SMALL CELL
LUNG CANCER
Small cell lung cancer (SCLC)
is one of two main categories of lung cancer, and derives its name from how the
cancer cells appear under a microscope. SCLC is less common, compared to
non–small cell lung cancer (NSCLC), and represents about 15 percent of all lung
cancers. It is almost exclusively found in individuals who have smoked. SCLC is
very aggressive and metastasizes to other parts of the body quickly. Treatment
options with SCLC are few and are usually limited to radiation therapy and/or
chemotherapy. SCLC is considered to be highly responsive to treatment, but
extensive stage small cell lung cancer (ES-SCLC) usually recurs within 5 to 6 months. When an individual with SCLC experiences
a relapse after initial therapy, the median survival is approximately 2 to 6
months. The length of time of the response to initial therapy influences how
likely it is that the disease will respond to subsequent treatment. If the time
of the relapse from the last day of the initial therapy is less than 3 months,
or there was no response to the initial treatment, then it is likely that the
response rate will be less than 10 percent to the follow-up therapy. If the length
of time to relapse is more than 3 months, then it is likely that the response
rate to follow-up therapy will be approximately 25 percent.
TARLATAMAB-DLLE (IMDELLTRA)
Tarlatamab-dlle (Imdelltra) is a bispecific
delta-like ligand 3 (DLL3)-directed cluster of differentiation 3 (CD3) T-cell
engager that binds to DLL3 expressed on the surface of cells, including tumor
cells and T cells. Tarlatamab-dlle (Imdelltra) causes T-cell activation,
release of inflammatory cytokines, and lysis of DLL3-expressing cells. The US
Food and Drug Administration (FDA) label contains black box warnings for
potentially serious side effects, including cytokine release syndrome (CRS) and
immune effector cell-associated neurotoxicity syndrome (ICANS). Because of the risks for
these syndromes, the FDA label includes a step-up dosing schedule and recommends
close monitoring for multiple days after the administration of tarlatamab-dlle
(Imdelltra).
Cytokine-release
syndrome
CRS is an acute, systemic inflammatory reaction driven by immune‑cell activation that can be triggered by immune‑based therapies. CRS is characterized by activated T cells
and macrophages releasing high levels of cytokines including interleukin‑6, interferon‑gamma, and tumor necrosis factor‑alpha, driving capillary leak, vascular instability, and
organ impairment. CRS can be potentially life‑threatening, presenting with symptoms such as pyrexia,
hypotension, fatigue, tachycardia, headache, hypoxia, nausea, and vomiting,
with complications that may include cardiac dysfunction, acute respiratory
distress syndrome, renal or hepatic failure, and disseminated intravascular
coagulation.
Immune
effector cell-associated neurotoxicity syndrome
ICANS is a potentially severe neuropsychiatric complication of immune‑based therapies characterized by symptoms such as
confusion, altered consciousness, language disturbances, tremors, seizures,
and, in severe cases, cerebral edema. ICANS arises from systemic cytokine‑driven inflammation leading to endothelial activation
and blood–brain barrier disruption, triggering an inflammatory cascade within
the central nervous system. Symptoms typically develop within days after
treatment, often following or overlapping with CRS, and can progress rapidly,
necessitating prompt recognition and supportive management, including
glucocorticoids and antiseizure therapy.
CLINICAL
TRIALS
DeLLphi-301
DeLLphi-301 (NCT05060016) is a phase 2, open label, randomized
clinical trial to evaluate the efficacy and safety of
the use of intravenous (IV) tarlatamab-dlle (Imdelltra)
administered every 2 weeks to individuals with ES-SCLC whose disease hase progressed
or recurred after they received previous treatment, including a
platinum-based regimen, and at least one other prior line of therapy. The
clinical trial includes three parts. In part 1, participants will receive either
low dose or high dose therapy. In part 2, participants will receive the dosage
determined in part 1. In part 3, a select group of participants will receive
the dosage determined in part 1, but with reduced monitoring. A key primary
endpoint was objective response rate (ORR) up to 24 months. Key secondary endpoints
included duration of response (DOR) and progression-free survival (PFS). In
part 1, 88 individuals were randomly assigned into a cohort that received tarlatamab-dlle
(Imdelltra) at a dose of 10 mg IV every 2 weeks, and 88 individuals were
randomly assigned into a cohort that received tarlatamab-dlle (Imdelltra) at a dose of
100 mg IV every 2 weeks. During part 2, an additional 12 individuals were
enrolled. The ORR was 40 percent in the cohort that received 10 mg and 32
percent in the cohort that received 100 mg. The median DOR was not reached. The
median PFS was 4.9 months in the 10-mg cohort and 3.9 months in the 100-mg
cohort. Cytokine-release syndrome (CRS) occurred in 51 percent of the 10-mg
cohort and 61 percent of the 100-mg cohort, with most being grade 1 or 2. Grade
3 CRS occurred in 1 percent of the 10-mg cohort and 6 percent of the 100-mg
cohort. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred
in 8 percent of the 10-mg cohort and 28 percent of the 100-mg cohort ,with most
being grade 1 or 2. Grade 3 or higher ICANS was not observed in the 10-mg
cohort and occurred in 5 percent of the 100-mg cohort.
DeLLphi-304
DeLLphi-304
(NCT05740566) is a phase 3, open label, randomized clinical trial to evaluate
the efficacy and safety of the use of tarlatamab-dlle (Imdelltra) in
individuals with ES‑SCLC who
experienced progression after chemotherapy treatment with a platinum agent. A
total of 509 individuals were enrolled in two cohorts. Individuals were
randomly assigned 1:1 to receive either tarlatamab-dlle (Imdelltra) (n=254) or
standard‑of‑care chemotherapy (n=255), consisting of topotecan,
lurbinectedin, or amrubicin. The primary endpoint was overall survival (OS).
Key secondary endpoints included PFS and participant‑reported outcomes related to symptoms such as dyspnea.
Treatment
with tarlatamab-dlle (Imdelltra) demonstrated a statistically significant
improvement in OS, with a median OS of 13.6 months (95 percent confidence
interval [CI], 11.1 to not estimable) compared with 8.3 months (95 percent CI,
7.0–10.2) for standard‑of‑care chemotherapy (P<0.001). The secondary endpoint of
PFS also favored tarlatamab-dlle (Imdelltra), with a median PFS of 4.2 months
(95 percent CI, 3.0–4.4) versus 3.2 months (95 percent CI, 2.9–4.2) for
chemotherapy (P<0.001). Improvements in participant‑reported dyspnea were additionally observed, showing a
statistically significant benefit for tarlatamab-dlle (Imdelltra) relative to
standard‑of‑care therapy at week 18. Grade 3 or higher adverse events,
and the incidence of adverse events leading to treatment discontinuation, were
lower in the tarlatamab-dlle (Imdelltra) cohort as compared to the standard‑of‑care
cohort. At interim analysis, 17.06 percent of individuals in the
tarlatamab-dlle (Imdelltra) cohort had experienced CRS compared to none in the
standard-of-care cohort. At interim analysis, 3.57 percent of individuals in
the tarlatamab-dlle (Imdelltra) cohort had experienced ICANS compared to none
in the standard-of-care cohort. There have been no deaths in the tarlatamab-dlle
(Imdelltra) cohort and one in the standard-of-care cohort.
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document
due to evaluation of criteria highlighted in the Company's off-label policy,
and/or review of clinical guidelines issued by leading professional
organizations and government entities.
