Evolving Options for SCLC Management Drive the Need for Increasingly Personalized Approaches

Tarlatamab-dlle (Imdelltra), lurbinectedin (Zepzelca), and emerging antibody-drug conjugates (ADCs) have set the small cell lung cancer (SCLC) treatment paradigm on a solid course toward a new era of innovation that may expand treatment options beyond standard chemoimmunotherapy and improve long-term outcomes for patients, according to Misty D. Shields, MD, PhD.

In an interview with OncLive®, Shields discussed the importance of the FDA’s accelerated approval pathway for expediting access to novel and effective treatments for patients with SCLC, therapies in development that may challenge the current extensive-stage SCLC (ES-SCLC) treatment paradigm, and drug classes to watch going forward.

Notably, she highlighted the potential clinical implications of findings from the primary analysis of the phase 3 DeLLphi-304 trial(NCT05740566), which showed that second-line treatment with tarlatamab (n = 254) generated a superior median overall survival of 13.6 months vs 8.3 months with chemotherapy in patients with relapsed SCLC (HR, 0.60; 95% CI, 0.47-0.77; 2-sided P < .001).1

Shields also emphasized the importance of exercising increased caution when considering treatment options for patients with brain metastases. She noted that although the phase 3 IMforte trial (NCT05091567) showed a statistically significant and clinically meaningful progression-free survival benefit in the first-line maintenance therapy setting with lurbinectedin plus atezolizumab (n = 242) vs atezolizumab maintenance (n = 241) in patients with ES-SCLC (HR, 0.54; 95% CI, 0.43-0.67; P < .0001), this trial did not include patients with central nervous system metastases, barring data extrapolation to this subgroup.2

Shields is a translational medical oncologist at Indiana University (IU) Health; as well as an assistant professor of clinical medicine in the Department of Medicine in the Division of Hematology/Oncology at the IU School of Medicine and an associate member of Experimental and Developmental Therapeutics at the IU Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.

In case you missed it, catch up on Shields’ insights about chemoradiotherapy and prophylactic cranial irradiation in SCLC, which she discussed in an earlier part of our conversation.

OncLive: Both lurbinectedin and tarlatamab were approved in the second-line setting for patients with SCLC under the FDA accelerated approval pathway. What is the importance of this program within the context of the SCLC treatment paradigm?

Shields: Therapies for SCLC are desperately needed. We saw approximately 4 decades of no advancements for patients diagnosed with SCLC. Although chemoimmunotherapy is beneficial for a small subset [of patients], up to 90% of patients with ES-SCLC will recur, and we know that that therapy, unfortunately, comes back even stronger post-platinum, with the extrachromosomal MYC amplification that we've seen and has been demonstrated by multiple investigators.

Working to have [agents with] different mechanisms of action outside of platinum rechallenge [is important]. This includes genome drugs like lurbinectedin, a minor groove binder, as well as tarlatamab, a bispecific DLL3/CD3 T-cell engager. These agents have generated consistent benefit for patients with relapsed SCLC.

We're seeing that paradigm be dynamic and move earlier, where patients are seeing lurbinectedin now in the maintenance setting and tarlatamab as a second-line therapy. The DeLLphi-304 trial showed superiority [with tarlatamab] over standard-of-care (SOC) chemotherapies. [Those findings were] presented at the 2025 ASCO Annual Meeting.

These are exciting therapies. They're needed. Patients need access to these therapies, as well as more, including the ADCs that are up and coming. These represent breakthroughs we haven't seen in approximately 4 decades for patients with SCLC. [Patients are] living longer, thriving, and getting their disease under control, which is needed.

What is the current standard treatment sequence for ES-SCLC?

The treatment for ES-SCLC is at least standardized for chemoimmunotherapy. Now we see the introduction of maintenance lurbinectedin with immunotherapy. I am treating patients with that regimen. We have to pause if they're patients who have brain metastases. This was not studied. [This population] was excluded from the IMforte trial that was presented at ASCO 2025, so we want to pause to make sure [we choose] the right patients for that consolidative therapy with lurbinectedin and immunotherapy.

The data are clear in the second-line setting [regarding] the role of tarlatamab over topotecan and amrubicin. The data may still be outstanding regarding the power of lurbinectedin. Those data might not be as clear-cut as those with topotecan. Most patients would [probably] be excited about avoiding topotecan and receiving tarlatamab instead.

Regarding the right sequence, chemoimmunotherapy has been established as the [first-line] SOC [for patients with ES-SCLC] as of 2019 with the FDA approval of atezolizumab (Tecentriq) followed by [the approval of] durvalumab [in 2020]. Now, we're seeing the introduction of consolidative therapies with lurbinectedin. The right patient has to be chosen [for this approach]. Tarlatamab [is standard in the] second-line setting.

We always want to look at clinical trials that might be available. This is how we establish research for the future today and how we can get those outcomes and those success stories now for patients. ADCs might be the next class of therapies we're seeing. [We are also seeing agents with] some novel mechanisms of action that dive at the biology of the disease that are upcoming, including cell cycle therapies, [data with which have] been recently published.

Which investigational agents in SCLC are especially promising?

The ADCs are most exciting, especially those targeting the markers that might be on neuroendocrine cells that confer poor prognosis, like B7-H3. Another exciting targeted therapy is the Aurora A kinase inhibitor alisertib [MLN8237]. That drives at the biology of MYC amplification and some of that signaling that is required for these cells to thrive, crippling them right at that breaking point.

We're seeing a lot of radioligands and agents coming about that are demonstrating good efficacy, as well as ADCs, even against DLL3. Those agents, post-tarlatamab, might be exciting options. We don't know the biology of what's going to show up with these cells after seeing these novel agents. That's where longitudinal liquid biopsies and having a better understanding of the disease following the management of mechanisms of resistance will help us identify novel targets to go forward with.

References

1. Rudin CM, Mountzios GS, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008
2. Paz-Ares LG, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16)suppl.8006