Small cell lung cancer (SCLC) remains one of the most aggressive and deadly forms of lung cancer, presenting a major challenge to clinicians and researchers alike. Historically, this type of lung cancer has presented numerous challenges to research, not just because of its low survival rate but also due to the nuances of the disease that make intensive study difficult. 

But this is exactly why more dedicated resources and innovative approaches to study design are even more urgent. People suffering from small cell lung cancer haven’t had many treatment options over the past couple of decades. And while we applaud the recent advancements in immunotherapy like atezolizumab, durvalumab, and tarlatamab, as well as the chemotherapy drug lurbinectedin, there is still much work to do.

The fact is, there is a tremendous amount that we don’t know, and we need to commit to more and better research to combat this disease.

“As a lung cancer specialist practicing in the southeastern part of the USA, where rates of lung cancer are higher, I see a lot of patients in my practice with SCLC,” said Christine Lovly, MD, PhD, FASCO, associate professor of medicine and cancer research at Vanderbilt University School of Medicine, co-leader of the Translational Research Interventional Oncology (TRIO) program, and a member of ALCMI’s Scientific Leadership Board. “While there have been tangible advances in the past 5 years, there is still a tremendous need to increase early detection of SCLC, to improve treatment outcomes, and most importantly, to make certain that all patients with SCLC, regardless of where they live, have access to state-of-the-art care.”

Understanding SCLC Research Urgency

SCLC is characterized by its rapid growth, early metastasis, and high propensity for relapse. Unlike non-small cell lung cancer (NSCLC), SCLC is strongly associated with cigarette smoking and exhibits distinct neuroendocrine features. The majority of patients present with extensive-stage disease, meaning the cancer has spread beyond the ipsilateral hemithorax and regional lymph nodes at diagnosis.  

Here’s what we’re up against:

• According to the CDC, approximately 10-15% of lung cancers are SCLC.
• The NIH says the median survival for extensive-stage SCLC is around 12 months.
• The 5-year survival rate for all stages combined is approximately 6%.
• According to the National Cancer Institute's SEER database, the 5-year relative survival rate for extensive-stage SCLC is roughly 3%.

Unfortunately, time is not on the side of someone diagnosed with small cell lung cancer. Given the speed of disease progression and grim outlook, ongoing research is desperately needed.

Challenges to Studying SCLC 

Conducting research into small cell lung cancer presents numerous challenges due to the disease’s inherent characteristics. 

Here are just a few of the reasons why:

• SCLC's aggressive nature and rapid progression equate to a narrow window of opportunity for patient enrollment. People diagnosed with SCLC often experience a swift decline in health, rendering them ineligible for trials shortly after diagnosis. 
• SCLC's tumor heterogeneity and the rapid development of drug resistance pose significant obstacles.
• The presence of paraneoplastic syndromes, such as Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and Lambert-Eaton Myasthenic Syndrome (LEMS), can complicate the clinical picture. These syndromes may also require specific management strategies that can interfere with the operation of the clinical trials.

There are also structural trial design challenges that complicate the organization and execution of clinical trials specific to small cell lung cancer. Here are just a few:

• The time it takes to screen and enroll patients in a trial can be considerable. In SCLC, this delay can result in patients dying before they even have the chance to participate.
• The prevalence of significant comorbidities often restricts the pool of eligible participants.
• Traditional cell lines and xenografts often fail to accurately replicate the complex tumor microenvironment and genetic heterogeneity of SCLC. These models may not accurately reflect the behavior of SCLC in patients.
• Unlike in non-small cell lung cancer, we lack reliable biomarkers for small cell lung cancer, making it more difficult to isolate an oncogene for more intensive study.
• Patients with SCLC may more often live in rural or underserved areas with limited access to oncologists and clinical trial access. 

Small Cell Lung Cancer Mysteries

Despite recent advancements in our understanding of small cell lung cancer, several significant unknowns persist, hindering the development of more effective therapies. 

One major area of uncertainty lies in the precise mechanisms driving the neuroendocrine differentiation that characterizes SCLC. While transcription factors like ASCL1 and NEUROD1 are known to play a role, the intricate signaling pathways and epigenetic modifications that orchestrate this process remain murky. Also, the molecular drivers of the neuroendocrine-to-non-neuroendocrine transformation, a key mechanism of treatment resistance, are not fully understood. Unraveling these mechanisms is crucial for developing strategies to prevent or reverse this transformation.   

Another significant unknown relates to the tumor microenvironment. While we recognize the importance of immune cell infiltration and the expression of immune checkpoint molecules, the precise interplay of these factors and their impact on treatment response remain unclear. A deeper understanding of the immune landscape of SCLC could pave the way for more effective immunotherapeutic approaches.

The lack of reliable biomarkers for early detection and treatment response also presents a major challenge. While liquid biopsies offer a promising avenue for monitoring tumor burden and identifying genetic alterations, the clinical utility of specific biomarkers in guiding treatment decisions hasn’t yet been established. Identifying predictive biomarkers that can accurately identify patients most likely to benefit from specific therapies is a critical unmet need.   

The optimal strategies for addressing minimal residual disease (MRD) following initial treatment also remain uncertain. How best to detect, monitor, and target MRD to prevent relapse is an area of active investigation. The development of more sensitive detection methods and the identification of therapeutic targets specific to MRD are essential for improving long-term outcomes in SCLC. These significant unknowns underscore the need for continued research and collaboration to unravel the complexities of SCLC and develop more effective therapies for this devastating disease.

There are many barriers to studying small cell lung cancer, but it is critical that we do so to better understand the disease and find targets for therapeutics. Despite encouraging advancements in immunotherapy and chemotherapy, the disease’s rapid progression, molecular complexity, and elusive biomarkers continue to challenge our ability to translate these breakthroughs into long-term survival. Moving forward, bridging these knowledge gaps through multidisciplinary research, enhanced clinical trial designs, remote decentralized clinical trials, and precision diagnostic techniques could ultimately transform treatment in the small cell lung cancer landscape. And now is the time to gird ourselves for the fight ahead.