On September 9, 2024 Amgen (NASDAQ:AMGN) reported the presentation of new data showcasing IMDELLTRATM (tarlatamab-dlle), a first-in-class delta-like ligand 3 (DLL3)-targeting Bispecific T-cell Engager (BiTE) molecule, at the 2024 World Conference on Lung Cancer (WCLC) in San Diego (Press release, Amgen, SEP 9, 2024, View Source [SID1234646420]).

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IMDELLTRA will be featured in two oral presentations at the "DLL3 Targeting BiTE Therapies in SCLC" session, taking place today at 2:00 p.m. PDT. New data from the global Phase 1b DeLLphi-303 study of IMDELLTRA combined with PD-L1 inhibitors in first-line maintenance extensive-stage small cell lung cancer (ES-SCLC) will be presented as a late-breaking abstract (#LBA OA10.04). Additionally, long-term results from the Phase 2 DeLLphi-301 study in previously treated ES-SCLC will be highlighted as an oral presentation (#OA10.03).

"Earlier this year, the FDA approved IMDELLTRA for patients with extensive-stage small cell lung cancer who progressed on or after platinum-based chemotherapy. Today, we are thrilled to share results showing long-term sustained benefit in this setting as well as initial evidence supporting a combination approach in front-line maintenance therapy," said Jay Bradner, M.D., executive vice president, Research and Development, and chief scientific officer at Amgen. "These data support our goal to deliver an effective targeted immunotherapy to more patients living with this aggressive cancer."

DeLLphi-303 Phase 1b Study Data in First-Line Maintenance Therapy
IMDELLTRA combined with a PD-L1 inhibitor as first-line maintenance therapy in ES-SCLC demonstrated a manageable safety profile with sustained disease control and positive survival outcomes. Key findings include:

IMDELLTRA plus a PD-L1 inhibitor: demonstrated a positive benefit: risk profile with no new or unexpected safety findings
IMDELLTRA plus durvalumab: disease control rate (DCR) of 62.5% (95% CI: 45.8-77.3) and median duration of disease control (DoDC) that was Not Estimable (95% CI: 3.9, NE)
IMDELLTRA plus atezolizumab: DCR of 62.5% (95% CI: 47.4-76.0) and median DoDC of 7.2 months (95% CI: 5.6, NE)
Following a median time of 3.5 months from first-line chemoimmunotherapy to first-line maintenance:
IMDELLTRA plus durvalumab showed a 9-month overall survival (OS) of 91.8% (95% CI: 76.6-97.3) and median progression-free survival (mPFS) of 5.3 months (95% CI: 3.5-NE)
IMDELLTRA plus atezolizumab showed a 9-month OS of 86.7% (95% CI: 70.3-94.4) and mPFS of 5.6 months (95% CI: 3.5-8.5)
"Tarlatamab has been a major breakthrough for patients with extensive-stage small cell lung cancer, who have had limited options for the past 30 years, and these data are impressive as a potential first-line maintenance treatment as well," said Sally Lau, M.D., oncologist and assistant professor of medicine, Perlmutter Cancer Center, NYU Grossman School of Medicine. "In particular, tarlatamab in combination with a PD-L1 inhibitor showed exciting safety and efficacy, which strongly supports continued evaluation in the ongoing Phase 3 DeLLphi-305 trial."

In patients receiving IMDELLTRA plus durvalumab, treatment-related adverse events (TRAEs) resulted in dose interruptions in 15% of cases and discontinuation in 8% of patients. In the IMDELLTRA plus atezolizumab treatment arm, TRAEs led to dose interruptions in 17% of cases and discontinuation of IMDELLTRA in 4% of patients. Cytokine release syndrome (CRS) was mostly grade 1-2, occurring primarily in cycle 1 and generally manageable with supportive care. Immune effector cell-associated neurotoxicity syndrome (ICANS) was infrequent overall, with a lower incidence and severity observed in the IMDELLTRA plus durvalumab treatment arm compared to IMDELLTRA plus atezolizumab treatment arm.

DeLLphi-301 Phase 2 Extended Follow-up Data in ES-SCLC
Extended follow-up data from the DeLLphi-301 Phase 2 study demonstrated sustained anticancer activity and a manageable safety profile with IMDELLTRA in patients with ES-SCLC previously treated with platinum-based chemotherapy.

Among 100 patients treated with IMDELLTRA 10 mg biweekly, the objective response rate (ORR) was 40%, with nearly half of the responders maintaining their response at data cutoff. Stable disease was observed in 30% of the patients, and the median duration of disease control was 6.9 months (95% CI, 5.4-8.6). Median OS for this group was 15.2 months and was similar regardless of progression-free interval (<90 days or 90+ days) after first-line platinum-based chemotherapy. IMDELLTRA demonstrated long-term tolerability with no new safety concerns identified. These findings support the continued use of IMDELLTRA in this patient population, underscoring its clinical significance.

