Keys to the world's biggest oncology event: Trojan horses and a blood test to guide a patient's future.

Fifteen years have passed since that iconic edition of the American Society of Cancer Research (ASCO) congress, where global oncology opened the door to revolutionary immunotherapy: a drug (ipilimumab) managed to improve survival in metastatic melanoma and turn around the prognosis of a group of patients who had until then been given up for dead. Science had managed to spur the immune system itself to combat tumor cells and entered a new era in the fight against cancer. It was the starting point of a revolution that is still underway and, as demonstrated this weekend at a new edition of ASCO, is far from having reached its peak . Personalized medicine is king, and immunotherapy is one of the great battering rams against cancer.

The latest major global oncology event has made it clear that the strategy of energizing the body's defensive army to fight malignant cells still has a long way to go. This is especially true in combination with other treatments, in earlier stages of the disease, or by increasingly refining the profile of patients who will benefit. "What we're seeing is that applying the innovation of targeted therapies and immunotherapy at earlier stages allows us to cure more patients," says Ernest Nadal, Director of Research at the Catalan Institute of Oncology, from Chicago (where ASCO is being held).

Oncologists are committed to increasingly optimizing established immunotherapy treatments, which currently only work in around 25% of cancer patients, while also using their ingenuity to design new strategies to penetrate resistant tumors. In this regard, new studies support the potential of so-called Trojan horses , which carry drugs to malignant cells; or of bispecific drugs , which present both lymphocytes and tumor cells to facilitate their destruction.

These are some of the key takeaways from the most important scientific conference in oncology:

Progress in lung tumors with a poor prognosis

Despite advances in some types of lung cancer, others still have few options. Small cell lung cancer is the most aggressive type of lung cancer, accounting for 15% of cases. It is almost always associated with smoking, is detected in advanced stages, and is very difficult to treat. The median survival rate is less than 13 months, and the number of patients who survive long-term is less than 10%.

Yesterday, Monday, a team led by Luis Paz-Ares, head of the Clinical Oncology Department at Madrid's Hospital 12 de Octubre, presented the results of a Phase III trial in Chicago that offers a therapeutic option for these patients. In the study involving 660 patients, patients received standard initial therapy and then, if they responded, were given maintenance therapy to prolong survival. The IMforte trial compared a group that received atezolizumab, an immunotherapy, with another that, in addition to atezolizumab, received lurbinectedin, a product created from a marine organism that feeds on plankton and detritus.

"Lurbinectedin increases the efficacy of immunotherapy because it's capable of inducing a more responsive immune context; the tumor becomes more immunogenic and responds better to immunotherapy," explains Paz-Ares. This combination as maintenance therapy reduced the risk of death by 27% over the 15-month follow-up of the study. "Out of every four deaths, you prevent one, and when there's longer-term follow-up, we'll be able to see if there's a cure," notes the leader of the study, which was published in The Lancet. and has been funded by the pharmaceutical company Roche.

Ernest Nadal, who was not involved in this research, believes that studies like this one are "super-relevant" because they target a type of tumor with a very poor prognosis and few therapeutic alternatives. The researcher, in fact, notes that another study has also been presented in this subgroup of lung cancer in which a bispecific drug is added to traditional chemotherapy, which brings lymphocytes closer to tumor cells and activates them to kill these malignant cells.

CAR-Ts are finding their place in solid tumors

Within this revolution in immunotherapies, one has changed the prognosis of a handful of hematological tumors: CAR-T cell therapy, which consists of extracting T lymphocytes from the patient—a type of immune cell responsible for the body's defense—modifying them in the laboratory to make them more effective, and returning them to the patient so they can better fight the tumor. At this ASCO, attempts have been seen to go beyond blood cancer and cross the pending frontier into solid tumors.

A phase 2 study presented at the congress and published in The Lancet revealed that patients with a type of gastric cancer treated with CAR-T therapy lived, on average, 40% longer than those treated with the traditional therapeutic approach for these cases: almost eight months compared to 5.5 months for people who received standard treatment. Another phase 1 trial presented at ASCO also showed "encouraging" results, according to its authors, in glioblastoma , a brain tumor with a very poor prognosis.

Elena Garralda, director of the Molecular Cancer Therapy Research Unit at the Vall d'Hebron Institute of Oncology (VHIO), who has not participated in any of these studies, summarizes the complexity of transferring CAR-T cells to solid tumors: “Finding an antigen [a decoy on the surface of the tumor that the immune system uses to identify malignant cells] is more difficult because solid tumors are more heterogeneous and there are also fewer antigens that are found only on malignant cells.”

