Tarlatamab and Durvalumab Enhance the SCLC Immunotherapy Paradigm

Isabel Preeshagul, DO, MBS

Several FDA approvals have expanded the previously sparse small cell lung cancer (SCLC) treatment armamentarium, shifting the standard of care (SOC) beyond traditional chemotherapy and toward immunotherapy-based strategies in both limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC), according to Isabel Preeshagul, DO, MBS.

In an interview with OncLive® following a State of the Science Summit™ on lung cancer, which she chaired, Preeshagul expanded on the significance of these regulatory milestones, including the December 2024 FDA approval of durvalumab (Imfinzi) after concurrent frontline chemoradiotherapy for the treatment of adult patients with LS-SCLC1 and the May 2024 accelerated FDA approval of tarlatamab-dlle (Imdelltra) for the treatment of patients with ES-SCLC who experience disease progression on or after platinum-based chemotherapy.2 Additionally, she discussed how comparable efficacy outcomes with the phase 3 IMpower133 (NCT02763579) and CASPIAN (NCT03043872) regimens engenders flexibility in frontline treatment selection.

“The key takeaway is that we have options now when previously, we didn’t. We have 2 FDA-approved options in the frontline setting: chemotherapy with atezolizumab [Tecentriq] or chemotherapy with durvalumab,” Preeshagul said about the significance of these regulatory decisions. “They’ve never been compared head to head, and there are pros and cons to both options. At this point…[treatment decisions] come down to what works best for the patient, what works best for their lifestyle, and what the oncologist feels most comfortable prescribing.”

Lastly, Preeshagul emphasized the need for biomarker-driven strategies to further personalize treatment and called for ongoing research to optimize frontline regimens and identify predictive biomarkers for treatment selection. Preeshagul is a thoracic medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in Montvale, New Jersey.

OncLive: What are the key distinctions between the IMpower133 and CASPIAN trials in ES-SCLC, and how might differences in survival outcomes, central nervous system activity, and maintenance schedules between these trials’ regimens influence frontline treatment selection?

Preeshagul: The CASPIAN trial investigated combining platinum-etoposide with durvalumab vs platinum-etoposide with placebo [in patients with first-line ES-SCLC]. [The Impower133 trial evaluated first-line atezolizumab plus platinum-etoposide in patients with ES-SCLC].

Although the [IMpower133] and CASPIAN regimens have not been [compared in] a head-to-head trial, I did do somewhat of a cross-trial comparison to see some of the pros and cons [of each regimen]. The CASPIAN data appeared to demonstrate a slightly better HR for survival and improved central nervous system penetration. We may need to watch that setting a bit more. Even though it wasn’t a blinded study, some of those adverse effects could have been attributed [to the study treatment] a bit better, and there may be some bias when interpreting those data, but it was an interesting find nonetheless.

The [IMpower133 and CASPIAN regimens are] both great frontline options. I tend to lean toward the CASPIAN regimen because the maintenance [therapy administration schedule] is every 4 weeks. However, we have some studies investigating chemotherapy plus atezolizumab with atezolizumab maintenance, and [some involving] antibody-drug conjugates [ADCs]. In [the context of those agents], I lean toward [the IMpower133 regimen] as well. However, there is no wrong choice, which is great.

How has the ADRIATIC trial helped redefine the SOC for LS-SCLC?

The ADRIATIC [trial] enrolled patients with LS-SCLC who were treated with concurrent chemotherapy and radiation, followed by durvalumab every 4 weeks for 2 years.

I was happy to see that the risk of pneumonitis [in this trial] was comparable between the placebo and experimental arms. [Overall, the regimen] seemed to be well tolerated, and there was a beautiful separation of the [survival] curves, so this is the new SOC for me. I was thrilled to see these data at the 2024 ASCO Annual Meeting, and I am excited that SCLC is being spotlighted [in the lung cancer field].

Overall, how have the FDA approvals of tarlatamab and durvalumab for the treatment of patients with chemotherapy-pretreated SCLC improved the treatment paradigm?

We now have options. We used to [only have] chemotherapy [followed by observation]. Then, [the SOC] became chemotherapy plus immunotherapy. However, there was really only topotecan and lurbinectedin ​​[Zepzelca] in the second-line setting. Now we have all these different options.

The approval [of durvalumab] following concurrent chemoradiation] for LS-SCLC based on the ADRIATIC data is practice changing. [Based on these findings], patients with LS-SCLC should receive concurrent chemotherapy and radiation followed by immunotherapy for 2 years with durvalumab, unless they have a contraindication, such as an autoimmune condition; for some reason the oncologist does not feel comfortable proceeding [with that regimen]; or the patient declines.

Now we also have tarlatamab [approved for ES-SCLC]. We’re realizing that DLL3 may be a marker we need to investigate more closely for patients with SCLC.

Despite recent therapeutic advances, what research is needed to address current challenges in managing SCLC?

Even though we have great options in the frontline setting, we all know that, at some point, these patients unfortunately progress. Is there something we could do in the frontline setting to enhance the [agents] we already have? Do we need to add ADCs to them? [Is the answer] combined treatment? Is there another marker we need to look for? Is it [SCLC-A subtype] or YAP1 [expression]? I’m curious to see what these markers might be and how we can potentially use them as predictive and maybe even prognostic markers to help guide treatment plans for our patients.

References

1. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-limited-stage-small-cell-lung-cancer
2. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. FDA. May 16, 2024. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer