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The research community is finally beginning to gain traction and make real progress in treating small cell lung cancer (SCLC).
The SCLC Hot Topic Meeting, hosted by the International Association for the Study of Lung Cancer, was held at the Memorial Sloan Kettering Cancer Center in New York from April 2-4. This unique gathering brings together basic researchers conducting preclinical studies, clinicians involved in patient care and clinical trials, and other types of scientists such as pathologists and bioinformaticians.
An essential component of such in-person meetings is the opportunity to engage with leaders in the field. One such person is Misty Shields, MD, PhD, a clinician scientist specializing in SCLC. In addition to running a research laboratory, seeing patients in her clinic, and conducting clinical trials, Dr. Shields is the founder of the Facebook group Small Cell SMASHERS, an online community dedicated to empowering and educating patients diagnosed with SCLC and other NETs. Dr. Shields partners with LUNGevity to host monthly fireside chats to bring experts in SCLC research and treatment to the patient community.
The excitement at the Hot Topic meeting was palpable. All attendees shared the common goal of improving outcomes for individuals diagnosed with small cell lung cancer and other neuroendocrine tumors. Their discussions were animated and eager, full of innovative ideas and interesting sidebars all fueled by research progress.
LUNGevity is proud to be the largest nonprofit funder of lung cancer research.
It's important to acknowledge that this progress in treating SCLC is possible because of the support from nonprofits, such as LUNGevity, and of course, federal agencies. We are deeply grateful to the National Cancer Institute for investing in SCLC research through the Recalcitrant Cancer Research Act of 2013. The investment by the NCI and the work of an international community of patients and their families, along with scientists and doctors, have made the progress we are seeing today possible.
-Upal Basu Roy, PhD, MPH, Executive Director of Research at LUNGevity
About SCLC and NETs
A neuroendocrine tumor (NET) is a type of cancer originating from neuroendocrine cells found in various parts of the body. SCLC is a subtype of neuroendocrine tumor. While some neuroendocrine tumors, such as SCLC, are highly aggressive, others, such as low-grade NETs, tend to grow slowly.
SCLC accounts for 15% of all diagnosed lung cancer cases. It is classified as limited stage (LS-SCLC) when the tumor is confined to one lung and can be treated with radiation. When SCLC has spread to the other lung or other parts of the body, it is referred to as extensive stage (ES-SCLC). Initial treatments for LS-SCLC and ES-SCLC typically involve chemotherapy and immunotherapy. Although ES-SCLC tumors initially respond to therapy, they inevitably recur.
Understanding the underlying mechanisms for evading tumor cell death is crucial for developing better treatments. This area is where the integration of basic/preclinical science with clinical research becomes essential.
Research Progress in SCLC
This year's SCLC Hot Topic Meeting exemplifies real-time advances aimed at improving outcomes for individuals diagnosed with SCLC.
Below are the top five key takeaways from the meeting that showcase the progress we are making in advancing the treatment options and improving the standard of care for people living with SCLC.
1. Small Cell Lung Cancers are Heterogeneous and Plastic
SCLC is now understood to consist of various subtypes rather than a single type of tumor cell. The best-known subtypes—which may respond to treatment differently—are:
- SCLC-A
- SCLC-N
- SCLC-P
- SCLC-I
For instance, the SCLC-I subtype responds best to chemotherapy-immunotherapy as the initial treatment for ES-SCLC. Research presented at the meeting showed that a single SCLC tumor may contain multiple subtypes of tumor cells, making SCLC tumors heterogeneous.
Additionally, subtypes such as SCLC-A, SCLC-N, and SCLC-P can switch from one cell type to another, demonstrating cellular plasticity and a new level of complexity to consider when developing next-generation treatment options.
Significance: Understanding tumor heterogeneity and cellular plasticity is crucial for effectively eliminating SCLC tumors by targeting multiple cell types within the tumor.
2. Rapid Translation of Subtype Biology to Clinical Practice
Clinicians have developed a clinical trial that tailors treatment based on the individual’s SCLC subtype. The phase 2 randomized clinical trial, SWOG S2409 (PRISM), will first identify a patient’s SCLC subtype and then match the patient to the appropriate treatment.
For example, patients with ES-SCLC typically receive chemotherapy-immunotherapy followed by immunotherapy maintenance. Based on subtyping results, patients enrolled in the clinical trial will receive an additional treatment alongside immunotherapy during maintenance. For instance, patients with SCLC-I will receive immunotherapy combined with monalizumab, a type of immunotherapy that activates immune cells such as natural killer cells and T cells.
Significance: After years of watching precision medicine become a reality for non-small cell lung cancer, this trial represents a significant milestone that proves precision medicine is achievable for SCLC.
3. Insights into Treatment Resistance from Preclinical Research
Preclinical research is enhancing our understanding of how SCLC cells develop resistance to chemotherapy and immunotherapy. SCLC cells evade chemotherapy by increasing their ability to repair damaged DNA (DNA damage repair response or DDR), allowing them to escape the effects of chemotherapy. Similarly, SCLC cells produce less MHC-I protein, enabling them to evade detection by the immune system.
Significance: Understanding these resistance mechanisms allows for the development of more effective treatments that can be designed to overcome drug resistance.
4. New Treatment Approaches Emerging from Preclinical Research
The rapid pace of research has led to the development of clinical trials testing new treatment approaches based on preclinical biology. For example, iadademstat, a drug targeting the LSD1 protein, is being tested in combination with immunotherapy maintenance as a first-line treatment for ES-SCLC. The LSD1 protein inhibits SCLC from producing the MHC-I protein.
The rationale behind this trial is that blocking LSD1 will restore MHC-I protein levels, enabling the immune system to recognize the cells. Additionally, preclinical research has led to the development of treatments such as antibody-drug conjugates (ADCs) targeting cell surface molecules like B7-H3 and SEZ6, and bispecific antibodies (BiTEs) targeting cell surface proteins like DLL3, which are already in the clinic.
Significance: Continued investment in preclinical research is essential for achieving more effective treatments for patients.
5. Evolution of SCLC Treatment Standards
Recent advances, such as the full approval of tarlatamab (a DLL3-targeting T-cell engager) for ES-SCLC that has become resistant to first-line treatment and the successful ADRIATIC trial (adding immunotherapy to chemoradiation as first-line treatment for LS-SCLC), exemplify how rapidly science is evolving to change the standard of care for SCLC treatment.
Significance: The ADRIATIC trial demonstrated that patients receiving chemoradiation combined with immunotherapy lived (on average) two years longer than those who did not receive immunotherapy, highlighting the shift in standard care toward newer regimens.
Don’t miss our coverage of the American Association for Cancer Research (AACR) Annual Meeting and the Annual Meeting of the American Society of Clinical Oncology (ASCO).
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