Read time: 9 minutes.
More than 22,000 cancer researchers from 81 countries got together for the annual American Association for Cancer Research (AACR) meeting in Chicago from April 25-30. This year’s meeting theme “Unifying Cancer Science and Medicine: A Continuum of Innovation for Impact” was a testament to AACR’s commitment to bridging the laboratory bench, the bedside, and the community.
Lung cancer research took center stage, unveiling a wave of promising advancements poised to reshape the landscape of detection, treatment, and ultimately, patient outcomes.
Major highlights of the meetings are discussed below.
1) Refining lung cancer screening
Early detection remains paramount in improving survival rates for lung cancer. Lung cancer screening is an important early detection modality. Currently, lung cancer screening is available to high-risk individuals who are currently defined as those between ages 50-80 with tobacco exposure (20-pack year history and current or former tobacco exposure – defined as those who have quit within the past 15 years).
Several presentations discussed how the current screening eligibility criteria are somewhat restrictive and a more nuanced discussion around risk is needed. Artificial intelligence (AI) models, such as Sybil, are now being tested to incorporate other risk factors including co-morbidities (such as COPD), occupational exposure, or a family history of lung cancer (first-degree relatives) in screening discussions.
Another important lung cancer risk factor is air pollution, specifically PM2.5 (particulate matter whose size is 2.5 micrometers) found both indoors (from sources such as cooking fuel) and outdoors (from industrial and vehicular emissions). Around 99% of the world lives in areas with high PM2.5 that exceed the World Health Organization thresholds. Researchers have identified a 14-protein biomarker signature that can be detected in the blood of mice exposed to PM2.5. While obviously an early development, we are making strides in developing new technologies that can quantify other types of lung cancer risk.
2) Advancing precision medicine for metastatic non-small cell lung cancer (NSCLC)
Targeted therapies continue to revolutionize the treatment of metastatic non-small cell lung cancer (NSCLC) driven by specific genetic alterations or driver mutations. However, the phenomenon of acquired resistance whereby cancer cells outsmart targeted therapies and start growing is a common issue associated with most targeted therapies. Two pressing questions are:
- Can we catch acquired resistance proactively before the cancer starts growing so treatments can be adjusted?
- What treatment options can be provided if a targeted therapy stops working?
ALK Fusions
Using blood from patients with ALK fusion-positive lung cancer, researchers have identified a type of circulating tumor cells (CTCs) that produce high levels of a protein called vimentin. These cells, known as mesenchymal circulating tumor cells, are found in patients whose tumors start growing while on treatment with ALK tyrosine kinase inhibitors or TKIs. This critical advancement suggests that such types of blood tests may be able to predict response to cancer treatment.
EGFR Mutations
Currently, three approaches are approved as first-line treatment for EGFR-mutant NSCLC:
- Osimertinib (a TKI) as a single drug
- Osimertinib plus chemotherapy
- Amivantamab (a bispecific antibody) plus lazertinib (a TKI)
While the combination approaches are stronger, acquired resistance is seen with all three treatment approaches. Treatment options beyond the first line are also being explored. At AACR25, results from a phase 1 clinical trial with SYS6010, a novel EGFR targeting antibody drug conjugate (ADC) looked promising in treating lung cancers that have stopped responding to currently available treatments.
Another important presentation focused on leptomeningeal disease (LMD) – the spread of cancer cells to the cerebrospinal fluid and leptomeninges, membranes that surround the brain. It is unclear whether available EGFR TKIs impact LMD. Results from the global THRILLS-NSCLC study showed that approximately 4.6% of patients with EGFR-mutant NSCLC develop LMD but using highly brain penetrant TKIs or brain radiation improves LMD outcomes.
Along with developing new treatment options, it is important to understand which patients will benefit from treatments. Detection of EGFR mutations from blood samples before starting EGFR drugs is prognostic of clinical outcomes i.e. patients whose blood had higher levels of mutant EGFR tumor DNA had worse treatment outcomes.
HER2 Mutations
This is a rapidly evolving space. Currently, trastuzumab deruxtecan, an antibody-drug conjugate (ADC) targeting HER2, is the only treatment approved for NSCLC with HER2 mutations that has received prior chemo-immunotherapy.
Zongertinib, a TKI, seems to be effective in controlling cancer growth in patients who have never received an ADC or those whose tumors have grown after an ADC treatment. It is currently being considered for approval by the United States Food and Drug Administration (FDA).
In addition to zongertinib, other HER2 targeting drugs such as SHR-A1811 (an ADC) were also discussed at AACR. Of course, what remains to be seen is how HER2-directed ADCs line up against HER2 TKIs in the treatment of HER2-positive NSCLC.
KRAS Mutations
Currently available KRAS-targeting drugs, sotorasib and adagrasib, work against KRAS G12C mutations, a specific type of KRAS mutation. We are moving beyond KRAS G12C to target other KRAS mutations. This is important because KRAS mutations are seen in 30% of NSCLC and KRAS G12C is a subset of these mutations.
An ongoing phase 1 trial of zoldonrasib (RMC-9805), an oral KRAS G12D inhibitor, suggests that this drug may be active against KRAS G12D-positive NSCLC. Another approach that is moving forward is a group of drugs called pan-KRAS inhibitors—drugs that target all types of KRAS mutations. One such drug is AMG410. It can be administered orally and does not affect wild-type, or “normal,” KRAS protein signaling. The first phase 1 clinical trial with this drug is being planned.
