Lurbinectedin Makes a Splash in Second-Line SCLC

Lurbinectedin (Zepzelca) has demonstrated impressive activity and tumor reduction in patients with small cell lung cancer (SCLC), and its addition to the treatment arsenal represents a promising development in a field with limited available options, according to Wade T. Iams, MD. However, questions pertaining to its clinical application remain.

“We finally have a new option for patients with relapsed SCLC,” Iams said. “We saw an [encouraging] overall response rate in these patients treated with lurbinectedin with a significant reduction in tumors, which compares favorably with previously available chemotherapy options.”

In June 2020, the FDA approved lurbinectedin for the treatment of patients with metastatic SCLC with disease progression after platinum-based chemotherapy. The regulatory decision was based on data from a phase 2 basket trial (NCT02454972), which showed that patients treated with the agent experienced an overall response rate (ORR) of 35.2%,¹ and 65% of those enrolled in the study experienced a reduction in tumor size.2

Additionally, in July 2020, the agent was added to the Clinical Practice Guidelines in Oncology by the National Comprehensive Cancer Network (NCCN) for the second-line treatment of patients with SCLC.

In an interview with OncLive^® during an Institutional Perspective in Cancer webinar on Lung Cancer, Iams, and assistant professor of medicine for the Division of Hematology/Oncology at Vanderbilt-Ingram Cancer Center, discussed the efficacy and safety of lurbinectedin in patients with SCLC, the impact of its approval on the paradigm, and remaining questions regarding its use.

OncLive^®: What was the significance of the accelerated FDA approval of lurbinectedin? How has it impacted clinical practice?

Iams: Lurbinectedin was only the second FDA-approved agent for patients with relapsed SCLC. The only previous option was topotecan. As such, this has been a significant development for patients who haven't seen many developments for decades. We're excited about more options for these patients in the clinic. This was great progress for the field.

What is known about the mechanism of action of lurbinectedin? What makes it unique from other agents?

Lurbinectedin is a transcription factor inhibitor that acts by blocking RNA polymerase at the site of active transcription. In the sense that it is a broad cytotoxic agent, we would place it in a category of more traditional cytotoxic chemotherapy. However, [lurbinectedin] differs from other cytotoxic chemotherapy agents [because of its] administration schedule. We're hopeful that the transcription factor profiles that are inhibited by lurbinectedin can potentially be more specific for SCLC, although that's under investigation.

A really intriguing dynamic, to me, is [whether there is] specificity of this agent for subtypes of SCLC, which is where the preclinical science in [this disease] is moving. [We’re] defining for subtypes by transcription factor profiles and [determining] what relationship this new agent may have to each subtype is a really intriguing [area of focus].

What should be known about the safety profile of this agent when used as a monotherapy?

When used as monotherapy, which is the FDA-approved application, the most common adverse effect [AE] observed was fatigue in a slight majority of patients. The vast majority [of patients] were not hospitalized; it was not a severe AE.

The big toxicity to be aware of is neutropenia, but I took that all the way to rate of febrile neutropenia, which typically guides our use of primary prophylactic growth factor for these patients. In the COVID-19 era, we've had ASCO recommendations to lower the threshold to use of primary prophylaxis growth factor down to 10% rates. Now, when we look at the monotherapy lurbinectedin data, [we see a] less than 10% rate of febrile neutropenia. Although, there is a much higher rate of grade 3 neutropenia without febrile neutropenia [with the agent]. Distinguishing between those 2 is a big component of looking at these toxicities. 

Patients did have more expected nausea, vomiting, and diarrhea. There was only 1 hospitalization, or grade 3 or higher toxicity, for a gastrointestinal event, and that was 1 episode of diarrhea. [Additionally], only 1 skin toxicity of grade 3 or higher [was observed], and less than 10% of patients had transaminase elevation of grade 3 or higher. No hospitalizations for acute kidney injury [occurred], although some creatinine elevation was observed. [However,] when we put that next to other chemotherapy toxicities [that we see], I would certainly describe it as very well tolerated.

How do you feel this agent fits into the treatment landscape? What are some questions that still need to be sorted out?

The big question when we look at the clinical application of lurbinectedin for patients with relapsed SCLC is, how do we feel about the time since they received their last platinum chemotherapy? The way that the study breaks down results is by 3 months since last platinum, or more than 3 months since last platinum.

The way that our NCCN guidelines break down that timeline is 6 months since last platinum chemotherapy vs 6 months after last platinum chemotherapy. The reason I harp on that point is because we know that reusing that platinum chemotherapy is more effective, particularly if patients have had 6 months since their last platinum. However, some folks also use that 3-month threshold clinically.

The application of lurbinectedin is a bit stronger compared with the other options [available] for patients who have relapsed in less than 3 months. When we get to the [patients who are] platinum sensitive, relapsed 3 months or even 6 months or later, I think there's more of a question about do you reinstitute that platinum that they had the first time around? That may be dependent on adverse effects and tolerance of that individual patient the first time they received it. Or do we use lurbinectedin? Lurbinectedin, again, is FDA approved for any of those scenarios, and it is an NCCN guidelines option for any of those scenarios, but it is a wrinkle, clinically, in the platinum-sensitive setting.

In the phase 3 ATLANTIS trial (NCT02566993), lurbinectedin was paired with doxorubicin; the trial failed to meet its primary end point of overall survival (OS). What should be taken away from these findings?

That is the key question in the field. I would reserve my comments until we see more comprehensive data from this trial. All we've seen is that the primary end point was OS, and it was not met. To reiterate the structure of the trial, [it was] a 1:1 randomization of lurbinectedin plus doxorubicin compared with dealer's choice of cyclophosphamide/doxorubicin/vincristine or topotecan. Lurbinectedin was given at a lower dose than [it had been] in the monotherapy trial. All we know is that [the study] did not meet its primary end point. I'd like to see the full data set before we can fully interpret [what these data mean for the field].

References

Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1

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 15):8506. doi:10.1200/JCO.2019.37.15_suppl.8506