Lurbinectedin and Tarlatamab: Emerging Second-Line Therapies in the SCLC Space

In a Pharmacy Times® interview, Megan May, PharmD, BCOP, FHOPA, FAPO, clinical oncology pharmacy specialist with Baptist Health Lexington, discusses lurbinectedin (Zepzelca; Jazz Pharmaceuticals) and tarlatamab (Imdelltra; Amgen), 2 emerging second-line therapies for small cell lung cancer (SCLC). She describes their mechanisms of action, how they differ from one another, and what ongoing research evaluating these agents looks like.

Pharmacy Times: Lurbinectedin has emerged as a promising second-line treatment option for SCLC. How does its mechanism of action differ from standard of care?

Megan May, PharmD, BCOP, FHOPA, FAPO: Lurbinectedin is a synthetic analog of a marine compound derived from a sea squirt species, it's actually an alkylating agent that affects SCLC by binding to the guanine residues in the minor groove of the DNA. This then triggers a cascade of events, and it affects the activity of transcription factors. It stalls the RNA polymerase II, affects DNA repair pathways, and also results in eventual cell death. The particular part to point out is a safety profile of lurbinectedin compared to our traditional chemotherapy. Myelosuppression is one of the main adverse effects (AEs) of lurbinectedin and chemotherapy. When looking at lurbinectedin in particular, there was a grade 3 or 4 neutropenia rate in [about] 41% of patients in trial, and a febrile neutropenia rate of 7%. This sounds like a significant number; however, when you compare this to our traditional topotecan (Hycamtin; GSK) that we were using previously, topotecan actually has double the rate of myelosuppression in this case, or even more.

Pharmacy Times: Tarlatamab is also generating interest as a second-line therapy. What is its mechanism of action, and how does it compare with lurbinectedin?

May: Tarlatimab is the first bispecific T cell antibody that's been approved in solid tumors as of now, it specifically targets delta-like ligand 3 (DLL3), and this is expressed on about 85% of SCLC cells. Due to this high percentage, you don't have to test for DLL3 prior to giving tarlatamab to a patient.

So how does it work? Tarlatamab activates the patient's own T cells by binding to CD3 on the T cell, and it attacks DLL3 on the SCLC cells. The [AEs] for tarlatimab are different from lurbinectedin. Since tarlatamab is a bispecific T cell antibody, there is a risk of [cytokine release syndrome] (CRS) and [immune effector cell-associated neurotoxicity syndrome] (ICANS). Because of this, there's specific recommended monitoring parameters...for example, after the first 2 doses of tarlatamab, it's recommended that the patient is observed for 22 to 24 hours from the start of an infusion in an appropriate health care setting. Also, it's recommended that patients stay within 1 hour of an appropriate health care setting for a total of 48 hours after the start of the tarlatamab infusion. These patients also need to be accompanied by a caregiver during these 48 hours due to the risk of CRS and ICANS. We don't have as much myelosuppression with tarlatamab, as we do with lurbinectedin.

Now, I think really the question is, how do we choose between lurbinectedin and tarlatamab in the second-line setting? These agents are very different in their mechanism and their [AE] profile. Some things that we consider are the patient, socioeconomic issues, so, do they have transportation to and from the infusion center? Are they able to stay in an observation state for 22 to 24 hours? Do they have an active caregiver? These are all different parts of a patient's situation that we take into consideration when making a treatment for second-line therapy.

Pharmacy Times: Are there any novel therapies or regimens featuring these agents coming in the pipeline that could further improve outcomes for patients with SCLC?

May: There is a lot of research going on for patients with SCLC. Specifically, an area of interest is moving lurbinectedin and tarlatamab into the treatment setting algorithm for SCLC. Some examples [are] the IMforte trial (NCT05091567), [which] is a phase 3 study where lurbinectedin is added to atezolizumab (Tecentriq; Genentech) in the maintenance setting for extensive-stage SCLC (ES-SCLC). So, once these patients finish induction therapy with carboplatin/etoposide and atezolizumab, they get [randomly assigned] to either receiving atezolizumab maintenance or atezolizumab plus lurbinectedin maintenance. So, it'll be really interesting to see if this efficacy brings lurbinectedin if up into the first-line maintenance setting. In particular, we also want to pay attention to what are the added toxicities when you move the treatment up in to the first-line maintenance setting.

Also looking at tarlatamab, we have the DeLLphi-305 study (NCT06211036)—and this is a similar study to what I just mentioned—where tarlatamab might be moved up to the maintenance setting. In this study, tarlatamab is given with durvalumab (Imfinzi; AstraZeneca) in the maintenance setting.

There are also some antibody-drug conjugates (ADCs) that are in trials looking at their effectiveness in SCLC. For example, ifinatamab deruxtecan (I-DXd; Daiichi Sankyo, Merck), it has shown clinically meaningful responses in pretreated patients with ES-SCLC in an interim analysis in the IDeate-Lung01 study (NCT05280470). It is a unique ADC because it's directed against the B7 Homolog 3 (B7-H3), which is part of the B7 family that includes immune checkpoint proteins such as PD-L1, so high and consistent expression of (B7-H3), has been shown across all molecular subtypes of SCLC, and this has been linked to a poor prognosis. So, this is a hopeful regimen that will be coming to light in this setting. There's also now a phase 3 study, the IDeate-Lung02 study (NCT06203210), looking at I-DXd.