Zepzelca (lurbinectedin), a recently approved drug for patients with metastatic (spreading) small-cell lung cancer, may be even safer than expected, according to data from 2 studies presented at the 2020 ASCO annual meeting.
Pooled safety analysis from the phase 3 CORAIL clinical trial and a phase 2 basket trial showed that the use of single-agent lurbinectedin as a second-line therapy is associated with significantly fewer hematologic side effects than the chemotherapy topotecan, which until recently was the only drug approved as second-line therapy for these patients.
Vivek Subbiah, MD, Clinical Medical Director, Clinical Center for Targeted Therapy, M.D. Anderson Cancer Center, Houston, Texas, presented the results from this pooled analysis. Although the investigators acknowledged limitations with indirect comparisons, the results showed fewer serious side effects, dose adjustments, treatment discontinuations, and use of supportive treatments in patients who received lurbinectedin versus those who received topotecan.
“Lurbinectedin has been shown to have a predictable and manageable safety profile, but we didn’t expect to see such a striking difference in toxicity,” said Dr. Subbiah. “A significant safety advantage in hematologic toxicities was observed with lurbinectedin versus topotecan,” he noted.
Small-cell lung cancer is an aggressive disease with currently limited treatment options. In June 2020, the FDA accelerated the approval of lurbinectedin, an inhibitor of active transcription, for the treatment of patients with metastatic small-cell lung cancer as a second-line treatment in patients whose disease progressed with or after receiving platinum-based chemotherapy. Topotecan is the only other drug approved for the second-line treatment of patients with metastatic small-cell lung cancer and is also used to treat platinum-resistant ovarian cancer.
Pooled Analysis of Data from 2 Studies
The FDA approval of lurbinectedin was based on data from a phase 2 basket study that combined patients with 9 types of cancer that included an expansion group of 105 patients with small-cell lung cancer. The results showed an overall response in 35% of the patients who received lurbinectedin therapy alone.
“Basket trials are a very interesting development in clinical research because they allow us to get multiple answers from the same study,” Dr. Subbiah explained. “For certain aggressive cancers, we might not have time to perform 9 separate studies. We need to be more efficient so that our patients can get access to these drugs quickly and safely.”
For this new analysis, Dr. Subbiah and colleagues pooled the safety results of 554 patients who received lurbinectedin treatment. The investigators took data from the phase 2 basket study and the phase 3 CORAIL study of lurbinectedin versus topotecan in patients with platinum-resistant ovarian cancer. Pooled data from the CORAIL and the basket studies were used for indirect comparison, whereas data from CORAIL were used for a direct comparison of lurbinectedin and topotecan.
Comparing Side Effects
A comparison between treatment regimens showed a significant difference in the rates of serious side effects. Dr. Subbiah noted that although 78.2% of the patients who received topotecan had grade 3 or 4 treatment-related neutropenia, only 32% of the patients who received lurbinectedin had this same adverse event.
The rates of severe anemia and thrombocytopenia were also significantly lower with lurbinectedin than with the chemotherapy: anemia was 56.3% with lurbinectedin and 18.7% with topotecan; the rate of thrombocytopenia was 33.3% with lurbinectedin versus 9.1% with topotecan.
Treatment-related dose reductions and delays were also lower with lurbinectedin treatment than with topotecan, and 32.2% of patients who received topotecan discontinued treatment because of side effects compared with only 15% of patients who received lurbinectedin.
In addition, 52.9% of the patients who received topotecan required transfusions versus 15.9% of the patients who received lurbinectedin. The use of granulocyte colony-stimulating factor was required in 70.1% of patients receiving topotecan versus 23.8% of patients receiving lurbinectedin.
The most common side effects with lurbinectedin were grade 1 or 2 fatigue, nausea, and vomiting.
“The challenge with topotecan is that it is associated with severe hematologic toxicity, and with an overall response rate of just 16%, so there’s only a modest clinical benefit,” said Dr. Subbiah. “Data from the basket trial, on the other hand, showed more than double the rate of overall response [with lurbinectedin].”
“There are major limitations with any indirect comparison,” he added, “but these results speak for themselves.”