Lurbinectedin Study Shows Single-Agent Potential in Second-Line Small Cell Lung Cancer

Anna F. Farago, MD, PhD

Lurbinectedin monotherapy as a second-line therapy in patients with small cell lung cancer (SCLC) elicited a 35.2% overall response rate (ORR) and may become the new standard of care for this patient population, explained Anna F. Farago, MD, PhD.

The ORR in this phase II study comprised partial responses occurring in 37 of 105 patients with SCLC. An additional 35 patients had stable disease, leading to a disease control rate of 68.6% (95% CI, 58.8%-77.3%). Furthermore, 65% of patients experienced tumor shrinkage; the median progression-free survival (PFS) was 3.9 months and median overall survival (OS) was 9.3 months.

“If you look at [ORR for lurbinectedin] compared with some of the recent randomized studies in second-line SCLC, that 35.2% response rate stands out as a high response rate compared with either topotecan or amrubicin,” said Farago, an assistant professor of medicine, Harvard Medical School and Massachusetts General Hospital.

In an interview with OncLive, Farago discussed the second-line data with lurbinectedin and its potential impact on the SCLC field.

OncLive: Could you discuss the data of single-agent lurbinectedin as a second-line treatment for patients with SCLC?

Farago: The data presented at this meeting was a phase II, single-arm study looking at the activity of lurbinectedin in patients with SCLC who had received 1 prior line of chemotherapy. The drug is a very interesting, marine-based drug. It's a synthetic analog of a previous marine-based drug called trabectedin (Yondelis). It appears to work by inhibiting activated transcription, which is an interesting target in SCLC because they are very transcriptionally active tumors and seem to depend on high levels of transcription from particular oncogenes and regions of the genomes.

This drug has been tested previously in some smaller phase I studies, mostly in combination with other chemotherapies. One study combines [lurbinectedin] with doxorubicin and another combines [lurbinectedin] with paclitaxel. Both combinations show some signal of activity in patients with SCLC.

The abstract presented at the 2019 ASCO Annual Meeting was a study designed to enroll up to 100 patients looking for a response rate of at least 30% with single-agent lurbinectedin. They reported the final results and confirmed a response rate of 35.2%, which is very encouraging.

Some of the other key secondary endpoints were presented, including a median duration of response of 5.3 months, a median PFS of 3.9 months, and a median OS of 9.3 months. Compared with recent randomized phase III studies, an OS of 9.3 months stands out. It's longer than we've seen with other studies.

That is encouraging and may be a sign of the significant clinical activity of lurbinectedin. However, it's important to note that if we look at SCLC studies over time, we see an upward trend of OS. Therefore, that may also partly reflect improvements in other therapies, including subsequent or supportive care. This study is somewhat limited as a single-arm phase II study. In the future, we hope to see practice-changing, randomized phase III data.

Are any ongoing randomized trials looking further into lurbinectedin?

There is a randomized phase III study called ATLANTIS, in which patients who receive 1 prior line of chemotherapy for SCLC are randomized 1:1 to receive either lurbinectedin in combination with doxorubicin compared with investigator's choice of topotecan or the regimen of cyclophosphamide, Adriamycin and vincristine, both of which are considered standard-of-care options. That study has completed enrollment. It's a 600-patient study with a primary outcome of measuring OS. We hope to see those results sometime in the next year.

A lot depends on what the results of that study are. To my knowledge, there is not currently a randomized study comparing single-agent lurbinectedin to a standard-of-care option. We look forward to seeing the ATLANTIS results. However, it's important to note that the dose of lurbinectedin in ATLANTIS is 2 mg/m² because it's combined with doxorubicin, whereas the dose in this single-arm phase II study was 3.2 mg/m². Whether that impacts differences now comes between those two studies, we'll have to see.

Could we evaluate lurbinectedin in combination with a checkpoint inhibitor?

I think that is a very viable, potential next direction. I would like to see whether that combination can potentially enhance the activity of lurbinectedin. There's some proposal that part of the mechanism of activity of lurbinectedin may be to impact the tumor microenvironment tumor-associated macrophages to help stimulate the immune system. Theoretically, combining that with a checkpoint inhibitor could be a viable strategy.

Is there potential for lurbinectedin to move to the first-line setting?

It will depend what we see in the second-line setting. If, in the second-line setting, we see positive results in randomized studies with lurbinectedin and it's becoming a new standard in the second-line setting, then the next step is to look into the first-line setting and potentially in the limited stage. However, we're not quite there yet.

What are your thoughts on the evolving SCLC paradigm?

It's been really exciting to see a lot of checkpoint inhibitors studies in SCLC recently. The IMpower133 study in the first-line setting has changed our practice. Now, most patients in the first-line setting are using carboplatin and etoposide plus atezolizumab (Tecentriq) based on a real survival benefit found in that study.

However, we've also had negative studies. We saw randomized data from CheckMate-331 in the second-line setting, where nivolumab (Opdivo) was not superior to topotecan. We also have phase II data from CheckMate-032 with nivolumab versus nivolumab/ipilimumab (Yervoy) in the second- and third-line setting. KEYNOTE-158 looks at pembrolizumab (Keytruda). There are some responses and even some durable responses in those studies, but we don't have randomized data in those contexts.

It's nice to see some activity, but I don't think that checkpoint inhibitors are superior to chemotherapy in the second-line setting. They are now an option in the third-line setting and beyond. There are some patients who will benefit, but we don’t yet know how to figure out who will most likely benefit. There are some signals from these studies, but they're somewhat conflicting. CheckMate-032 looked at tumor mutational burden and found a high correlation with higher likelihood of response and better outcomes. In KEYNOTE-158, they looked at PD-L1 measured by combined positive score. There was a correlation with improved outcomes and a positive PD-L1 score. This is different study to study; I don't think we have a solid sense yet of the best biomarker to use.

Paz-Ares LG, Perez JMT, Besse B, et al. Efficacy and safety profile of lurbinectedin in second-line SCLC patients: results from a phase II single-agent trial. J Clin Oncol. 2019;37(suppl; abstr 8506). doi: 10.1200/JCO.2019.37.15_suppl.8506.