Study Reveals Insights into Therapeutic Vulnerabilities for Rare, Aggressive Lung Cancer

A multi-institution study of nearly 600 patients with a rare and aggressive form of lung cancer offers new insights into the comparative effects of existing therapies and potential targets for future treatments. It was published Aug. 19 in Nature Communications.

“This work represents one of the largest collaborative efforts to date in large cell neuroendocrine carcinoma. By bringing together data from nearly 600 patients worldwide, we have created a foundation that can help accelerate the development of biomarker-driven and more effective therapies,” says first author Amin Nassar, MD, a medical oncology-hematology fellow at Yale Cancer Center.

Comprehensive analysis of the real-world patient data revealed no significant difference in overall survival related to treatment of large cell neuroendocrine carcinomas (LCNEC) with chemotherapy, chemoimmunotherapy, or immunotherapy.

The limited success of immunotherapies could be related to the study findings of significantly lower incidence of tumor-infiltrating lymphocytes (TILs) in LCNEC tumors compared to other lung cancers.

While no clear best treatment option was discovered, the close analysis of patient data found that in nearly 6% of cases there were genetic changes in the tumors that could be targeted with existing drugs for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Moreover, Yale researchers determined a transcriptomic classifier that reclassified more than 70% of “unclassified” tumors into biologically meaningful SCLC-like or NSCLC-like subtypes.

Additionally, “this study shows how cooperation between institutions and integrating clinical and molecular insights can identify potential therapeutic targets,” says senior author Anne Chiang, MD, PhD, associate professor of medicine (medical oncology and hematology). Specifically, the close analysis revealed that some LCNEC subtypes showed specific markers, including FGL-1 and SPINK1 in NSCLC-like tumors and DLL3 in SCLC-like tumors, pointing to possible targets for treatment.

The Yale-led study, which included several dozen researchers from the U.S, Norway, Spain, Belgium, Germany, Italy, and England, concluded that prospective clinical trials tailored to the genetic profiles of different LCNEC tumor types are critically important to evaluating the efficacy of new therapies.