ASCO 2023: Progress for Metastatic (Stage 4) Non-Small Cell Lung Cancer

By Andrew Ciupek, PhD, Associate Director, Clinical Research, GO2 for Lung Cancer

New research on metastatic (stage 4) non-small cell lung cancer (NSCLC) was a hot topic at the 2023 American Society of Clinical Oncology (ASCO) meeting. Data from several studies was shared, including new developments for both people living with NSCLC with driver mutations (like ALK, EGFR, and more) and those without.  

Targeted therapy 

Targeted therapies are aimed at a certain “target” in cancer cells. Their goal is to stop the change (driver mutation) that is making the cancer grow. We learned about promising new information from targeted therapy trials focused on several different driver mutations. 

EGFR 

New targeted therapies 

About 30% of people with NSCLC have an EGFR mutation. New targeted therapies can help greatly increase survival for this large part of the lung cancer community.   

• The EVEREST trial demonstrated that the newer EGFR targeted therapy Zorifertinib (AZD3759) was more effective as a first treatment for EGFR+ NSCLC with brain metastasis then the already approved EGFR targeted therapies Iressa (gefitinib) and Tarceva (erlotinib). 
• The WU-KONG6 trial showed promising data that some NSCLC with an EGFR exon 20 mutation may respond to the newer targeted therapy Sunvozertinib (DZD9008) after progression on other therapies. 

Resistance to targeted therapy 

For many people with EGFR-positive (EGFR+) NSCLC, resistance, where the cancer starts to grow or spread again while still being treated with a targeted therapy, is an issue. Researchers are focused on new approaches to deal with resistance. 

• The Keynote-789 study showed that giving the immunotherapy Keytruda (pembrolizumab) with chemotherapy was not any better at treating targeted therapy resistant EGFR+ lung cancer than chemotherapy alone. This finding suggests most people with EGFR+ NSCLC benefit less from immunotherapy than people with other types of lung cancer. 
• Early data from the SYMPHONY study showed that some people with EGFR+ NSCLC that had developed resistance to other EGFR targeted therapies may respond to the new EGFR targeted therapy called BLU-945. 

KRAS 

For decades, it was thought that the KRAS mutation could not be targeted. The first targeted therapy for KRAS, Lumakras (sotorasib), was approved in 2021 with a second approval, Krazati (adagrasib), just last year. Researchers are hard at work to unlock more targeted therapy options for people with KRAS positive lung cancer. 

• The SCARLET trial showed early signs that the already approved Lumakras (sotorasib) and chemotherapy together could be a promising therapy for people with NSCLC with a KRAS G12C mutation. 
• The CodeBreaK 200 trial showed that the KRAS G12C targeted therapy Lumakras (sotorasib) had promising effectiveness in treating brain metastasis (cancer that has spread to the brain). 
• The KontRASt-02 study showed early data that the new KRAS G12C inhibitor, JDQ443, may have promising activity in KRAS G12C-positive NSCLC that had previously been treated with chemotherapy and immunotherapy. 

ROS1 

ROS1 is a less common genetic mutation that affects 1-2% of people with non-small cell lung cancer. New targeted therapies have helped improve the prognosis of ROS1 lung cancer in recent years. 

• The TRIDENT-1 trial is looking at the new ROS-1 targeted therapy repotrectinib, which indicated it may have promising activity when treating ROS-1+ NSCLC, even with brain metastasis. 

BRAF  

BRAF is another less common genetic mutation that affects 1-2% of people with non-small cell lung cancer. Historically, chemotherapy had limited efficacy on people with a BRAF mutation. Targeted therapy has become the standard of treatment with new research continuing to improve outcomes.   

• The PHAROS trial showed that a combination of the BRAF targeted therapy encorafenib and the MEK targeted therapy Mekinist (trametinib) showed positive results in treating NSCLC with a BRAF V600E mutation, especially as a first treatment. This may represent a new, additional treatment option for this type of lung cancer. 

Immunotherapy 

Immunotherapy is a type of cancer treatment that helps the body’s own immune system find and attack cancer cells. There is ongoing research to better understand which people respond well to immunotherapy and if there is any way to predict their response—like combining immunotherapy with other types of treatment. 

• In the CHOICE-01 trial, a newer immunotherapy called toripalimab showed promising results when given together with chemotherapy as a first treatment for NSCLC without EGFR or ALK mutations. This may represent an additional immunotherapy-based option for these people with lung cancer. 

Non-biomarker specific treatment 

We also saw research presented looking at new options to treat NSCLC that do not require a specific biomarker or mutation to be present.  

• The TROPION-Lung02 trial showed that Dato-DXd (datopotamab deruxtecan), a new type of cancer treatment called an antibody drug conjugate (ADC), given with immunotherapy and chemotherapy, had promising results as both a first treatment for NSCLC and after progression on other treatments. 
• The Lunar trial showed a new type of cancer therapy called tumor-treating fields, which are electrical fields believed to disrupt cancer cell growth given through a device worn by patients. Tumor-treating fields given with other standard treatments improved outcomes specifically in people with NSCLC that had received chemotherapy by itself as a first treatment.