About DeLLphi-303 Study
Preclinical studies indicated that IMDELLTRA upregulated PD-L1 expression and demonstrated increased cytotoxic activity when combined with a PD-L1 inhibitor.1,2

The DeLLphi-303 study is a Phase 1b, multicenter, open-label study evaluating the safety and efficacy of first-line IMDELLTRA in combination with standard-of-care chemoimmunotherapy, followed by IMDELLTRA plus PD-L1 inhibitor, in patients with ES-SCLC.

DeLLphi-303 will also evaluate IMDELLTRA in combination with a PD-L1 inhibitor as first-line maintenance only following standard-of-care chemoimmunotherapy. This part of the study includes 88 patients assigned to receive either IMDELLTRA 10 mg administered intravenously (IV) every two weeks plus atezolizumab 1680 mg IV every four weeks (n=48), or IMDELLTRA 10 mg IV every two weeks plus durvalumab 1500 mg IV every four weeks (n=40). The study protocol allowed for switching of PD-L1 inhibitor for the maintenance treatment, from that received by the patient during initial first-line treatment with platinum-based chemotherapy.

The primary endpoint in DeLLphi-303 is safety and tolerability of IMDELLTRA in combination with a PD-L1 inhibitor, with or without chemotherapy. For the investigation of IMDELLTRA in front-line with chemoimmunotherapy followed by maintenance with a PD-L1 inhibitor, the secondary endpoints include ORR, duration of response (DoR), DCR, PFS and OS. For the investigation of IMDELLTRA in first-line maintenance following front-line standard-of-care chemoimmunotherapy, the secondary endpoints include DCR, PFS, and OS, beginning from the start of first-line maintenance.

About DeLLphi-301 Study
The U.S. Food and Drug Administration accelerated approval of IMDELLTRA is based on results from the Phase 2 DeLLphi-301 clinical trial, in which IMDELLTRA at 10 mg or 100 mg dosed once every 2 weeks was evaluated in patients with SCLC who were refractory to or relapsed after one platinum-based regimen, with or without a checkpoint inhibitor, and at least one other line of therapy. The primary efficacy endpoint was ORR per RECIST 1.1 by blinded independent central review. In part 2 of the study, additional patients were enrolled at the 10 mg dose until 100 patients were reached, and Part 3 was a safety sub-study that evaluated a shortened monitoring period at a medical facility following administration of the first two doses of IMDELLTRA. Across all parts, patients received an initial 1 mg step up dose on day 1, followed by the 10 mg or 100 mg target doses on days 8 and 15 of cycle 1, and then every two weeks in 28-day cycles until disease progression.

About IMDELLTRA (tarlatamab-dlle)
IMDELLTRA received accelerated approval from the U.S. Food and Drug Administration on May 16, 2024. IMDELLTRA is a first-in-class immunotherapy engineered by Amgen researchers that binds to both DLL3 on cancer cells and CD3 on T cells, creating a cytolytic synapse between T cells and cancer cells. The activated T cells then mediate lysis of DLL3-expressing SCLC cells.1,3 DLL3 is a protein that is expressed on the surface of SCLC cells in ~85-96% of patients with SCLC, but is minimally expressed on healthy cells, making it an exciting target.4,5

IMDELLTRATM (tarlatamab-dlle) U.S. Indication
IMDELLTRA (tarlatamab-dlle) is indicated for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

Cytokine release syndrome (CRS), including serious or life-threatening reactions, can occur in patients receiving IMDELLTRATM. Initiate treatment with IMDELLTRATM using the step-up dosing schedule to reduce the incidence and severity of CRS. Withhold IMDELLTRATM until CRS resolves or permanently discontinue based on severity.
Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including serious or life-threatening reactions, can occur in patients receiving IMDELLTRATM. Monitor patients for signs and symptoms of neurologic toxicity, including ICANS, during treatment and treat promptly. Withhold IMDELLTRATM until ICANS resolves or permanently discontinue based on severity.
WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS): IMDELLTRATM can cause CRS including serious or life-threatening reactions. In the pooled safety population, CRS occurred in 55% of patients who received IMDELLTRATM, including 34% Grade 1, 19% Grade 2, 1.1% Grade 3 and 0.5% Grade 4. Recurrent CRS occurred in 24% of patients, including 18% Grade 1 and 6% Grade 2.

Most events (43%) of CRS occurred after the first dose, with 29% of patients experiencing any grade CRS after the second dose and 9% of patients experiencing CRS following the third dose or later. Following the Day 1, Day 8, and Day 15 infusions, 16%, 4.3% and 2.1% of patients experienced ≥ Grade 2 CRS, respectively. The median time to onset of all grade CRS from most recent dose of IMDELLTRATM was 13.5 hours (range 1 to 268 hours). The median time to onset of ≥ Grade 2 CRS from most recent dose of IMDELLTRATM was 14.6 hours (range: 2 to 566 hours).

