Presentations by MSK researchers at the 2024 annual meeting of the American Society of Clinical Oncology revealed encouraging clinical trial results and promise of a more sensitive “liquid biopsy,” all of which could improve lung cancer treatment.
Researchers from Memorial Sloan Kettering Cancer Center (MSK) reported important advances in the treatment of lung cancer at the June 2024 annual meeting of the American Society of Clinical Oncology (ASCO). Scientists presented promising results from two clinical trials that are testing combination therapies to treat lung cancer at different stages. Another presentation revealed the potential of using circulating tumor DNA (ctDNA) in the blood — known as a liquid biopsy — to detect lung cancer cells lingering after surgery.
Combination Therapy Effective as First-Line Treatment for Non-Small Cell Lung Cancers
Sotorasib (Lumakras™) is a targeted drug designed to treat non-small cell lung cancers driven by a mutation called KRAS-G12C. The drug was approved in 2021 by the U.S. Food and Drug Administration for treating advanced disease. The approval was based on results from a clinical trial called CodeBreaK100, co-led by MSK lung cancer expert Bob Li, MD.
MSK played a major role in the development of sotorasib and other drugs targeting KRAS, which is responsible for about one-quarter of lung cancers. Researchers now are trying to build on this success by testing sotorasib earlier in the disease course, combining it with other treatments.
Dr. Bob Li
Dr. Li presented results from a new clinical trial, CodeBreaK101, suggesting that sotorasib shows great potential as a first-line treatment for certain lung cancer patients when it is combined with the chemotherapy drugs carboplatin and pemetrexed.
Most people responded to the drug combination — meaning their tumor shrank or disappeared — and the treatment appeared to be safe.
“We urgently need better first-line treatments for people with KRAS-G12C mutations, and using sotorasib as part of a combination could be the answer,” says Dr. Li, who led the phase 1B international trial.
The study tested the drug combination in 58 patients with KRAS-G12C-mutated non-small cell lung cancer. The patients had received either no treatment or two or more previous other treatments before receiving the drugs.
- In the 37 first-line patients, 65% responded to the drug. The disease was controlled in 100% of patients, with a median progression-free survival (meaning the disease did not get worse) of nearly 11 months.
- In the 21 previously treated patients, 42% responded to the drug, and the disease was controlled in 84% of patients.
The main side effects, such as low white blood cell counts, were similar to side effects seen in patients taking chemotherapy drugs.
Dr. Li says the lasting results in the first-line treatment setting were especially encouraging.
“The mutated KRAS protein was considered to be undruggable for decades, and the development of sotorasib and other KRAS-G12C inhibitors has been a major milestone in treating non-small cell lung cancer patients,” Dr. Li says. “Now we are seeing real promise in developing a new first-line treatment for patients by expanding international clinical trials.”
This study was funded by Amgen Inc.
Drug Combination Shows Promise in Lung Cancer That Has Spread to the Brain and Spinal Cord
Many non-small cell lung cancers are driven by mutations in a gene called EGFR. Drugs targeting these cancers can be effective at keeping the disease controlled. Unfortunately, many EGFR-mutated lung cancers eventually spread to the brain or the tissue that lines the brain and spinal cord (the leptomeninges).
Although more than 50% of people with metastatic EGFR-mutated lung cancers have the disease spread to these sites, they are often excluded from clinical trials testing new EGFR-targeting drugs. This prevents them from possibly benefiting from new treatments, especially when the cancer develops resistance to existing EGFR-targeting therapies.
Dr. Helena Yu
MSK medical oncologist and lung cancer specialist Helena A. Yu, MD, is now leading the first clinical trial testing a new therapy in this patient group. Patients in the phase 2 study have EGFR-mutated lung cancer that has spread to the brain or spinal cord and has developed resistance to earlier therapies.