ROS1 Fusions
Currently approved ROS1 drugs come with neurological side effects because these drugs may also block the TRK protein necessary for brain function. A new third-generation TKI, JYP0322, seems to spare the TRK protein and therefore may come with less side effects. As further results with this drug are awaited, it’s important to note that this drug works in patients whose cancers have progressed on prior ROS1 TKIs.
3) Moving the needle in treatment and treatment monitoring in small cell lung cancer (SCLC)
Small cell lung cancer comprises 15% of all diagnosed lung cancer. Patients diagnosed with limited-stage SCLC (LS-SCLC), or extensive-stage SCLC (ES-SCLC), receive some form of chemo-immunotherapy as the first treatment. We are seeing advances in both the technologies and the treatments being developed for this disease.
With current technology, we can only identify how patients with SCLC respond to chemo-immunotherapy by scanning them to detect cancer growth. Researchers at the National Cancer Institute have developed a blood test that can:
- Measure SCLC tumor DNA fraction (i.e. how much SCLC tumor DNA is in the blood.) Patients with a high tumor DNA fraction seem to have worse outcomes
- Measure blood immune cells that can predict response to immunotherapy. Patients whose blood have a higher level of immunosuppressive cells do not respond as well to immunotherapy
While still preliminary, such a test can revolutionize how we monitor patients receiving treatment. An important component of precision medicine is the ability to identify which patients will benefit from a treatment and then tailor the treatment accordingly.
We have used a one-size-fits-all approach for treating SCLC in the past, but this is now changing. SCLC is now known to consist of various subtypes rather than a single type of tumor cell. The best-known subtypes—which may respond to treatment differently—are:
- SCLC-A
- SCLC-N
- SCLC-P
- SCLC-I
Recently, a biomarker test that can identify the subtypes of SCLC in patient samples had been developed. This test is now being deployed as part of a clinical trial (SWOG 2409) where patients will be matched to a customized treatment based on their tumor subtype.
On the treatment side, we are exploring innovative modalities to treat SCLC. A new radioligand therapy using actinium-225 that targets the DLL3 protein on the surface of SCLC cells is now in clinical trials for patients with ES-SCLC. This approach is interesting because it exploits two characteristics of SCLC: it is very responsive to radiation, and it makes a high level of DLL3 protein. This type of treatment approach can “personalize” radiation and ensure it is only delivered to cancer cells.
4) Improving our understanding of which patients require aggressive treatment for early-stage NSCLC
Depending on the size and location of the tumor and a person’s overall health, early-stage NSCLC is commonly treated with surgery. However, over the past three years, the FDA has approved three new approaches as part of this early-stage treatment paradigm:
- Neoadjuvant treatment before surgery with an immunotherapy-chemotherapy combination or a targeted therapy
- Adjuvant treatment after surgery with an immunotherapy-chemotherapy combination
- Combination of both neoadjuvant and adjuvant therapy
While adding these treatments has improved the outcomes of early-stage NSCLC as compared to surgery alone, we are still learning which patients require these additional treatments.
New technology discussed at AACR25 suggests that the level of ctDNA in a patient’s blood at the time of surgery may predict which patients will have worse outcomes and therefore may require more aggressive therapy. Not only did patients with high “pre-surgery” ctDNA have worse outcomes, but the levels of pre-surgery ctDNA could predict where the cancer would recur (within the lung, outside the lung but excluding the brain, or in the brain). The data also showed “post-surgery” ctDNA predicted which patients may benefit from additional adjuvant treatment.
As such tests to detect minimal residual disease in early-stage lung cancer become more refined, they will be increasingly used to decide which patients require additional treatment versus surgery alone.
5) Harnessing artificial intelligence for predictive drug development and treatment planning
Artificial intelligence (or AI) seems to be popping up everywhere, and the field of cancer research is no exception. Researchers are leveraging AI to screen drugs, starting with over a million compounds and narrowing it down to just five drugs of interest to prevent progression and metastasis of early-stage lung adenocarcinoma.
Other emerging uses of AI include using patient data to predict the likelihood of a patient having cachexia, a metabolic syndrome characterized by severe fatigue and weight loss, and the development of a non-invasive liquid biopsy to accurately identify lung cancer subtypes in tumors with mixed histology. Researchers are using AI to speed their searches for optimal biomarkers and drug compounds allowing them to quickly narrow the field of potential options, but they are also carefully testing their approaches with tried-and-true methods to ensure the effectiveness of the results and the safety of the patients.
6) Survivorship is now becoming part of the entire conversation
Traditionally, AACR has been very focused on technology and treatment. As treatments are improving and people are living longer and better lives with advanced cancer, it was great to see a session dedicated to survivorship at this year’s meeting. Currently, more people are living with advanced lung cancer than with advanced breast, colon or prostate cancers.
Jill Feldman, patient advocate and co-founder of the EGFR Resisters, reminded all researchers that living longer due to new drugs is not the same as living well on new drugs. While several new treatments offer longer survival benefits, they often come with a higher side effect burden that may have a significant impact on a person’s quality of life. New survivorship interventions are being developed to address these needs.
Thank you for joining LUNGevity for our coverage of AACR25. Researchers are hard at work bringing us the next generation of technologies and therapies. Some of their incredible work will be discussed at the upcoming American Society of Clinical Oncology (ASCO) meeting. You can join LUNGevity on X/Twitter for live coverage of the ASCO25 meeting. As always, LUNGevity will bring you an article highlighting the key takeaways from the meeting.
Deeper Reading: