Lurbinectedin Approval Ignites a Spark for Precision Medicine in Small Cell Lung Cancer

The approval of lurbinectedin (Zepzelca), a selective inhibitor of oncogenic transcription, reinvigorated the treatment landscape of small cell lung cancer (SCLC), which had been stagnant for decades prior, said Nisha A. Mohindra, MD, who added that since this approval, research has been ongoing to evaluate novel combinations with lurbinectedin and deliver more precise treatments based on histologic subtypes. 

“Certainly, SCLC has needed another agent beyond topotecan, so it is nice to finally see another FDA approval,” said Mohindra. “[Lurbinectedin] has definitely become a consideration in my treatment paradigm [for patients with SCLC]. We can now biologically or molecularly divide this disease into subsets and then pick out agents that match [the patient’s disease] biology…so we can really try to tease out who to treat with this drug.”

On June 15, 2020, the FDA granted an accelerated approval to lurbinectedin for the treatment of patients with metastatic SCLC who have disease progression following platinum-based chemotherapy.¹ 

The regulatory decision was based on findings from a single-arm, open-label, phase 2 basket trial (NCT02454972), which demonstrated a 35.2% overall response rate and 68.6% disease control rate in 105 patients with SCLC. These patients were treated with 3.2 mg/m² of lurbinectedin as a 1-hour intravenous infusion once every 3 weeks until progressive disease or unacceptable toxicity. Additionally, the median duration of response was 5.3 months with the agent.² 

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer, Mohindra, a thoracic oncologist at the Robert H. Lurie Comprehensive Cancer Center of Northwestern Medicine and an assistant professor of medicine (hematology and oncology) at Northwestern University Feinberg School of Medicine, discussed the integration of lurbinectedin into the SCLC paradigm and remaining questions regarding future therapeutic directions. 

OncLive^®: What about the mechanism of action of lurbinectedin makes it a unique addition to the SCLC armamentarium?

Mohindra: Lurbinectedin is a selective transcription inhibitor. The drug itself binds to the DNA promoter region to prevent other transcription factors from binding. Ultimately, this leads to intracellular pathways that lead to [cell] death without transcription. [The mechanism of action] is novel; we haven’t had an agent like this in the SCLC [paradigm]. The data that led to the FDA approval [of lurbinectedin] certainly gave us another option in this setting, which we hadn’t had for at least 2 to 3 decades. 

How did the FDA approval of lurbinectedin reshape the treatment of patients with SCLC?

The approval [of lurbinectedin] was based off of [data from] a basket trial, which looked at 105 patients with SCLC. This approval opened up another second-line agent for SCLC, which is a pretty recalcitrant disease. The prognosis [of patients with SCLC] has always been an issue that we have struggled with. [Until the approval of lurbinectedin], we really only had topotecan as an FDA-approved agent.

What is interesting is that [the approval of lurbinectedin] came at a time where our first-line setting was starting to evolve. We were starting to use chemoimmunotherapy more often, so what to use [in the second-line setting] was a big question. To have another option [in that setting] opened up therapeutic options for this patient population.

The way the data were presented, [investigators] looked at both patients who had had chemotherapy within the last 90 days or patients with a [chemotherapy-free] interval beyond 90 days.

Could lurbinectedin have other clinical implications in this setting that have not yet been fully explored?

Lurbinectedin not only inhibits transcription within the tumor itself, but a number of other cells’ transcription can be affected as well. Macrophages in the tumor microenvironment [are affected. Data] showed decreased transcription of IL-6 and IL-8 from macrophages [with lurbinectedin]. Can [lurbinectedin] be used with immunotherapy? [That is the subject of] ongoing investigation in clinical trials.

Beyond lurbinectedin, what other research efforts are being made in SCLC that could contribute to the wave of precision medicine?

A number of really nice publications [have read out] in the past couple of months that have highlighted how much effort is being made in SCLC. [The publications provide] the first, nice, comprehensive look at how we can apply precision oncology methodology to this disease, which has been lacking. A number of agents are being looked at in trials. Certainly, [the field is] continuing on with immunotherapy, but other agents, such as CHEK1 or PARP [inhibitors are also being evaluated. How do we use these agents better? What are the right combination [strategies]? What are the right sequences of treatment?

Will molecular subtyping play a role in sequencing patients?

A group of investigators are really interested in trying to figure out how to bring [molecular sequencing] into the clinic; how do we get patients [with SCLC] adequately sequenced? [How do we get] adequate tissue and the right populations? Leaning off of some of the work that has been done in non–small cell lung cancer: Can we bring some kind of big, umbrella trial to SCLC? We are in the beginning [stages] of that, but I know there are a lot of efforts [ongoing] to look at how to we can do that in the future.

There have been some FDA withdrawals for immunotherapeutic agents, such as pembrolizumab (Keytruda), in SCLC. Could these agents still be considered for patients or are additional data required to show that these agents are safe and effective? 

It’s a great question, and certainly the field has evolved. Even our frontline setting changed [from] when the trials of immunotherapy in the later-line settings were first [conducted]. Certainly, these agents could be considered in the right clinical scenario, but the data are telling us that we should be thinking beyond these [agents] or looking at them in clinical trials to see if there is something else, we can add to them.

Two indications were removed in the past several months, so we have to figure out whether there is a role for immunotherapy beyond the first-line setting. Some ongoing trials will, hopefully, help answer that question, but it has become more of a question beyond the first-line setting. 

References

1. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. News release. FDA. Published June 15, 2020. Accessed April 2, 2021. https://bit.ly/39CxOxW.
2. 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