Tarlatamab Sustains Responses, Shows Long-Term Tolerability in Heavily Pretreated SCLC

The bispecific T-cell engager (BiTE) tarlatamab-dlle (Imdelltra) demonstrated durable responses, favorable survival outcomes, and long-term tolerability in patients with previously treated small cell lung cancer (SCLC) regardless of their chemotherapy-free interval following first-line therapy, according to updated data from the phase 2 DeLLphi-301 study (NCT05060016) presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a median follow-up of 16.6 months, patients who received the 10 mg dose of tarlatamab (n = 100) in the dose-evaluation and -expansion portions of the study had an objective response rate (ORR) of 40% (95% CI, 30.3%-50.3%). Furthermore, 3% of patients achieved a complete response, 37% achieved a partial response, 30% had stable disease, 20% experienced disease progression, and 10% were not evaluable (NE) or had no post-baseline scan.

Additionally, the disease control rate (DCR) was 70% (95% CI, 60.0%-78.8%) in this group. Sustained disease control lasting at least 52 weeks was reported in 26% of patients, and the median duration of disease control was 6.9 months (95% CI, 5.4-8.6). Notably, tumor shrinkage was seen in 72% of patients.

Among responders to tarlatamab, (n = 40), the median duration of response (DOR) was 9.7 months (95% CI, 6.8-NE), with 43% of responses ongoing at the data cutoff date of January 12, 2024. The median time to response was 1.4 months (IQR, 1.3-1.4).

Further efficacy analysis showed that the median progression-free survival (PFS) was 4.3 months (95% CI, 2.9-5.6); 6- and 12-month PFS rates were 39.2% and 24.0%, respectively. At a median follow-up of 20.7 months, the median overall survival (OS) was 15.2 months with tarlatamab, and the Kaplan-Meier estimate for OS at 18 months was 46%. In the chemotherapy-free interval cohorts, the 6-, 12- and 18-month OS rates were 73.4%, 57.0%, and 46.0%, respectively. Accordingly, investigators concluded that OS was similar regardless of PFS interval after first-line platinum treatment (< 90 days vs ≥ 90 days).

“This is an indicator of the likelihood of response to treatment and durability of response,” presenting author Jacob Sands, MD, stated during an oral presentation of the data. “These overlapping curves represent a new paradigm in the second line and beyond, where the chemotherapy-free interval is not a determinant of the likelihood of response to therapy, nor the durability of that response.”

Sands is a physician and serves as the oncology medical director of the International Patient Center at Dana-Farber Cancer Institute, as well as an assistant professor at Harvard Medical School in Boston, Massachusetts.

DeLLphi-301 Overview and Trial Design

Patients with previously treated SCLC following 2 or more prior lines of therapy, including platinum-doublet therapy, were eligible for enrollment onto the open-label phase 2 trial. An ECOG performance status of 0 or 1 and measurable disease were required; treated or stable brain metastases were permitted in eligible patients.

Patients enrolled onto the dose-evaluation portion of the study (part 1) were randomly assigned 1:1 to either 10 mg (n = 88) or 100 mg of tarlatamab (n = 88) in part 1 of the study. In the 10 mg group, 1 mg of the agent was administered on day 1, followed by 10 mg on days 8, 15, and then every 2 weeks thereafter. Similarly, patients in the 100 mg group were treated with 1 mg of tarlatamab on day 1, followed by 100 mg on days 8, 15, and every 2 weeks thereafter.

Following dose selection, 12 patients were permitted to receive tarlatamab on the 10 mg schedule in the dose-expansion portion of the study (part 2). Notably, the 10 mg dose schedule was the schedule approved by the FDA, Sands stated in the presentation. In part 3 of the study, investigators utilized this as a reduced inpatient monitoring period during which 34 patients were treated on the same 10 mg dosing schedule.

ORR per RECIST 1.1 criteria by blinded independent central review (BICR) served as the primary end point of the study. Secondary end points included DOR, DCR, PFS per RECIST 1.1 criteria by BICR, OS, treatment-emergent adverse effects (TEAEs), and tarlatamab serum concentrations. The data cutoff date was January 12, 2024, for all efficacy end points excluding OS, for which the data cutoff date was May 16, 2024.

The median age of participants treated was 64 years (range, 35-82) in parts 1 and 2, and 66 (49-80) in part 3. The majority of participants were male (part 1 and 2, 72%; part 3, 71%); either Asian (41%; 6%), Black (0%; 3%), or White (58%; 91%); were current or prior smokers (92%; 97%); and had an ECOG performance status of 0 (26%; 29%) or 1 (74%; 71%).

The median number of prior lines was 2 in both parts 1/2 (range, 1-6) and part 3 (range, 2-6). Similarly, 65% of patients had 2 prior lines of therapy in both study portions. A total of 33% and 35% of patients in parts 1/2 and 3, respectively, had 3 or more prior lines of therapy. Additionally, 74% and 82% of patients had prior exposure to anti–PD-(L)1 therapy in these respective groups.

Furthermore, 28% of patients enrolled in parts 1/2 experienced disease progression less than 90 days after receipt of first-line platinum therapy compared with 21% of participants in part 3. Brain metastases were reported in 23% and 12 % of patients in parts 1/2 and part 3, respectively; 39% and 35% in these respective groups had liver metastases. Tumors expressing DLL3 were present in 96% (n = 83) of patients in parts 1/2 vs 94% (n = 16) in part 3.

“This represents a heavily pretreated group of patients with SCLC, the majority having prior anti–PD-[L]1 treatment, which now represents the standard of care [SOC] in the first-line setting,” Sands emphasized.

In the primary analysis of the DELLphi-301 study, tarlatamab demonstrated antitumor activity along with a manageable safety profile in patients with previously treated SCLC.

"This was previously published in The New England Journal of Medicine," Sands explained, "which led to the FDA granting tarlatamab accelerated approval for the treatment of [patients with] extensive-stage SCLC. Here we present the efficacy and safety outcomes from the extended follow-up."

Updated Safety Analysis of Tarlatamab

The most common tarlatamab-related AEs (TRAEs) over time were cytokine release syndrome (CRS), pyrexia, decreased appetite, dysgeusia, and fatigue. Although tarlatamab demonstrated long-term tolerability, with no new safety concerns in the extended analysis, TRAEs led to dose interruption in 16% of patients and discontinuation in 4%.

“The longer patients are on therapy, the more manageable the toxicity profile appears to become,” Sands summarized.

Treatment-emergent CRS events typically occurred following the first or second dose of therapy in cycle 1, with most being grade 1 or 2 AEs. Regarding the overall incidence of CRS, 32%, 29%, and 4% of patients experienced grade 1, 2, and 3 CRS, respectively. CRS recurrence occurred in 21% of patients at grade 1, and 4% at grade 2. The median time to resolution was 3 days (95% CI, 3-4).

Ten percent of patients experienced grade 1 immune effector cell associated neurotoxicity syndrome (ICANS) and 5% had grade 2 ICANS. ICANS events were all grade 1/2 and primarily early-onset, with most events occurring from 0 to less than 3 months (grade 1, 8%; grade 2, 3%) or 3 to less than 6 months (5%; 1%) vs 6 to less than 12 months (0%; 2%).

Based on these findings, Sands concluded that, “The phase 3 DeLLphi-304 study (NCT05740566) comparing the efficacy and safety of tarlatamab with SOC chemotherapy is currently in progress.”

References

1. Sands J, Cho BC, Ann MJ, et al. Tarlatamab sustained clinical benefit and safety in previously treated SCLC: DeLLphi-301 phase 2 extended follow-up. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract OA10.03.
2. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980