This year, the first three weeks of September were packed with lung cancer research updates at the World Conference on Lung Cancer (WCLC) from September 7-10 in San Diego followed by the European Society for Medical Oncology (ESMO) conference from September 13-17 in Barcelona.
We wish we could have cloned ourselves and been in both places; however, we were able to attend WCLC in person and ESMO virtually. It’s impossible to condense so much lung cancer science into a single blog, so this year we're sharing four conference updates. Be prepared! You will see the names of lots of new drugs!
This blog is the first in the series and will focus on metastatic non-small cell lung cancer (NSCLC). Stage IIIC and stage V NSCLC are considered metastatic and are treated based on the absence or presence of targetable biomarkers. If the cancer does not have a targetable biomarker, it's treated with some form of immunotherapy.
You can read the other update blogs from these fall science meetings:
- Early-Stage and Locally Advanced NSCLC
- Small Cell Lung Cancer Highlights
- Screening and Early Detection
What’s New in Immunotherapy?
Immunotherapy with drugs called checkpoint inhibitors is the mainstay of the first treatment (also referred to as first-line treatment) for metastatic NSCLC that does not have targetable biomarkers.
FDA-approved checkpoint inhibitors block the PD-L1 protein on cancer cells, or the PD-1 or CTLA-4 protein on immune T cells. Currently, either one immunotherapy or a combination of immunotherapy and chemotherapy is used to treat metastatic NSCLC. These treatments sometimes do not work for people with lung cancer; therefore, new treatment options are needed. Several new drugs are looking promising in clinical trials:
Bispecific antibodies are a new type of immunotherapy with a single antibody that can bind to two target proteins (antigens). This two-pronged approach makes for a powerful drug.
- Ivonescimab for metastatic NSCLC that makes high amounts of the PD-L1 protein.
- The drug blocks the PD-1 protein on T cells and a protein called VEGF found in the tumor.
- Rilvegostomig for metastatic NSCLC that makes high amounts of the PD-L1 protein
- The drug blocks the PD-1 protein and the TIGIT protein.
- Volrustomig + chemotherapy
- Volrustomig blocks the PD-1 and CTLA-4 proteins on the immune T-cell.
Other approaches being tested include:
- Belrestotug + dostarlimab for metastatic NSCLC that makes high amounts of the PD-L1 protein
- Belrestotug blocks a protein called TIGIT, while dostarlimab blocks PD-1 on T cells. Dostarlimab is already approved for treating some cancers.
- Relatlimab + nivolumab + chemotherapy
- Relatlimab blocks a protein called LAG3 on immune T cells and reenergizes the cells. Nivolumab blocks the PD-1 protein on T cells and is already approved to treat metastatic NSCLC.
What About Options for People Whose Cancers Respond to Immunotherapy But Then Come Back?
This is an area of intense research. Several new approaches are being tested in clinical trials:
- Viral immunotherapies like CAN-2409 that can be directly injected into the cancer.
- Nogapendekin alfa inbakicept, which activates natural killer cells, a type of immune cell. This drug was approved for non-muscle invasive bladder cancer in 2024.
What About NSCLC With a Targetable Biomarker?
If the cancer has a targetable biomarker, it is treated with a targeted therapy. Targeted therapies can be a pill, a combination of pills, or given as an infusion in the clinic.
ALK-Positive Lung Cancer
Currently, lorlatinib or alectinib is the preferred first treatment option for ALK-positive lung cancer. The cancer can become resistant to these treatments by developing new ALK mutations. NVL-655, a fourth-generation ALK tyrosine kinase inhibitor, blocks ALK mutations seen in lorlatinib-resistant NSCLC. This drug also crosses the blood-brain barrier and can treat brain metastasis. Of note, NVL-655 seems to have fewer neurological side effects.
BRAF-Positive Lung Cancer
Longer patient follow-up from the encorafenib and binimetinib combination clinical trial for BRAF V600E-positive NSCLC shows that this combination is effective in sustained cancer control. This combination was approved by the FDA in 2023.
