Prognosis for SCLC remains poor
About two-thirds of patients with SCLC have extensive-stage (ES) disease at diagnosis with a median overall survival (OS) <12 months. [Semin Oncol 2025;52:14-18]
“The first major breakthrough in systemic therapy for ES-SCLC over the past three decades was the addition of immunotherapy [atezolizumab and durvalumab] to chemotherapy, which yielded a marginal OS benefit of 2–2.7 months,” noted Wolf. [N Engl J Med 2018;379:2220-2229; Lancet 2019;394:1929-1939]
Despite having a good initial response to first-line treatment, SCLC relapses quickly due to the emergence of resistance mutations while on treatment. [Nature 2024;627:880-889] Hence, treatment options for SCLC are limited after progression on first-line therapy.
Tarlatamab for patients with pretreated SCLC
Tarlatamab is a bispecific T-cell engager (BiTE) molecule. It binds to delta-like ligand 3 (DLL3) expressed on the surface of cancer cells and to CD3 on T-cells, leading to T-cell–mediated tumour cell lysis. [Clin Cancer Res 2021;27:1526-1537]
The phase I DeLLphi-300 and phase II DeLLphi-301 trials evaluated the use of tarlatamab in heavily pretreated patients with SCLC. [J Clin Oncol 2023;41:2893-2903; N Engl J Med 2023;389:2063-2075]
Durable anti-cancer responses
At a median follow-up of 16.6 months, the objective response rate (ORR) in patients who received tarlatamab 10 mg (n=100) in DeLLphi-301 was 40 percent. [Sands J, et al, WCLC 2024, abstract OA10.03] “The ORR in this heavily pretreated population is remarkable when compared with about 20 percent reported for topotecan, the current standard second-line treatment for SCLC,” commented Wolf. [J Clin Oncol 2007;25:2086-2092]
Tumour shrinkage was observed in 72 percent of patients. Among responders to tarlatamab (n=40), the median duration of response was 9.7 months.
Impressive survival outcomes
At a median follow-up of 20.7 months, the median OS was 15.2 months with tarlatamab. (Figure 1) [Sands J, et al, WCLC 2024, abstract OA10.03]
“After 1 year and 18 months, respectively, 57 and 46 percent of patients were still alive. Although these are early data, there seems to be a plateau developing, which could translate to long-term disease control,” remarked Wolf.
The OS was similar regardless of progression-free interval (<90 days vs ≥90 days) after first-line platinum-based therapy.
Manageable long-term safety and tolerability
Cytokine release syndrome (CRS) occurred in 53 percent of patients, and was primarily after the first or second dose in cycle 1 and cycle 2, with most events being of grade 1 or 2 in severity (in 32 and 20 percent of the patients, respectively). [Sands J, et al, WCLC 2024, abstract OA10.03]
“Inpatient monitoring is recommended for cycle 1 on day 1 [first exposure] and cycle 1 on day 8 [dose escalation], as these are the highest risk points for CRS,” advised Loong. “In our clinical trial experience, tarlatamab-associated CRS is relatively short-lived and self-limiting. Hence, we generally use dexamethasone and reserve tocilizumab only for very severe [grade ≥3] CRS.”
Immune effector cell–associated neurotoxicity syndrome (ICANS) was seen in 15 percent of patients. ICANS occurred infrequently, primarily with early onset (<6 months) and there were no grade 3 adverse events.
“Tarlatamab-related adverse events led to treatment discontinuation in only 4 percent of patients, which shows that it is very well tolerated,” pointed out Wolf.
Summary
Extended follow-up data for tarlatamab confirmed durable anticancer activity and long-term tolerability in previously treated patients with SCLC. There were no new safety concerns. CRS was mostly grade 1/2, occurring primarily in cycle 1 and generally manageable with supportive care.
