Keys takeaways from the world’s biggest cancer research conference: Trojan horses and blood tests as treatment guides

It’s been fifteen years since that iconic edition of the American Society of Clinical Oncology (ASCO) conference, when the global oncology community opened the door to revolutionary immunotherapy: a drug (ipilimumab) succeeded in improving survival in metastatic melanoma, changing the outlook for a group of patients who had previously been considered beyond hope.

Science had managed to stimulate the body’s own immune system to fight tumor cells, ushering in a new era in the battle against cancer. It was the starting point of a revolution that is still ongoing and, as this past weekend’s ASCO conference once again demonstrated, is far from reaching its peak. Personalized medicine now leads the way — and immunotherapy is one of the field’s strongest weapons against cancer.

The latest major gathering in global oncology has made one thing clear: the strategy of mobilizing the body’s own immune defenses to fight malignant cells still has plenty of potential. Especially when combined with other treatments, used in earlier stages of the disease, or applied with increasing precision to the right patient profiles

“What we are 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, speaking from Chicago.

Oncologists are increasingly focused on optimizing established immunotherapy treatments, which currently only work for about 25% of cancer patients, while also pushing the boundaries of innovation to develop new strategies for targeting resistant tumors. In this effort, recent studies highlight the promise of so-called Trojan horses — agents that deliver drugs directly into cancer cells — and bispecific drugs, which bring immune cells and tumor cells together to facilitate their destruction.

Here are some of the important findings that were presented at oncology’s most important conference:

Progress in lung tumors with poor prognosis

Despite advances in certain types of lung cancer, others still have limited treatment options. Small cell (or microcellular) lung cancer is the most aggressive of these tumors, accounting for 15% of cases. It is almost always associated with smoking, detected in advanced stages and very difficult to treat. Average survival is no longer than 13 months, and and fewer than 10% of patients survive long term.

On Monday, a team led by Luis Paz-Ares, who is the chair of the medical oncology department at Madrid’s 12 de Octubre University Hospital, presented the result of a phase III study that offers a therapeutic option to such patients. In the study, which involved 660 participants, patients first received standard initial therapy. Those who responded were then given maintenance treatment to prolong survival. The IMforte trial compared one group receiving atezolizumab, an immunotherapy, with another group that received both atezolizumab and lurbinectedin — a compound derived from a marine organism that feeds on plankton and organic debris.

“Luberinectedin increases the efficacy of immunotherapy due to its ability to induce a more responsive immunological context. The tumor becomes more immunogenic and responds better to immunotherapy,” says Paz-Ares.

As a maintenance therapy, this combination reduced the risk of death by 27% over the 15-month follow-up period of the study. “You prevent one in every four deaths, and when there is long-term follow-up, we will be able to see if it leads to any cure,” says the lead author of the study, which was published in the journal The Lancet and funded by the pharmaceutical company Roche.

Ernest Nadal, who did not participate in the investigation, believes that research like this is “highly significant,” as it targets a form of cancer with a particularly poor prognosis and limited treatment options.

The researcher also recalls that another study targeting this subgroup of lung cancer was presented, involving a bispecific drug that brings lymphocytes closer to tumor cells and activates them to kill these malignant cells. Instead of the traditional chemotherapy treatment, this innovative drug was administered, yielding superior results. “This is good news for patients because those chemotherapies are quite toxic and not very effective,” he explains.

CAR-T therapies seek their place in solid tumors

Within the immunotherapy revolution, one approach has transformed the prognosis of several hematologic cancers: CAR-T cell therapy. This treatment involves extracting a patient’s T lymphocytes — a type of immune cell responsible for defending the body — modifying them in the lab to enhance their effectiveness, and reinfusing them into the patient to better fight the tumor. At this year’s ASCO, researchers have been exploring attempts to go beyond blood cancers and cross the remaining frontier of treating solid tumors.

A phase II study presented at the conference and published in The Lancet revealed that patients with a type of gastric cancer treated with the CAR-T therapy lived on average 40% longer than those treated with the therapeutic approach that is traditional for such cases: nearly eight months, compared to 5.5 among people receiving the standard treatment. Another phase II trial presented at ASCO also showed “encouraging” results, according to authors, in glioblastoma, a brain tumor with a very poor prognosis.

