Advances in 2L treatment for ES-SCLC: Navigating the options

By Naveed Saleh, MD, MS | Medically reviewed by Nitin Chandramouli, MD FACP
Published April 1, 2024

Key Takeaways

  • Second-line (2L) treatment of ES-SCLC is particularly challenging, especially in cases where the chemotherapy-free interval is ≤6 months.

  • In light of limited options, 2L re-treatment with platinum-based therapy has long been standard of care, with other options including lurbinectedin, topotecan PO or IV, and irinotecan.

  • Immunotherapy options are being investigated as treatment for R/R disease, with trials ongoing.

First-line (1L) standard of care for the treatment of extensive-stage small-cell lung cancer (ES-SCLC) includes platinum plus etoposide, plus an immune checkpoint inhibitor, such as atezolizumab or durvalumab.

Although 1L therapy often results in rapid responses, effective treatment becomes more difficult with progression. This is especially true in cases where there is a chemotherapy-free interval (CTFI) of ≤6 months.

“Further research on immunotherapies and combination regimens is ongoing, and continuing work on the subcharacterization of SCLC may lead to better precision of therapies that promote more durable responses in individual patients with ES-SCLC,” wrote authors in a review in Frontiers in Oncology.[] 

2L in platinum-sensitive SCLC

Different clinical trials offer different definitions for platinum sensitivity, as the review authors explain. The FDA approvals of topotecan and lurbinectedin define platinum sensitivity by the enrollment criteria of each respective trial.

In the aggregate, platinum sensitivity should be considered on a spectrum, although definitive cutoff times for CTFI exist. For example, NCCN defines it as >6 months, whereas ESMO defines it as ≥3 months.

A longer CTFI boosts the chances of a clinically meaningful response to other cytotoxic agents.

Related: Mastering toxicity in ES-SCLC: A case study with Dr. Jared Weiss

The preferred regimen in patients with a CFTI >6 months is rechallenge with the original regimen or similar platinum-based regimen. The exception is treatment with immune checkpoint inhibitors (ICIs). Re-treatment with platinum-based therapy has long been standard of care and dates back to an era of fewer options.

Intriguingly, results of a study with a median follow-up time of 22.7 months demonstrated that the median PFS was significantly longer in the combination chemo group vs the topotecan group, or 4.7 months vs 2.6 months (stratified HR: 0.57; P = 0·0041).[] However, OS did not differ in either arm. 

NCCN guidelines

In patients with CFTI >6 months, the NCCN recommends clinical trial enrollment and re-treatment with platinum-based doublets as preferred 2L regimens.

Other recommended regimens include lurbinectedin, topotecan PO or IV, and irinotecan. During subsequent systemic therapy in ES-SCLC, response assessment by chest/abdomen/pelvis (CAP) CT is recommended every two to three cycles.[]

Related: Research insights: Managing neurologic events in ES-SCLC


Topotecan works by inhibiting topoisomerase-1, preventing malignant cells from repairing double-stranded DNA damage. As discussed in the Frontiers in Oncology review article, this was the first drug approved (1996) for 2L therapy in relapsed SCLC. IV topotecan was approved based on a 2L trial that included patients with a CTFI ≥60 days.

Although outcomes with topotecan 1.5 mg/m2/day were not significantly different from CAV (cyclophosphamide 1000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) for OS (25.0 vs 24.7 weeks) or median PFS (13.3 vs 12.3 weeks), this agent was correlated with improved symptom control. 

PO topotecan (2.3 mg/m2/day) was approved as 2L therapy on the basis of a randomized trial involving patients who were not candidates for continued IV chemotherapy. In that trial, patients taking PO topotecan had a significantly longer OS than the patients receiving best supportive care (25.9 vs 13.9 weeks; adjusted HR=0.61). Additionally, there were improvements in symptom control and quality of life.

In another trial, PO topotecan 2.3 mg/m2/day was compared to IV topotecan 1.5 mg/m2/day as 2L therapy for SCLC (CTFI ≥90 days). Patients in both arms exhibited a similar ORR of 18.3% vs 21.9% and a similar median OS of 33.0 vs 35.0 weeks.


This was the first agent approved for SCLC (2020) following topotecan. It is a synthetic alkaloid that covalently binds DNA, generating double-strand breaks, and disrupts DNA-protein interactions and RNA transcription. 

Lurbinectedin’s accelerated approval was based on the primary endpoint of ORR (35.2%) and median duration of response (5.3 months) from the SCLC cohort in a phase 2 basket trial in adults with progressing metastatic SCLC following platinum-based chemo.[]

“Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile," the researchers said. "Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial."

In the trial, neutropenic fever occurred in 5% of patients, as primary G-CSF prophylaxis was not permitted in trial.

In clinical practice, however, primary G-CSF prophylaxis may be prudent—especially in patients at increased risk for prolonged neutropenia or infection.

Related: Palliation of dyspnea in ES-SCLC: Identifying etiology and targeted treatment

Additional options

Although irinotecan and paclitaxel don’t have FDA approval as 2L therapies, as noted by the Frontiers in Oncology authors, they are common treatment options for ES-SCLC. Data on their efficacy are limited, but their adverse effects are well understood based on treatments for other cancers. 

“Irinotecan has shown responses with weekly dosing and is generally well tolerated, with diarrhea being a notable toxicity,” the authors said. “We generally start with dosing 100 mg/m2 on Days 1 and 8 of a 21-day cycle. Paclitaxel can be dosed every 3 weeks or weekly and has similarly shown responses. We prefer weekly dosing (6 weekly doses of an 8-week cycle) due to the toxicity profile.”

Temozolomide is another choice, per NCCN guidelines, and can be considered due to its excellent CNS penetration. It is a standard choice in brain tumors secondary to SCLC, which remain recalcitrant even after whole-brain radiation.

CTFI ≤6 months

In this setting, the NCCN preferred that regimens overlap with those for CTFI >6 months. These include clinical trial enrollment, lurbinectedin, topotecan PO or IV, irinotecan, and re-treatment with platinum-based doublet therapy.

Other recommended strategies include nivolumab or pembrolizumab (if the patient was not previously treated with an ICI), paclitaxel, temozolomide, CAV, docetaxel, gemcitabine, and oral etoposide.

ORR is typically low for these patients, and mPFS is short, representing an unmet need of newer therapy options with better efficacy given the difficulty in treating such patients.

Future directions

Immunotherapies are being investigated to stimulate a stronger immune response. For instance, tarlatamab has demonstrated good potency and specificity, promoting SCLC lysis. Tarlatamab is a bispecific T-cell engager molecule that targets not only delta-like ligand 3 (DLL-3) but also CD3 on T cells. Its potency is evident even in cell lines with low DLL-3 expression.

Currently, a phase 1 study investigating tarlatamab plus pembrolizumab in patients with R/R SCLC is ongoing.

What this means for you

Options are limited regarding 2L treatment for ES-SCLC; however, preclinical and clinical trials are ongoing. The NCCN's main recommendations specify re-treatment with platinum-based doublet therapy and clinical trial enrollment for patients with this advanced lung cancer.

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