The trial tested a combination of two new targeted therapies, amivantamab (Rybrevant®) and lazertinib (Leclaza®) in 42 patients being treated at MSK. The patients were split into two groups — 20 had brain metastases, and 22 had leptomeningeal metastases. Results showed the drug combination is effective:
- 30% of brain metastases patients and 33% of leptomeningeal metastases patients showed a response to the drug — meaning the tumors shrank — in cancer outside the brain and spinal cord;
- 40% of brain metastases patients showed a response to cancer within the brain.
- Patients with brain metastases and leptomeningeal disease remained on the treatment for a median of 6 months and 8.3 months, respectively — long enough to see a benefit against the cancer.
There were no serious side effects, which had been a concern in a potentially higher-risk population with cancer in the central nervous system.
“These results suggest that this drug combination is a promising treatment for these patients with metastatic disease to the brain and leptomeninges after first-line therapy stops working,” Dr. Yu says. “It also shows the importance of including people with brain metastases and leptomeningeal disease in clinical trials, as they can clearly benefit from new treatments.”
This study was funded by Janssen Oncology.
A More Powerful Liquid Biopsy To Detect Minimal Residual Disease in Early-Stage Non-Small Cell Lung Cancer
Early-stage non-small cell lung cancer can be effectively treated with surgery, but sometimes stray cancer cells remain in the body. This is known as minimal residual disease (MRD), and it can lead to cancer recurrence. But doctors don’t know which patients have MRD and can only monitor them closely with CT scans for evidence that the disease has returned.
One potential way to detect the presence of these lingering cancer cells is to look for circulating tumor DNA (ctDNA), small fragments of DNA shed by cancer cells into the bloodstream. A form of “liquid biopsy,” these noninvasive tests look for ctDNA that contains genetic information specific to the tumor.
Dr. James Isbell
Liquid biopsies are already commonly used in the treatment of stage 4 lung cancers, which produce high levels of ctDNA. These ctDNA tests, or assays, can detect the presence of cancer by identifying genetic variants that are associated with human cancer and distinct from the genetic makeup of a person’s normal DNA.
Early-stage lung cancers, however, do not shed much DNA. This makes it very difficult to detect DNA fragments from cancer cells in early-stage disease — especially against the background of vast amounts of circulating DNA shed by normal cells.
“We urgently need a way to find the needle in the haystack, to pinpoint the ctDNA and differentiate it from the normal DNA in early-stage patients,” says MSK thoracic surgeon James M. Isbell, MD.
At ASCO, Dr. Isbell presented results from a study showing that a new experimental assay called PhasED-Seq is far more sensitive than current tests. The PhasED-Seq technology analyzes the entire cancer cell genome, looking for multiple genetic variants on the same fragment of ctDNA. This greatly increases the power of the test, enabling it to conclusively identify cancer DNA even in the tiniest amounts.
“This new assay increases the sensitivity a hundredfold, from 100 parts per million to 1 part per million,” Dr. Isbell says.
The research team studied the ctDNA of 46 MSK stage 1 to stage 3 lung cancer patients using both assay types. The PhasED-Seq test found MRD in twice as many patients (12) as the conventional test did (6). And the detection of MRD appeared to be valid for predicting recurrence — all 12 PhasED-Seq patients had their cancer return.
“The more sensitive PhasED-Seq can provide critical information about whether MRD is present, helping doctors make better-informed treatment decisions,” Dr. Isbell says. “Patients in whom MRD is detected after surgical removal of the primary cancer may benefit from additional therapies, such as chemotherapy and immunotherapy, to reduce the risk their cancer will return.”
In the short term, PhasED-Seq will likely be used in clinical trials to validate whether it reliably identifies patients whose cancer will recur. If so, it could receive approval for widespread clinical use.
“This research could not be done without the overwhelming support of our patients and the MSK multidisciplinary lung cancer team, not to mention the extensive collaboration my colleague Dr. Bob Li and I have had with Dr. Maximilian Diehn and his colleagues at Stanford over the past several years,” Dr. Isbell says.
The PhasED-Seq technology was developed by Foresight Diagnostics.
