Highlights of AACR 2024: Where the Laboratory Meets the Patient

Upal Basu Roy, PhD, MPH
Title of article with research-related photos

Read time: 7 minutes

It’s spring! The daffodils bloom, the days become longer, and I attend the annual meeting of the American Association for Cancer Research (AACR). For those of you who are new to this meeting, it is the largest gathering of laboratory scientists and clinicians in the world—coming together to discuss how to take science from the bench (laboratory) to patients and communities. This year’s meeting was held in sunny San Diego and brought together more than 23,000 attendees. Below I summarize key meeting highlights that are of interest to the lung cancer community. 

Lung Cancer in People Without Tobacco Exposure

Also referred to as lung cancer in never-smokers (LCINS). This year, an entire session was focused on this topic, which goes to show that the topic is top-of-mind for scientists and doctors alike. Women without tobacco exposure are twice as likely to develop lung cancer as compared to men without tobacco exposure. Most LCINS tend to be adenocarcinomas—a type of non-small cell lung cancer (NSCLC).

Data presented at the meeting discussed how LCINS in those of Asian ancestry and those of European/Caucasian ancestry tend to be different. Tumors from people of European/Caucasian ancestry tend to have more KRAS mutations, whereas mutations in the EGFR and the TP53 genes seem to be more common in tumors from patients of Asian ancestry. These findings are important because they help guide treatment decisions.

In addition, an analysis of lung cancer risk factors in 10 highly populated countries showed that air pollution is a major risk factor for LCINS in China, India, Pakistan, and Nigeria. The researchers noted that policy-level changes are required in these countries to help address this increasing risk factor of lung cancer.   

The discussions about whether lung cancer screening should be offered to individuals without tobacco exposure are still ongoing. Some studies show the benefit of screening in certain specific populations like Asian women without tobacco exposure.  

Small Cell Lung Cancer

We are rethinking our understanding of small cell lung cancer (SCLC). Traditionally, SCLC was considered a tumor that was only caused by tobacco exposure. More recent research indicates that there are three types of SCLC: classical SCLC (associated with tobacco exposure and seen in older adults), atypical SCLC (seen in younger people without tobacco exposure), and a third category—histologically transformed SCLC. As the name indicates, this type of SCLC develops when adenocarcinoma cells with a targetable biomarker “transform” into SCLC after treatment with targeted therapies. Why does this matter? Each of these types of SCLC has distinct molecular profiles that help doctors decide what treatment to select. 

Speaking of treatment, immunotherapy (in combination with chemotherapy) is the mainstay of treatment for newly diagnosed extensive-stage SCLC. If the immunotherapy-chemotherapy combination stops working, a new drug, lurbinectedin, is sometimes prescribed. Recent data shows that lurbinectedin can make immunotherapy more effective in SCLC cells. This is very exciting because this finding has the potential to increase the effectiveness of immunotherapy in SCLC.  

EGFR+ Non-Small Cell Lung Cancer

Mutations in the EGFR gene in lung cancer were first documented in 2004. While we have come a long way with treatment options for newly diagnosed EGFR+ NSCLC, patients are at risk of recurrence because the cancer cells can become resistant to treatment. This makes improved treatment options a clear need for the EGFR community.

A new brain-penetrating drug called BDTX-1535 seems to work well in EGFR+ NSCLC that has become resistant to osimertinib (the preferred drug for newly diagnosed EGFR+ NSCLC). BDTX-1535 may be effective on mutations like C797S and other “non-classical” EGFR mutations that help cells escape the effects of osimertinib. A phase 1 clinical trial is ongoing.  

A new treatment combination (osimertinib + chemotherapy in the FLAURA2 trial) was recently approved as a first-line treatment option for EGFR+ NSCLC. Now, a blood test looking at EGFR mutations in circulating tumor DNA (ctDNA) can predict whether a patient will benefit from this treatment combination. Those who have a high level of ctDNA in their blood may get more benefit from this combination. This is great news because now we may have a way to determine if a patient needs osimertinib alone or the osimertinib-chemotherapy combination.  

KRAS+ Non-Small Cell Lung Cancer

With two FDA-approved drugs, adagrasib and sotorasib, that block the effects of the KRAS G12C mutation in NSCLC, researchers are expanding to target other KRAS mutations (such as KRAS G12D) or other parts of the KRAS signaling pathway. RMC-9805, a KRAS G12D targeting drug, seems promising in phase 1 trials. NMF-006 is a drug targeting the GSTP protein in the KRAS pathway. NMF-006 is being tested in patients whose tumors have different types of KRAS mutations.  

Of course, scientists are also studying how cancer cells escape the effects of adagrasib and sotorasib. Research shows mutations in the KEAP1 and the STK11 genes and a high NRF2 signature predicts response to adagrasib. This finding is exciting because these co-occurring mutations can be tested using currently available biomarker tests and need to be considered when monitoring treatment response.  

Other Oncogene-Driven Non-Small Cell Lung Cancer: ALK+

NSCLC is treated with tyrosine kinase inhibitors. New research shows that a specific type of immune cells, CD8 positive T-cells, are required for these tyrosine kinase inhibitors to work effectively. CD8 positive T-cells are the most powerful effectors in the anticancer immune response. This finding unlocks ways to harness the immune response in the treatment of ALK+ NSCLC that we have not previously explored. We are also learning that changes in the MET gene (MET amplifications) are important in driving resistance in ALK+ and in RET+ NSCLC. MET-blocking drugs are now entering the “what’s next” for these oncogene-driven types of NSCLC.  

Making Immunotherapy More Effective in Advanced NSCLC

Immunotherapy is an important component of the treatment of newly diagnosed NSCLC without actionable oncogenic driver mutations. However, currently available immunotherapies are effective in 20-25% of patients. Scientists are therefore focused on making immunotherapy more effective. A new off-the-shelf (ready-to-use) cancer vaccine PDC*lung01 in combination with immunotherapy is looking promising in a Phase 2 trial of newly diagnosed NSCLC. Though the number of patients enrolled in the trial is small, this is a reminder that lung cancer vaccines will soon become part of the treatment arsenal.  

Identifying Which Patients With Advanced NSCLC Will Respond to Immunotherapy:

Around 50% of patients develop major side effects from immunotherapy. Researchers shared the results of a new test that looks at proteins in the blood to predict the clinical benefits of immunotherapy. This is a real gamechanger because, in the future, it may be used to identify which patients will develop side effects. Doctors may also be able to use it to monitor side effects proactively and decide if treatment needs to be changed. 

Similarly, researchers are looking at ctDNA-based blood tests to predict which patients may benefit from immunotherapy. We need to integrate such liquid biopsies to understand the extent and spread of cancer and predict which patients will benefit from immunotherapy. Right now, we depend on scans to catch cancer growth, which may not detect changes in the cancer early enough.  

Moving to tumor tissue itself, looking at the number of chromosomes in a tumor can provide a preview of what to expect when a patient receives immunotherapy. Normal cells have 46 chromosomes. Tumor cells are often aneuploid, i.e. they may have extra or missing chromosomes. Tumors with a high degree of aneuploidy are less likely to respond to immunotherapy. Adding radiation to tumors with high levels of aneuploidy may improve the effectiveness of immunotherapy. To sum it up, this is very important information to know because tumor sequencing as part of routine biomarker testing can also help a clinician understand the degree of aneuploidy in the tumor and decide if a patient will benefit from immunotherapy.  

It's hard to do justice to five days of awesome science in a short blog. But that’s a good problem to have. Please stay tuned for our next conference update—ASCO 2024, which is being held in June.  

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