Treatments Move Beyond Immunotherapy for SCLC

In recent years, immunotherapy has shown to be the most promising treatment for patients with small cell lung cancer (SCLC). However, many challenges remain with these agents, including toxicity and efficacy, and more options are needed to properly treat different subtypes of this disease.

Over the past 30 years, there has been little improvement in survival for patients with SCLC and the clinical outcomes of patients remains poor due to the disease’s high proliferative rate, strong tendency for early widespread metastasis, and acquired chemoresistance.

Investigators are now assessing novel agents that are shifting the treatment paradigm of extensive disease-SCLC. Like in the non–small cell lung cancer space, immune checkpoint inhibitors and the development of immunotherapy may provide patients with a new therapeutic approach for the treatment of their SCLC.

Still, the efficacy of anticancer immunity in SCLC is low because of the low expression of PD-L1, MHC antigen and incidence of resistance to immunotherapy. In addition, there is a strong need for personalized treatments and personalized molecular therapies in this space.

“Large-scale profiling studies have provided important biological insight into the genomic, epi-genomic, and proteomic landscapes of SCLC. Such genomic profiling of SCLC have identified a few directly targetable alterations, such as DNA damage, neuroendocrine transcriptional networks, epigenetic modifiers, and global transcriptional addiction of SCLC tumors…All these strategies suggest potential combinational therapy approaches both with the currently used treatment for SCLC and/or with new drugs, such as the PARP and WEE1 inhibitors,” wrote authors in data published in ScienceDirect.

According to omics profiling, SCLC is among the tumors with the highest mutational burden. This is due to the high genomic instability from the impairment of the 2 relevant tumor suppressor genes, RB1 and TP53, and long-term exposure to tobacco carcinogens. To negate this, investigators began developing immune-checkpoint inhibitors as single agents or in combination with chemotherapy for this patient population. This led to the FDA approval of nivolumab (Opdivo) in 2018, and pembrolizumab (Keytruda) in 2019.

However, only a small subset of patients had prolonged benefit and subsequent larger phase studies failed to demonstrate overall survival benefit with these agents in earlier lines.

When immune-checkpoint inhibitors were combined with chemotherapy in first-line, better results were achieved. In the phase 3 trials IMpower133 (NCT02763579), CASPIAN (NCT03043872), and KEYNOTE-604 (NCT03066778), combination strategies with atezolizumab (Tecentriq), durvalumab (Imfinzi) with or without tremelimumab (Imjudo), and pembrolizumab, showed benefits. Adding anti-PD1/PD-L1 therapies to a standard platinum-etoposide doublet also led to a median OS improvement by approximately 2 months vs chemotherapy alone. This resulted in an increase of 12-months OS rate by almost 10%, even though the benefit was not statistically significant in the pembrolizumab trial.

Based on these positive findings, the FDA granted approvals to atezolizumab and durvalumab in combination with platinum-etoposide for untreated extensive disease-SCLC patients. This ultimately became the new standard frontline treatment in this space.

Another thing to note for SCLC is that the high incidence of genomic aberrations observed in SCLC is linked with DNA damage repair and genomic instability mechanisms. New agents targeting DNA damage repair for SCLC include PARP inhibitors.

Multiple studies of various PARP inhibitors, including olaparib, veliparib, talazoparib, and rucaparib, have been conducted. These PARP inhibitors work to reduce the effectiveness of the cell's DDR by inactivating the initial PARP response to single strand DNA breaks. These agents also increase the amount of PARP-1 and PARP-2 that is connected to the chromatic structures of the damaged DNA and holds them there.

Moreover, cell cycle checkpoint and apoptosis pathways also have revealed promising results in a few different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context.

“Future research and improved clinical outcomes for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments,” concluded the authors.

All in all, novel treatments beyond just immunotherapy are needed in SCLC due to the significant intratumoral molecular heterogeneity in this type of cancer. Each subtype of SCLC demonstrates unique vulnerability to different therapies, including PARP inhibitors, Aurora kinases, or BCL-2, and more.

However, further studies with SCLC-relevant molecular alterations are needed to provide preclinical validation of new therapeutics responses and allow for a deeper understanding when treating patients with SCLC.

REFERENCE:

Meijer JJ, Leonetti A, Airò G, et al. Small cell lung cancer: Novel treatments beyond immunotherapy. Semin Cancer Biol. 2022;86(Pt 2):376-385. doi:10.1016/j.semcancer.2022.05.004