A prospective translational study presented at the European Society of Medical Oncology (ESMO) 2022 Congress, held in Paris, from September 9-13, identified a differential expression of genes encoded for costimulatory molecules and cytokines between patients with extensive small-cell lung cancer (eSCLC) who responded with longer progression-free survival so the new first-line standard of care platinum-etoposide plus atezolizumab (PEA) and those who had shorter PFSs.

Dr. Martina Lorenzi, of the University of Padova, Italy, discussed the study design, results, and the implications of the research.

PW: What are the unmet needs of patients with eSCLC?

Dr. Lorenzi: eSCLC is an aggressive disease with a dismal prognosis. During the past 40 years, the standard of care for first-line therapy has been platinum-based chemotherapy. Although patients with eSCLC initially respond well to chemotherapy, the disease typically progresses within 1 year. This disease is still associated with extremely poor outcomes, with a median overall survival (OS) of about 10 months.

The addition of immunotherapy to standard platinum-based chemotherapy became the new standard of care due to improving outcomes demonstrated in several RCTs. However, longer benefit appears evident for a selected group of patients, although no predictive markers have been identified so far to help select patients who are more likely to benefit from immunotherapy. Identifying biomarkers will help address this unmet medical need.

PW: How does the addition of PD-L1 inhibitors to front-line chemotherapy impact eSCLC outcomes?

Dr. Lorenzi: Several studies consistently established the superiority of adding immunotherapy to standard chemotherapy in eSCLC, although the clinical benefit remains limited to a few months. For example. the phase 3 IMpower133 trial evaluated atezolizumab plus carbo-etoposide for four cycles followed by atezolizumab maintenance compared to chemotherapy. This study established a new standard of care showing that the combination significantly prolongs OS.

The CASPIAN study demonstrated the same magnitude of benefit with durvalumab plus standard platinum-based chemotherapy as the IMpower133 trial with a median OS of 13 months with the combination therapy compared with 10.3 in the standard of care arm. Of note, the KEYNOTE 604 trial with the anti-PD1 agent pembrolizumab met the primary PFS endpoint, but not the co-primary OS endpoint. Therefore, it was not approved.

PW: How is the gene expression profile affected by adding atezolizumab to frontline platinum-etoposide?

Dr. Lorenzi: Our study is a single-center prospective translational study on patients with eSCLC receiving first-line PEA, investigating the predictive value of circulating and tissue biomarkers. At ESMO, we reported preliminary data of gene expression profile on tumor tissue samples collected at baseline. We investigated the gene signatures before the start of treatment to identify an upfront predictive signature score.

PW: Why is understanding the gene expression profile important?

Dr. Lorenzi: We identified predictive and prognostic immune signatures in patients with eSCLC receiving chemo-immunotherapy through GEP analysis. We found that a higher ratio between cytotoxic T cell and tumor-infiltrating lymphocytes (TILs) signature scores were associated with longer OS, PFS, and time-to-treatment failure, suggesting a positive role of T cells in patient response and outcome.

On the other hand, macrophages seem to have a negative role in patient prognosis, as a higher ratio between macrophages and TILs signature scores was linked with a worse outcome.

Understanding the biology and tumor microenvironment of this disease is the basis for developing new treatments or new targets to modulate. Moreover, predictive biomarkers may help to select patients for intensive treatment strategies.

PW: Is this a step towards the use of other immune-modulating options for the future?

Dr. Lorenzi: Of course. Establishing that there is a differential expression of genes encoded for costimulatory molecules and cytokines or chemokines between responders and non-responders and in patients with longer compared to shorter survival is hypothesis-generating and could encourage drug research on these pathways.

For example, we found that the CXCL13-mRNA, encoding a chemokine that plays a critical role in lymphocyte infiltration, is overexpressed in patients with longer OS, so maybe targeting this pathway could enhance immune response and outcomes. Obviously, further investigations are needed.