Liquid biopsy guides the future of cancer patients

Science has advanced in the detection of molecular fingerprints —biomarkers—that provide a wealth of information about tumors and even allow for advance decision-making regarding treatment or patient prognosis. “Molecular cancer diagnosis is another emerging area, and having greater molecular knowledge of tumors will help us better select treatments and patients. What this conference demonstrates is that the world of molecular diagnosis is beginning to merge with the world of therapy,” summarizes Aleix Prat, head of Oncology at the Hospital Clínic de Barcelona.

An example of this, the doctor explains, is the SERENA-6 study, presented at the congress and published in The New England Journal of Medicine. In this study, scientists tested liquid biopsy —a technique that detects biological traces of the tumor in blood—in patients with a type of metastatic breast cancer to detect and treat treatment resistance before the disease progressed.

The trial followed patients with hormone receptor-positive advanced breast cancer. These patients initially receive hormonal treatments, such as aromatase inhibitors, until they stop working and the next step is decided. Normally, that decision is made with diagnostic imaging techniques, but in this trial, it was performed with a liquid biopsy. “The image is a snapshot of what happened a long time ago, and the blood is a snapshot of what's happening now, and that's a very important conceptual change,” says Emilio Alba, head of the Medical Oncology Service at the Virgen de la Victoria University Clinical Hospital in Málaga, one of the hospitals that, under the leadership of Javier Pascual, participated in the trial.

The biopsy was used to identify mutations that cause resistance to hormonal treatments before they were visible on imaging. Switching from the aromatase inhibitor to camizestrant, an oral drug that overcomes resistance, reduced the risk of disease progression or death by 56%, but the study was presented too early to know whether this will translate into improved overall survival.

“Liquid biopsy gives us information to change treatment before the patient progresses. It allows us to move forward,” explains Prat, who did not participate in the study. Nadal also describes this research as “disruptive”: “Instead of waiting for the disease to progress radiologically, we monitor the patient with a liquid biopsy and change treatment based on the information provided by the blood, not the CT scan. Liquid biopsy saves you time,” he says.

'Trojan horses' and other advanced therapies to corner cancer

Elena Garralda, director of the Molecular Cancer Therapy Research Unit at the Vall d'Hebron Institute of Oncology (VHIO), recalls the year 2010 of the immunotherapy explosion: "It was the first revolution because we understood immunotherapy's ability to generate lasting responses. Now we are trying to expand that benefit because all tumors tend, in one way or another, to escape the immune system, but we have only found a way to reverse that evasion in a small percentage of patients," she adds. Garralda asserts that this year's ASCO has delved into the development of new technologies , such as bispecific drugs or immunoconjugates, which are those promising Trojan horses .

Among the new treatments for different types of breast cancer presented at ASCO, one of the trends is precisely the application of Trojan horses in earlier stages of the disease—a targeted drug combination that delivers a potent chemotherapy drug to the desired site to destroy the tumor. "We have to start thinking that when breast cancer metastasizes, Trojan horses will be the treatments that are positioned first," says Javier Cortés, director of the International Breast Cancer Center (IBCC) in Barcelona, ​​from Chicago.

One of the trials that presented results for this type of drug was Destiny-Breast09. The study evaluated the combination of the Trojan horse trastuzumab-deruxtecan with pertuzumab, an inhibitor of the Her2 protein, which causes accelerated tumor growth. The combination of the conjugate and pertuzumab reduced the risk of disease progression or death by 44% compared to the current standard of care.

Another presentation using a similar tool is the Ascent-04 study. This trial tested the combination of sacituzumab and govitecan, a Trojan horse with a similar mechanism, and pembrolizumab, an immunotherapy, as first-line treatment in patients with advanced triple-negative breast cancer with PD-L1 expression. The study showed a 35% reduction in the risk of progression or death compared with standard chemotherapy plus pembrolizumab.

Ernest Nadal suggests that tumor-targeted chemotherapy using these strategies "allows for higher doses of localized chemotherapy, which explains the greater efficacy in some tumors," but also clarifies that "overwhelming efficacy is not always achieved." The doctor also highlights the emergence of bispecific and trispecific therapies, which present the lymphocyte with one or more tumor markers. "Work is underway on new, more advanced forms of immunotherapy targeting multiple tumor antigens."