Dr Konstantinos Leventakos: Identification of Biomarkers in SCLC Is Crucial

For some patients with lung cancer, targeted therapies are common; but for patients with small cell lung cancer (SCLC) identifying biomarkers to predict treatment response remains an urgent need, explained Konstantinos Leventakos, MD, PhD, assistant professor of oncology and medicine, Mayo Clinic, Rochester, Minnesota.

In an interview with The American Journal of Managed Care^® (AJMC^®), Leventakos discussed diagnosis of SCLC and what impact the identification of biomarkers could have for patients.

AJMC: How is SCLC typically diagnosed and what are some of the most used diagnostic tools and imaging modalities?

Leventakos: Small cell lung cancer is diagnosed through the pathologic examination of biopsy material after sampling a lung lesion on the metastatic area. Initially, the diagnosis of a lung mass is usually done after the patient has been found to have a lung mass or areas of known metastasis. Many times the workup starts because the patient has symptoms. Usually, the diagnosed workup could include a CT or an x-ray.

Proper diagnosis of small cell lung cancer is done with bronchoscopic or ultrasound-guided biopsy in order to have proper staging of the disease. Staging is done by full body imaging that may include CT of the chest, abdomen, pelvis, or PET CT and an MRI of the brain.

Interestingly, a recent retrospective analysis from a single institution, Henry Ford Cancer Institute, suggested that small cell lung cancers diagnosed through the lung cancer screening program had better overall survival rates than those diagnosed clinically. This is a call for action to improve the implementation of lung cancer screening programs.

AJMC: Can you discuss any specific biomarkers that have been shown to be predictive of response to targeted therapies in SCLC, and how do you use this information to guide treatment decisions?

Leventakos: In contrast to other types of lung cancer where targeted therapies are very common for patients, in small cell lung cancer, biomarkers predicting response to therapy are still urgently needed. The initial treatment of small cell lung cancer is a combination of chemotherapy and immunotherapy for the patient who can tolerate that since there are no specific biomarkers. Multiple groups have suggested that SLFN11 expression is a potential biomarker of sensitivity of both DNA-damaging chemotherapy and PARP inhibition.

Expression of PD-L1 on a tumor cell has been shown to be correlated for efficacy of immunotherapy in many solid tumors. However, this is a biomarker that has not clinically helped in the treatment of small cell lung cancer since it has a lot of variation in prevalence, heterogeneous expression in small cell lung cancer, and unclear correlation with between the PD-L1 expression and the results of immunotherapy. Some immunotherapy studies showed that high tumor mutation burden has been associated with improved overall response rate, overall survival, and progression-free survival. Still, in everyday clinical practice, it is suggested that immunotherapy is given despite expression of immunotherapy markers.

As a conclusion, ongoing research for identification of biomarkers will be critical in the next years. It is of note to suggest that there is a lot of research on the subtypes of small cell lung cancer based on RNA sequencing rather than DNA sequencing. There have been transcriptomic subtypes described that may be the future biomarkers. One of them actually has been associated with better outcomes with immunotherapy.

AJMC: Can you discuss any challenges or limitations associated with using biomarkers to guide treatment decisions in SCLC and how would you address these challenges?

Leventakos: One of the challenges with the limitations of biomarkers is that currently we do not have results of clinical trials that provide strong evidence for use of specific targeted treatments. Most recently at the 2023 American Society of Clinical Oncology annual meeting, we showed the results of the study SWOG S1929. In this study, 79% of the patients had evaluable tissue where SLFN11 was positive. And 106 patients were randomized. The study evaluated the addition of PARP inhibitor (talazoparib) to standard of care maintenance immunotherapy (atezolizumab) following frontline chemoimmunotherapy.

There was some overall benefit in progression-free survival but not overall survival. This study demonstrated the feasibility of conducting biomarker selected trials in small cell lung cancer, showing the way for future evaluation of novel therapies in selected small cell lung cancer populations.

AJMC: How do you see the role of biomarkers evolving in the management of small cell lung cancer in the coming years?

Leventakos: Small cell lung cancer is an area of active research and most recently the subtypes of small cell lung cancer based on transcriptomic analysis are better defined. We expect to develop clinical trials specifically for each subtype. Other notable targets of interest include: when it comes to immunotherapy, CD47, PTIP, DLL3; for DNA damage response, PARP, WEE1, and CDK7; epigenetic targets include EZH2 and LSD1; and signaling pathways like AKT/mTOR and BCL2. And there are other biomarkers like Exportin that are undergoing more translational research.

AJMC: What implications do you think this will have for clinical practice?

Leventakos: The identification of specific biomarkers will lead to major changes for clinical practice. A patient’s clinically relevant biomarker will be identified after they undergo specific biomarker testing. This is something new for patients outside of a clinical trial. We already know that small cell lung cancer is very dynamic, so I expect that in the future, we will be proceeding with biopsies in the recurrent stage to adjust treatment as needed.