Recent Advances in Small-Cell Lung Cancer - Episode 6
Vivek Subbiah, MD: Small-cell lung cancer in the relapse/refractory setting still is an aggressive cell malignancy. Uniformly, almost all patients relapsed. So far, we’ve had topotecan as the only FDA-approved agent in the past 2 decades in second-line small-cell lung cancer, platinum-sensitive disease. Again, the challenge, as you mentioned, with topotecan is due to its modest clinical benefit; the objective response from various clinical trials range anywhere from 5% to 24%, and median overall survival from other topotecan studies that we could see is 6 to 8 months. In these patients who have shorter overall survival, they show some significant hematologic toxicity as well. We needed different drugs in our armamentarium, especially in the second-line setting and that are non–immuno-oncology (I/O).
Recently, several new agents failed to demonstrate benefit in the second-line setting. Enter, lurbinectedin. Lurbinectedin is a selective inhibitor of oncogenic transcription. By inhibiting active transcription in the tumor-associated macrophages, lurbinectedin downregulates IL-6, IL-8, CCL2, and begets. As we all know, a small-cell lung cancer is transcription-addicted tumor. Recently, 4 molecular small-cell lung cancer subtypes have been defined by differential expression of 4 key transcription regulators. Initial lurbinectedin antigen tumor activity in small-cell lung cancer was observed in phase 1 to 2 study in combination with anthracycline/doxorubicin. Interestingly, that trial showed an objective response rate of 37% and a duration of response of 5.2 months.
Most recently, lurbinectedin was FDA approved. This approval was based on a multicohort basket study. Efficacy was demonstrated in a PharmaMar-led basket study, which is a multicenter, open-label, multicohort study, with only 105 patients with metastatic small-cell lung cancer who had disease progression on or after platinum-based chemotherapy. I was one of the co-investigators for this clinical trial for this multiarm clinical trial that enrolled not only small-cell lung cancer patients but also aggressive tumor types like Ewing sarcoma and germ cell tumors. Again, this specific small-cell lung cohort enrolled 105 patients with metastatic SCLC (small-cell lung cancer) vibrations with metastatic small-cell lung cancer. Patients received 3.2 mg/m2 of lurbinectedin by intravenous infusion every 21 days until disease progression of unacceptable toxicity. The main outcome measures were confirmed overall response rate as determined by the investigative assessment using the RECIST version 1.1 and response duration. Among the 105 patients enrolled, the objective response rate was 35%, with a median response duration of 5.3 months. The objective response rate for independent review committee was 30%, with the median response duration of 5.1 months. The most common adverse event that we saw more than 20% of the time in these patients enrolled on the clinical trial was myelosuppression. This is a chemotherapy, and the most common adverse effects were myelosuppression, fatigue, and some patients had elevated creatinine. We need to be cognizant that these patients have all come from cisplatin-, platinum-, and etoposide-based therapy. They have borderline renal function, including some liver function abnormalities and this glucose, nausea, decreased appetite… Vomiting and cough were also seen together with diarrhea.
The recommended phase 2 dose for the FDA label was 3.2 mg/m2 every 21 days. It received an accelerated FDA approval. The benefit observed with lurbinectedin compares favorably with what we historically see with topotecan. This is a current standard of care in terms of both anti-tumor activity and safety. Lurbinectedin is FDA approved, and it was also added to the NCCN (National Comprehensive Cancer Network) guidelines on June 7, 2020.
Let’s talk to Dr Ganti and Dr Chiang on how they think the approval will impact the treatment armamentarium in small-cell lung cancer. First, Dr Ganti.
Apar Ganti, MD: Lurbinectedin is the first drug that has been approved in this setting for a long time, and we are all excited about it. We finally have some alternative to topotecan. As Dr Chiang mentioned earlier, topotecan was available, but no one really liked it because of the myelosuppression and the toxicity associated with it. As you mentioned earlier, the outcomes were not great. Response rates ranged between 10% and 25%, with a median overall survival between 6 and 8 months. There was a big need to improve upon that. Lurbinectedin seems to have done that, at lease in some measure. As far as my practice is concerned, I will be using more of this drug in this cohort of patients. From the phase 2 basket trial that you just described, it appears that the adverse effect profile was very manageable. Myelosuppression was not as significant compared with topotecan, with the understanding that these 2 drugs have not been compared head-to-head in a clinical trial. There is an ongoing phase 3 trial comparing the combination of lurbinectedin and doxorubicin with topotecan, and that will give us more details and a better idea of what the exact benefit of lurbinectedin is. Based on this phase 2 data, I think that this would be a useful addition to our armamentarium in regard to small-cell lung cancer.
Vivek Subbiah, MD: Do you have any other insight into this drug, Dr Chiang?
Anne Chiang, MD, PhD: I think this is a great option for our patients. We have this epic treatment plan built, we’ve been pushing to get this drug into patients, and it’s actually available. I just got an email this week. We’re very excited. I think that patients are excited. It’s well tolerated, and 35% overall response rate is much better than what we’ve seen with our standard agents. I think this is a great option.
Transcript Edited for Clarity