An Oncologist’s View: Navigating the Unique Challenges of Transformed Small Cell Lung Cancer

Matthew Reiss MSE PhD, Manager, Precision Medicine & Navigation, GO2 for Lung Cancer, and Jared Weiss MD, Section Chief of Thoracic and Head & Neck Oncology, Professor of Medicine, University of North Carolina at Chapel Hill 

It is common for cancer cells to change over time as people receive treatment for lung cancer. Cancer cells change or mutate, often in small ways, to avoid being harmed by cancer treatments. When a treatment that has worked well on a patient stops being effective, we know that the cancer has changed. This concept is known as “drug resistance” because the cancer resists the effects of the treatments.

In rare cases, drug resistance can cause non-small cell lung cancer (NSCLC) cells to change into small cell lung cancer (SCLC) to resist drug treatment. This diagnosis is known as transformed small cell lung cancer (tSCLC). While uncommon, tSCLC occurs most commonly in people treated with certain targeted therapies targeting EGFR. It may also occur in people receiving other types of treatment for other lung cancer biomarkers.

tSCLC is a complex and rare subtype of lung cancer still being studied to understand why this type of change happens in some people and not others, as well as how to best treat it. tSCLC poses a particularly unique challenge to healthcare providers as it brings together characteristics of both NSCLC and SCLC, requiring them to adjust their treatment plans and making it especially difficult to manage.

To help remove some of the mystique that comes with a tSCLC diagnosis, we sat down with Dr. Jared Weiss from the University of North Carolina at Chapel Hill to discuss his views on the distinct challenges of treating tSCLC, his optimism for ongoing research into tSCLC, and his advice for people coping with a diagnosis.

What makes tSCLC different from NSCLC or SCLC?

Cancer happens when a once healthy cell in the body acquires enough mistakes (mutations) in its instructions to forget how to do its job. Instead, the cell learns to make copies of itself to spread and grow (or, in other words, become cancer). The nature of the resulting cancer is largely dependent on 2 things:

• What kind of cell went bad
• What mutations happened to change it

Most NSCLC comes from glandular cells of the lungs (adenocarcinomas) or squamous cells (squamous cell carcinoma), while most SCLC comes from neuroendocrine (hormone signaling) cells. tSCLC is a rare cell type characterized by NSCLC cells changing histology (their nature) to become SCLC.

How does the approach to treating tSCLC differ for you as a provider? What types of challenges does it entail?

The greatest challenge with tSCLC is identifying it. We don’t do enough testing of sites of progression (where the cancer continues to grow), especially for biomarker-driven cancers like EGFR- and ALK-positive NSCLC. These are very important for identifying resistance mechanisms, which can improve our choice of therapy. Further, SCLC transformation can only be identified by tissue biopsy. While liquid (blood) biopsy can help identify risk factors for the possibility of transformation, only tissue biopsy can define if it has actually transformed.

We are in the infancy of understanding tSCLC. Chemotherapy holds the greatest promise for treatment at this time. It seems that PD-L1 immunotherapy drugs are less likely to help.

What advice would you give to patients and families coping with tSCLC, especially regarding a better understanding of their diagnosis, treatment options, and support resources?

For rare diagnoses, seeking a second opinion from a specialist in that area can be very useful. Someone who thinks about SCLC every day might have ideas that contribute to better care, especially for a rare subtype like tSCLC. Beyond offering clinical trial options and advice on the treatment itself, such visits can be valuable in having complex information explained in another way.

In your opinion, what type of research into tSCLC should the field be focusing on right now?

As a clinician who sees a lot of SCLC, I’d like to learn more about how the specific biology of tSCLC interacts with new and emerging therapies. For example, Imdelltra (tarlatamab-dlle) is a newly approved drug for SCLC targeting DLL3. I would like to know if tSCLC is more, less, or similarly likely to express DLL3 so that I can know whether to prioritize or de-prioritize this treatment for my tSCLC patients.