There is a lung cancer that grows furiously, very quickly and very aggressively. It is a small cell (or microcytic) tumor, a disease that expands rapidly and, when it appears, is usually already very advanced, with metastases in other organs and a very unfavorable prognosis. Its biology is so violent that science had not taken the lead for decades, with little more than chemotherapy to deal the first blow, but without many more weapons to defend itself when it reappeared. However, that journey through a kind of therapeutic desert has begun to come to an end. Step by step, with discrete but firm results, a new generation of drugs has begun to open a gap of light in this disastrous tumor.
Oncologists are not setting off fireworks or getting complacent, but they admit that the new constellation of treatments for small cells invites optimism. Above all, in a tumor that in 70% of cases is detected in very advanced stages and whose five-year survival does not exceed 5%. In this context, and after decades without conclusive positive results for new drugs, the first immunotherapy, which arrived five years ago with modest results, was a shock. Since then, trials of new drug combinations, studies with promising molecules and, especially, the entry 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 2024, nearly 33,000 cases of lung cancer will be diagnosed in Spain, according to calculations of the Spanish Society of Medical Oncology. Of them, around 15% will be microcytic, a tumor extremely linked to smoking, typical of heavy smokers. “It is the most aggressive tumor, with a very high proliferation capacity. It is usually diagnosed in advanced stages and can go to the liver or brain [con metástasis en esos órganos]. Furthermore, when it debuts, the patient is very symptomatic. It is a tumor that puts patients on the edge,” describes Ernest Nadal, director of the Thoracic Tumors Program at the Catalan Institute of Oncology.
In this context, therapeutic options are limited. As it is detected late, the possibility of surgery to remove the tumor is “anecdotal,” admits Luis Paz-Ares, head of the Medical Oncology service at the 12 de Octubre Hospital in Madrid. Chemo and radiotherapy are the most common tools, but they are far from being infallible: “The prognosis is poor because despite being sensitive to chemotherapy and radiotherapy, this sensitivity is short-lived and the tumor becomes resistant,” he explains. Peace-Ares.
Attempts to incorporate innovative strategies that have already been used in other types of lung cancer, searching for molecular targets to attack or formulas to reactivate the immune system, have also not borne fruit. The behavior and environment of the tumor cells themselves work against it, explains the oncologist from 12 de Octubre: “It has no therapeutic targets. There are no aberrations or alterations in the oncogenes that initiate the disease. And, furthermore, it has a very immunosuppressive immunological context and immunotherapy tends to be less effective.”
An orphan disease
As a result of tobacco, the tumor has many mutations, but none have been found in any of those key genes in cancer proliferation. And if that were not enough, tumor cells have the ability to evade the immune system: they camouflage themselves and prevent the lymphocytes, which are part of the body’s army, from recognizing and killing them. “The main strategy is chemotherapy. If nothing is done, within weeks, we could lose the patient. The fraction of long survivors is very small. Therefore, as it is such an orphan disease, any progress is hope,” Nadal reflects.
The first ray of light came five years ago with the introduction of the first immunotherapies in combination with traditional chemotherapy. This meant, in the words of Margarita Majem, an oncologist at the Sant Pau Hospital in Barcelona, “a small improvement”, but nothing comparable to the impact that immunotherapy has had on non-small cell lung cancer and other types of tumors. Paz-Ares agrees: “It benefits a little. “Three or five year survival has gone from being between 2% and 5% to reaching 12% or 15%.” Survival increased discreetly, but, at least, it broke the unfortunate dynamics of the last 30 years, in which 60 molecules were tested in 40 trials and all were negative.
After that turning point, other therapeutic approaches have appeared that are effective in combating this complex tumor. Last year, a phase II study was presented with a new drugtarlatamab, an antibody that works as an intermediary, putting lymphocytes in contact with tumor cells so that these soldiers of the body recognize them and annihilate them. “We are beginning to understand how we can intervene in the immunological context and that is what has happened with tarlatamab,” explains Paz-Ares, lead author of this research. The molecule is a bispecific antibody with two arms: one binds to the lymphocyte and the other attaches to a protein present in the membrane of tumor cells, and presents them so that the immune system identifies and kills these malignant cells.
According to the investigation, 40% of the patients responded—the tumor shrank. And the median survival reached 14 months. “With more follow-up, we are seeing that the median survival exceeds 18 months. We speculate that there will be an impact on survival,” Paz-Ares predicts. The US regulatory agency (FDA) has already approved this treatment.
Cautious optimism
Tarlatamab is the most promising treatment so far, but it is not without risks. There may be side effects, such as neurotoxicity (confusion, behavioral alteration) or cytokine release syndrome, the most worrying: when the immune system is stimulated, lymphocytes begin to release substances, such as cytokines, and a species is generated. of systemic inflammation that, if not treated in time, can lead to multiple organ failure and death. Paz-Ares explains that cytokine storm occurred in 50% of cases, but less than 5% were severe symptoms.
Enriqueta Felip, group leader of Thoracic Tumors and Head and Neck Cancer of the Vall d’Hebron Institut d’Oncologia (VHIO), assures, however, that it is “a relevant drug.” “The toxicity, which initially worried us a little, is manageable. We see lasting responses and that is very relevant in this situation,” he adds. Majem agrees, but calls for caution: “It has been seen to work well and opens a door to a new therapy that is hope, but we are still learning which patients exactly are going to benefit the most.”
At the latest 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 “promising antitumor activity.” “It is a combination that has been shown to be very effective in preclinical studies and we have validated very important remission rates in pretreated patients. In this study, with a high number of patients, the survival rat
es are in an appreciable range for this clinical context,” says Paz-Ares, head of the research presented at the congress.
The response rates, Majem considers, are “quite interesting.” Above all, in patients especially sensitive to chemotherapy. “This combo presents promising results and the toxicity profile is that of chemotherapy, known risks that we know how to manage,” she adds. Patients are already being recruited to validate the findings in a phase III trial.
Shift in expectations
Although the majority of patients are usually diagnosed in advanced stages, there are around 25% of patients who can be detected with a localized tumor. In these cases, the prognosis is, to begin with, more favorable, but new therapeutic approaches are also being investigated to improve survival. “Every year, we diagnose 60 cases of small cell lung cancer and, of them, between 10 or 12 are localized. There is some hope there: the combination of chemotherapy with radiotherapy can cure a small fraction (around 20% or 25%), although the majority, very often end up relapsed later with metastases. Now there is a study to test immunotherapy after chemo and radiotherapy,” says Nadal.
It refers to Adriatic studio, in which the benefit of adding durvalumab, a type of immunotherapy that reactivates immune cells to attack the tumor, is tested. Felip assures that “if the study is positive, there will be a change in clinical practice.” The preliminary data, presented at ASCO, showed that the median survival after giving durvalumab as consolidation therapy in these localized tumors was 56 months, compared to a median of 33 months among patients who received placebo. “The data is encouraging,” says Nadal.
With all this new therapeutic arsenal in the making, the journey through the desert is leaning towards its end. Neither new immunotherapies nor drug combinations “will have a cure,” Majem warns, but they are small steps forward that “improve survival. Nadal agrees: “We are beginning to see, taking into account the severity of the disease and the modest results, that there is a shift in the level of expectations that we can have. But you don’t have to be content, you have to continue.”
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