, but we’re still learning which patients will benefit the most.”
At the new meeting of the American Society of Medical Oncology (ASCO), which began last week in Chicago, a phase I / II study with a new combination of chemotherapies was also presented: lurbinectedin with irinotecan, which showed “activity promising antitumor.” “It is a combination that has been shown to be very effective in previous studies and we have confirmed very significant remission rates in pretreated patients. In this study, with a higher number of patients, the survival rates are at a satisfactory level for this clinical situation,” said Paz-Ares, head of the research presented at the conference.
The response rates, Majem thinks, are “very interesting.” Above all, patients are even more sensitive to chemotherapy. “This combo shows promising results and the toxicity profile is that of chemotherapy, known risks that we know how to manage,” he added. Patients are already being recruited to confirm the findings in the trial phase. A III.
Go back and forth in hope
Although most patients are diagnosed in advanced stages, there are around 25% of patients who can be found with a local tumor. In these cases, the prognosis is, to begin with, more favorable, but new treatment methods are also being researched to improve survival. “Every year, we investigate 60 cases of small cell lung cancer and, of them, between 10 or 12 are in the community. There is a hope: the combination of chemotherapy with radiotherapy can cure a small fraction (around 20% or 25%), although the majority, often ending in a later relapse with metastases. Now there is research to test immunity after chemo and radiotherapy,” said Nadal.
He points to the Adriatic study, which tested the benefit of adding durvalumab to conventional therapy, a type of immunotherapy that also activates immune cells to attack the tumor. Felip assures that “if the study is positive, there will be a change in clinical practice.” Preliminary data, presented at ASCO, showed that the median survival after giving durvalumab as therapy in local tumors was 56 months, compared to a median of 33 months among patients who received a placebo. Nadal said: “The data is encouraging.
With all this new pharmaceutical weaponry in the works, the journey through the desert is drawing to a close. Neither new vaccines nor drug combinations “will be a cure,” Majem warned, but they are small steps forward that “improve survival.” Nadal agreed: “We are beginning to see, seeing how serious the disease is and the results are modest, that the level of expectation that we can have has changed. But you don’t have to be satisfied, you have to move on.” Jessica Mouzo (EP)
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