New therapies lurbinectedin and tarlatamab bring hope for small cell lung cancer treatment

The treatment strategy for small cell lung cancer (SCLC), one of the least curable lung cancers, is about to change.

This is thanks to the introduction of the cytotoxic anticancer drug lurbinectedin, which has fewer side effects than conventional cytotoxic therapies, in the second-line treatment of small cell lung cancer and the recent development of the bispecific antibody therapy tarlatamab as a third-line treatment.

Small cell lung cancer, which mainly occurs in smokers, accounts for 15-20 percent of all lung cancers. The cancer is aggressive and spreads very quickly, and unlike other types of lung cancer, it is not divided into stages 1, 2, 3, or 4 but into limiting and expanding stages.

On the Korean Association for Lung Cancer (KALC)’s YouTube channel “Ask Me Anything About Lung Cancer,” Professor Lee Jii-bum of the Department of Medical Oncology at Yonsei Cancer Hospital pointed out that the latest treatments for small cell lung cancer are lurbinectedin, which can be administered as a second-line treatment, and tarlatamab, which has recently become a hot topic as a third-line treatment.

SCLC is highly inoperable but shows good response to chemotherapy and radiotherapy

Small cell lung cancer is often diagnosed at a very advanced stage at diagnosis. It is categorized as “limited stage”' when the cancer is only in one lung and “extensive stage” when it has spread to other organs, and 70 percent of small cell lung cancer cases are extensive at diagnosis.

“The characteristic of small cell lung cancer is that a significant proportion of patients have already metastasized to organs other than the lungs at the time of diagnosis,” Professor Lee said. “Because it is a very fast-growing and systemic cancer, it is often inoperable at the time of diagnosis.”

The good news is that small cell lung cancer responds well to chemotherapy and radiation. “If you are diagnosed with a limited stage of small cell lung cancer at the time of diagnosis, you should actively receive chemotherapy and radiotherapy together,” Lee said. “Even if you have completed chemotherapy and radiotherapy and are well cured, you should also receive prophylactic brain radiotherapy to prevent brain metastasis, as it often metastasizes to the brain.”

Professor Lim Chae-hong of the Department of Radiation Oncology at Korea University Ansan Hospital agreed.

“When radiation therapy is given to small cell lung cancer, it tends to respond quickly, so it is recommended to start early at the time of diagnosis. When it is in the limited stage, chemotherapy and radiation therapy are given together, and when it is in the expanded stage, chemotherapy is given. Then radiation therapy is given when it is more favorable according to the course of treatment,” Professor Lim said.

One of the characteristics of small cell lung cancer is that it is easy to spread to the brain and cause brain metastasis,” Lim explained.

“Even if it is not diagnosed, results are showing that more than 50 percent of brain metastases were present at autopsy, so preventive radiotherapy is performed. Two weeks of radiotherapy to the brain reduces the chance of brain metastasis, which has a good effect on the course of the cancer,” he added.

Atezolizumab is 1st-line treatment for expanded-stage SCLC

The current treatment strategy for expanded stage small cell lung cancer is to use the immuno-oncology drug atezolizumab plus etoposide in combination with the cytotoxic anticancer drugs carboplatin or cisplatin.

In a clinical study (Impower 133) comparing atezolizumab plus etoposide plus carboplatin to the placebo arm, etoposide plus carboplatin, progression-free survival (PFS) -- time from drug treatment to disease progression -- was 5.2 months in the atezolizumab plus etoposide plus carboplatin arm and 4.3 months in the placebo arm.

Overall survival (OS) was 12.3 months in the atezolizumab plus etoposide plus carboplatin arm and 10.3 months in the etoposide plus carboplatin arm.

“In small cell lung cancer, atezolizumab showed efficacy independent of PD-L1 and TMB expression,” Professor Lee said.

2-line treatment for expanded stage SCLC goes up using cytotoxic anticancer agent lurbinectedin

If the combination of atezolizumab, etoposide, and carboplatin as a first-line treatment for expansive small cell lung cancer is not effective, another treatment option can be used, and the new drug lurbinectedin is expected to improve its efficacy.

“Carboplatin combination chemotherapy is called platinum-based chemotherapy, and in the case of metastatic small cell lung cancer that has failed the first-line platinum-based chemotherapy, lurbinectedin can be administered as a second-line therapy,” Lee said.

Lurbinectedin is a cytotoxic anticancer drug that kills cancer by inhibiting DNA transcription in cancer cells. It is more effective and has fewer hematologic toxicities, such as platelet thrombocytopenia and bone marrow dysfunction, than conventional anticancer drugs, including topotecan, belotecan, and irinotecan.

“The side effects of lurbinectedin are similar to those of other cytotoxic antineoplastic agents, with neutropenia and thrombocytopenia due to bone marrow dysfunction, but they are less frequent than other agents,” Professor Lee said. “These side effects may require treatment with leukocyte-stimulating agents or antibiotics as needed.”

“In the phase 2 study, lurbinectedin had an overall response rate of 35 percent, a median duration of response of 5.3 months, a median progression-free survival of 3.5 months, and a median overall survival of 9.3 months,” Lee said. “The overall response rate, duration of treatment, and overall progression-free survival were slightly longer than topotecan, belotecan, and irinotecan.”

Lurbinectedin is administered once every three weeks and takes about an hour to administer. “The principle is to take CT scans every two to three months during chemotherapy and monitor the response to chemotherapy, and if there is a response and no side effects, continue treatment,” she added.

Tarlatamab, a bispecific antibody therapy for 3rd-line treatment of advanced SCLC

When second-line treatment for SCLC fails, another new treatment is also available that is expected to improve outcomes. Tarlatamab has emerged as a new bispecific T-cell-engaging antibody developed to target DLL3 and CD3.

“Small cell lung cancer is known as a type of neuroendocrine cancer, and DLL3 is abnormally expressed in small cell lung cancer. Tarlatamab is a drug that binds to CD3 on T-cells and binds to DLL3 on cancer cells, causing the immune cells to attack the cancer cells,” Professor Lee said, noting that it helps the immune cells better sensitize the cancer cells, increasing the effectiveness of the treatment.

“When we looked at the results of 10 mg or 100 mg of tarlatamab every two weeks in patients with small cell lung cancer who had failed previous treatments, the overall response rate was 40 percent and 32 percent,” Lee said. “We found that the 10 mg group had a higher response rate and fewer side effects.”

The higher objective response rate reported by patients who received 10 mg of tarlatamab every two weeks was likely due to lower side effects. “Patients responded better because they could continue for a little longer,” she explained.

The most common side effect of tarlatamab is cytokine release syndrome or cytokine storm. This is because tarlatamab causes immune cells to become overly active, resulting in symptoms including high fever and chills.

“Other symptoms may include rumbling, vomiting, and headache, which usually occur during the first or second dose, so conservative treatment with fluids is sufficient to continue treatment,” Professor Lee added.