EGFR-Positive Lung Cancer
There is definitely lots of excitement in this space with two new treatment approaches recently approved as the first-line treatment—osimertinib plus chemotherapy (based on the FLAURA2 trial) and amivantamab plus lazertinib (based on the MARIPOSA trial).
Before these new approaches, osimertinib as a single drug was used to treat EGFR-mutant lung cancer. There were lots of discussions about which is the best option: osimertinib alone, the FLAURA2 approach, or the MARIPOSA approach. Depending on whether the cancer has other “co-mutations” that were detected when the tumor was tested for biomarkers or whether the person was diagnosed with brain metastases, different approaches may be appropriate. Each of these approaches comes with unique side effects. These need to be discussed with patients so that their preferences can be taken into account when making a treatment choice. Other drugs such as rilertinib are being developed as first-line treatment options for EGFR-positive lung cancer.
Moving beyond tyrosine kinase inhibitors, a new bispecific antibody (PM8002/BNT327) that blocks the PD-L1 protein and the VEGF protein (which helps cancer cells grow blood vessels and receive nourishment from the blood) is effective in shrinking tumors when combined with chemotherapy, especially in patients whose tumors have stopped responding to EGFR tyrosine kinase inhibitors.
It is important to note that not all EGFR mutations are the same. A group of EGFR mutations called PACC mutations don’t respond to osimertinib. New research suggests that these mutations may be treated with firmonertinib, which is already approved in China. Similarly, EGFR exon20 mutations are unique and are typically treated with amivantamab. A new tyrosine kinase inhibitor, zipalertinib, seems to work in controlling NSCLC that has stopped responding to amivantamab.
HER2-Positive Lung Cancer
There are some very important developments in this space! Two new drugs targeting HER2 mutations, BAY2927088 and zongertinib, are showing promise in treating NSCLC that has previously been treated with other drugs. Zongertinib also seems to be active in treating brain metastasis. Both these drugs are taken as pills. Studies testing whether they can be used as first-line treatment are ongoing.
KRAS-Positive Lung Cancer
NSCLC with KRAS G12C mutations is typically treated with some form of immunotherapy as the first treatment option. If the cancer returns, two drugs, adagrasib and sotorasib, are available. Research is now addressing whether we can move KRAS G12C-blocking drugs into the first-line setting. Combining a new KRAS G12C-blocking drug, olomorasib, with immunotherapy and chemotherapy as the first treatment option is showing promise. Other KRAS G12C-blocking drugs, such as divarasib and D3S-00, are being tested as additional options. Lastly, drugs targeting other KRAS mutations, such as KRAS G12D (ASP3082), are being developed.
ROS1-Positive Lung Cancer
Zidesamtinib is a tyrosine kinase inhibitor that penetrates the brain and is effective against brain metastasis. New data suggest it works in controlling tumors that have stopped responding to current ROS1 cancer drugs. Another drug, talrectinib, also seems to be effective in controlling ROS1-positive lung cancer in people who have not received any treatment as well as those who have received prior tyrosine kinase inhibitor treatment.
If you have NSCLC with a known biomarker, make sure to visit the LUNGevity Patient Gateways to get information specific to your type of lung cancer.
Where Do Antibody-Drug Conjugates (ADCs) Fit In?
No conference update is now complete without a mention of ADCs. They are a new group of medicines made up of a monoclonal antibody chemically linked to a drug. The monoclonal antibody binds to specific proteins or receptors found on certain types of cells, including cancer cells. The linked drug enters these cells and kills them without harming other cells. An ADC, trastuzumab deruxtecan, is currently approved for HER2-positive lung cancer. Other ADCs that target specific biomarkers, such as MET or HER3, and those targeting proteins, such as TROP2, continue to move forward in clinical development.
If you weren’t able to join us for the International Lung Cancer Survivorship Conference on September 20-21, you can still watch the recordings by registering here. There is a lot of great information for people living with metastatic NSCLC.