Small cell lung cancer (SCLC) remains an aggressive subtype with historically limited therapeutic options, though recent advances have expanded the treatment armamentarium. The integration of immunotherapy into first-line regimens and the development of novel agents for relapsed/refractory disease have begun to alter clinical practice, with ongoing research focused on further improving outcomes across disease stages, according to Sonam Puri, MD.
In a presentation at a recent State of the Science Summit on lung cancer, Puri reviewed the current state of therapy for SCLC, highlighting the recent approval of the T-cell engager tarlatamab-dlle (Imdelltra) in this setting. She also discussed emerging treatment strategies on the horizon, underscoring their potential to further refine and expand options for patients.
Puri serves as the Clinical Research Medical Director at the Moffitt Cancer Center in Tampa, Florida.
OncLive: Historically, chemotherapy has been the standard of care for SCLC. How have durvalumab and tarlatamab reshaped this treatment paradigm?
Puri: Both immune checkpoint inhibitors and, now, T-cell engager therapy have changed the treatment landscape in the timeframe they were introduced. Immunotherapy is now part of first-line treatment for SCLC, and the two phase 3 studies that incorporated immunotherapy into practice included IMpower133 [NCT02763579], evaluating atezolizumab [Tecentriq], and CASPIAN [NCT03043872], evaluating durvalumab [Imfinzi] with first-line chemotherapy for extensive-stage SCLC [ES-SCLC]. In both studies, the addition of immunotherapy led to a significant improvement in overall survival in treatment-naive, ES disease.
Building on that, we’ve seen that regimens benefiting ES-SCLC are also likely to benefit patients in earlier stages treated with curative intent. Due to high relapse rates, there remains significant mortality even in earlier stages. Recently, the phase 3 ADRIATIC trial [NCT03703297] demonstrated that durvalumab as consolidation therapy after concurrent chemoradiation for limited-stage SCLC led to meaningful improvement in outcomes and survival.
Tarlatamab represents a paradigm shift for relapsed/refractory SCLC. Historically, this setting had minimal effective options and poor durability of response. Tarlatamab, a DLL3-targeted T-cell engager, functions as a form of targeted immunotherapy and has demonstrated promising and durable responses.
What are the next areas of research or emerging approaches in SCLC?
It’s an exciting time to be a SCLC researcher. We’re moving toward more personalized treatments, novel targets, and innovative approaches. Antibody-drug conjugates have shown promising activity, both in preclinical and early clinical settings. Beyond DLL3, we’re investigating other targets such as CEACAM6. Radiopharmaceuticals are also in development, targeting receptors such as DLL3 and SSTR. More sophisticated T-cell engagement strategies, including trispecific T-cell activators, and [strategies for] engaging other immune cells to enhance tumor targeting are on the horizon.
How have the phase 2 PHAROS (NCT03915951) and phase 3 CROWN (NCT03052608) trials advanced the understanding of oncogenic drivers in NSCLC, and what key insights have they provided?
The targeted therapy field for NSCLC remains a leader in personalized oncology, with new targets and improved targeted agents continually emerging.
PHAROS was a phase 2 study evaluating encorafenib [Braftovi] plus binimetinib [Mektovi] in both treatment-naive and previously treated patients with BRAF V600E–mutated NSCLC. This combination, already established in melanoma, demonstrated favorable safety and efficacy, and is now a preferred regimen for this molecular subset.
CROWN was a phase 3 trial comparing first-line lorlatinib [Lorbrena], a later-generation ALK inhibitor, with crizotinib [Xalkori], an earlier-generation ALK inhibitor, in advanced ALK-positive NSCLC. Lorlatinib demonstrated superior efficacy, including enhanced intracranial activity, establishing it as a preferred first-line treatment for ALK-positive disease.
What strategies can be implemented to accelerate and improve the early detection of lung cancer?
Regardless of advances in the treatment of advanced disease, the greatest opportunity to improve survival in lung cancer lies in early detection, as most patients are diagnosed at a late stage. Strategies to address this span the patient care continuum.
Increasing patient awareness of lung cancer screening criteria, as well as expanding these criteria to capture a broader range of at-risk populations, is essential. Improving access to screening through mobile units, [such as] the mobile screening program at Moffitt Cancer Center, can help reach underserved areas.
Establishing dedicated lung nodule clinics and implementing nodule tracking programs can reduce the risk of missed follow-up for incidentally detected nodules. Incorporating biomarkers and radiomics offers the potential to better stratify nodule risk, minimize unnecessary observation, and more accurately identify nodules that require biopsy. Additionally, advancing biopsy techniques to make them less invasive while improving tissue quality for molecular testing will further support earlier and more precise diagnosis.