Elena Garralda, director of the cancer molecular therapy research unit at the Vall d’Hebron Oncological Institute (VHIO), who did not participate in any of these studies, explains why translating CAR-T to solid tumors is so complex. “Finding an antigen [a marker on the surface of the tumor that helps the immune system identify malignant cells] is more difficult because solid tumors are more heterogeneous, and there are also fewer antigens found only in malignant cells.”

Liquid biopsies are the future for cancer patients

Science has advanced when it comes to the detection of molecular fingerprints, or biomarkers, that provide a wealth of information about tumors and even enable earlier decisions to be made about treatment and patient prognosis.

“Molecular diagnosis of cancer is another emerging area, and greater molecular knowledge of tumors will help us to better select treatments and patients. What this conference shows is that the world of molecular diagnosis is beginning to merge with the world of treatment,” summarizes Aleix Prat, head of oncology at Barcelona’s Hospital Clinic.

One sign of this, says Prat, is the SERENA-6 study that was presented at the conference and published by The New England Journal of Medicine. In it, scientists tested liquid biopsy — a technique that detects biological traces of tumors in the blood — on patients with a type of metastatic breast cancer to detect and treat resistance to treatment before the disease progresses.

The trial followed patients with advanced hormone receptor-positive breast cancer. These patients first receive hormone treatments, such as aromatase inhibitors, until they stop working and the next step is decided upon. Normally, the decision is made using diagnostic imaging techniques, but in this trial, it was based on liquid biopsy.

“Imaging provides a snapshot of what happened in the past, and blood, a snapshot of what is happening now, and that is a very important conceptual change,” says Emilio Alba, director of the medical oncology intercenter unit at the Virgen de la Victoria University Hospitals of Málaga, one of the sites that participated in the study, under the leadership of Javier Pascual.

The biopsy was used to identify mutations causing resistance to hormonal treatments before they became visible on imaging. Replacing the aromatase inhibitor with camizestrant, an oral drug that overcomes resistance, reduced the risk of disease progression or death by 56%. However, the study was presented too early to determine whether this will translate into an improvement in overall survival.

“Liquid biopsy gives us information in order to change the treatment before the patient goes any further. It allows us to advance,” explains Prat, who did not participate in the investigation.

Similarly, Nadal calls the study “disruptive”: “Instead of waiting for the disease to progress radiologically, the patient is monitored using liquid biopsy and their treatment is changed based on the information that the blood reveals, rather than CT scans. The liquid biopsy allows for more time,” he says.

Trojan horses and other advanced cancer treatments

Garralda recalls how in 2010, immunotherapy exploded onto the research scene: “It was the first revolution, because it led us to understand the ability of immunotherapy to generate lasting response. Now we are trying to expand those benefits, because all tumors tend, in one way or another, to escape the immune system, and yet we have only figured out how to reverse that evasion in a small percentage of patients,” she comments.

Garralda says that this year’s ASCO delved deeper into the development of new technologies, such as bispecific drugs and immunoconjugates, which are promising Trojan horses.

Among the new treatments for different types of breast cancer presented at ASCO, one of the trends is the application of Trojan horses in the earliest stages of disease. These combinations include a targeted drug that carries a powerful chemotherapy drug to the desired location to destroy the tumor.

“We have to start thinking that when breast cancer metastasizes, Trojan horses will be the first line of treatment,” says Javier Cortés, director of the International Breast Cancer Center in Barcelona, speaking from Chicago.

One of the trials that presented results of this type of drug was Destiny-Breast09. The study evaluated the combination of the Trojan horse trastuzumab-deruxtecan with pertuzmab, a Her2 protein inhibitor that 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.

The Ascent-04 study presented research on a similar tool, in its case, the combination of Sacituzumab Govitecan, a Trojan horse with a mechanism similar to Trastuzumab-Deruxtecan, and Pembrolizumab, an immunotherapy, was tested as a first-line treatment in patients with advanced triple-negative breast cancer expressing PD-L1. The study showed a 35% reduction in the risk of progression or death, compared to standard chemotherapy plus pembrolizumab.

Nadal says that chemotherapy that attacks tumors via this type of strategy “allows for higher doses of localized chemotherapy, which explains the higher efficacy on some tumors,” but also cautions that “overwhelming efficacy is not always achieved.”

The doctor also highlights the emergence of bispecific and “trispecific” antibodies, which introduce one or more tumor markers to the lymphocyte. “Work is underway on new, more advanced forms of immunotherapy targeting multiple tumor antigens.”

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