There is a lack of promising investigational treatments in late-stage development for small-cell lung cancer (SCLC) in the second-line setting and beyond, according to a systematic review published in Clinical Lung Cancer.

The review did reveal positive phase 2 data with tyrosine kinase inhibitors (TKIs) and some checkpoint inhibitors. However, there was limited phase 3 data, and most studies reported low-quality or very low-quality evidence.

The researchers reviewed publications from the past 5 years that reported results from prospective, interventional studies of patients with relapsed SCLC. 

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Of the 77 publications identified, 59 reported on phase 2 trials, 6 on phase 3 trials, 5 on phase 2/3 trials, and 2 on phase 4 trials. The studies also included a phase 1b/2a trial, a phase 1b trial, a real-world study, and 2 studies for which designs were not specified.

The publications reported data on TKIs (n=24), topoisomerase I inhibitors (n=15), immune checkpoint inhibitors (n=11), alkylating agents (n=9), and PARP inhibitors (n=6). The remaining 18 publications reported data on chemotherapy, small-molecule inhibitors, an antibody-drug conjugate, a monoclonal antibody, an antimetabolite, a Plk-1 inhibitor, and a dendritic cell-based vaccine.

Most phase 2 studies of TKIs reported positive results, but there were no phase 3 trials of TKI-based regimens. The most common TKIs evaluated were apatinib alone and anlotinib alone or in combination with S-1, penpulimab, irinotecan, docetaxel, etoposide, or camrelizumab. Positive results were seen with pazopanib, chiauranib, and cediranib plus olaparib.

The researchers also found positive results with PARP inhibitors, including olaparib alone, olaparib plus ceralasertib, olaparib plus cediranib, and fluzoparib plus SHR-1316. PARP-based regimens without positive results included olaparib plus durvalumab and veliparib plus temozolomide.

The researchers found positive results with lurbinectedin alone but negative results with lurbinectedin plus doxorubicin when compared with topotecan or cyclophosphamide, doxorubicin, and vincristine. They found promising preliminary results with temozolomide plus talazoparib, but there were no other publications reporting positive data for alkylating agents.  

The team found positive phase 2 results or encouraging preliminary results for single-agent pembrolizumab, camrelizumab plus apatinib, penpulimab plus anlotinib, and pembrolizumab plus amrubicin or paclitaxel.

However, there was a lack of clear benefit in studies of other checkpoint inhibitors, including single-agent nivolumab, single-agent atezolizumab, durvalumab plus olaparib, and durvalumab plus tremelimumab and stereotactic body radiotherapy. Nivolumab plus ipilimumab conferred promising efficacy but high toxicity. There were no positive phase 3 trials of checkpoint inhibitor-based regimens or ongoing phase 3 trials of such regimens.

The researchers found positive results with irinotecan monotherapy, better outcomes with belotecan than with topotecan, and better outcomes with combination irinotecan, cisplatin, and etoposide than with topotecan alone. They found positive results with a formulation of hyaluronic acid and irinotecan plus carboplatin, combination irinotecan plus carfilzomib, irinotecan plus apatinib, and a liposomal formulation of irinotecan.

However, the researchers noted that most of the publications analyzed — 69% — reported low-quality or very low-quality evidence.

“Despite clear paradigm shifts in the management of many other tumor types in recent years, this review confirms the elusive nature of efficacious and tolerable second- and later-line treatment options for patients with SCLC,” the researchers concluded. “[T]hus, relapsed SCLC remains an area of high unmet need.”

Disclosures: This research was supported by Ipsen. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Caro RB, Chen Y, Dowlati A, Eason P. Current and emerging treatment options for patients with relapsed small-cell lung carcinoma: A systematic literature review. Clin Lung Cancer. Published online February 7, 2023. doi:10.1016/j.cllc.2023.01.012