Clinical signs and symptoms of CRS included pyrexia, hypotension, fatigue, tachycardia, headache, hypoxia, nausea, and vomiting. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Administer IMDELLTRATM following the recommended step-up dosing and administer concomitant medications before and after Cycle 1 IMDELLTRATM infusions as described in Table 3 of the Prescribing Information (PI) to reduce the risk of CRS. Administer IMDELLTRATM in an appropriate health care facility equipped to monitor and manage CRS. Ensure patients are well hydrated prior to administration of IMDELLTRATM.

Closely monitor patients for signs and symptoms of CRS during treatment with IMDELLTRATM. At the first sign of CRS, immediately discontinue IMDELLTRATM infusion, evaluate the patient for hospitalization and institute supportive care based on severity. Withhold or permanently discontinue IMDELLTRATM based on severity. Counsel patients to seek medical attention should signs or symptoms of CRS occur.

Neurologic Toxicity, Including ICANS: IMDELLTRATM can cause serious or life-threatening neurologic toxicity, including ICANS. In the pooled safety population, neurologic toxicity, including ICANS, occurred in 47% of patients who received IMDELLTRATM, including 10% Grade 3. The most frequent neurologic toxicities were headache (14%), peripheral neuropathy (7%), dizziness (7%), insomnia (6%), muscular weakness (3.7%), delirium (2.1%), syncope (1.6%), and neurotoxicity (1.1%).

ICANS occurred in 9% of IMDELLTRATM-treated patients. Recurrent ICANS occurred in 1.6% of patients. Most patients experienced ICANS following Cycle 2 Day 1 (24%). Following Day 1, Day 8, and Day 15 infusions, 0.5%, 0.5% and 3.7% of patients experienced ≥ Grade 2 ICANS, respectively. The median time to onset of ICANS from the first dose of IMDELLTRATM was 29.5 days (range: 1 to 154 days). ICANS can occur several weeks following administration of IMDELLTRATM. The median time to resolution of ICANS was 33 days (range 1 to 93 days).

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Patients receiving IMDELLTRATM are at risk of neurologic adverse reactions and ICANS resulting in depressed level of consciousness. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, in the event of any neurologic symptoms until they resolve.

Closely monitor patients for signs and symptoms of neurologic toxicity and ICANS during treatment. At the first sign of ICANS, immediately evaluate the patient and provide supportive therapy based on severity. Withhold IMDELLTRATM or permanently discontinue based on severity.

Cytopenias: IMDELLTRATM can cause cytopenias including neutropenia, thrombocytopenia, and anemia. In the pooled safety population, decreased neutrophils occurred in 12% including 6% Grade 3 or 4 of IMDELLTRATM-treated patients. The median time to onset for Grade 3 or 4 neutropenia was 29.5 days (range: 2 to 213). Decreased platelets occurred in 33% including 3.2% Grade 3 or 4. The median time to onset for Grade 3 or 4 decreased platelets was 50 days (range: 3 to 420). Decreased hemoglobin occurred in 58% including 5% Grade 3 or 4. Febrile neutropenia occurred in 0.5% of patients treated with IMDELLTRATM.

Monitor patients for signs and symptoms of cytopenias. Perform complete blood counts prior to treatment with IMDELLTRATM, before each dose, and as clinically indicated. Based on the severity of cytopenias, temporarily withhold, or permanently discontinue IMDELLTRATM.

Infections: IMDELLTRATM can cause serious infections, including life-threatening and fatal infections. In the pooled safety population, infections, including opportunistic infections, occurred in 41% of patients who received IMDELLTRATM. Grade 3 or 4 infections occurred in 13% of patients. The most frequent infections were COVID-19 (9%, majority during the COVID-19 pandemic), urinary tract infection (10%), pneumonia (9%), respiratory tract infection (3.2%), and candida infection (3.2%).

Monitor patients for signs and symptoms of infection prior to and during treatment with IMDELLTRATM and treat as clinically indicated. Withhold or permanently discontinue IMDELLTRATM based on severity.

Hepatotoxicity: IMDELLTRATM can cause hepatotoxicity. In the pooled safety population, elevated ALT occurred in 42%, with Grade 3 or 4 ALT elevation occurring in 2.1%. Elevated AST occurred in 44% of patients, with Grade 3 or 4 AST elevation occurring in 3.2%. Elevated bilirubin occurred in 15% of patients; Grade 3 or 4 total bilirubin elevations occurred in 1.6% of patients. Liver enzyme elevation can occur with or without concurrent CRS. Monitor liver enzymes and bilirubin prior to treatment with IMDELLTRATM, before each dose, and as clinically indicated. Withhold IMDELLTRATM or permanently discontinue based on severity.

Hypersensitivity: IMDELLTRATM can cause severe hypersensitivity reactions. Clinical signs and symptoms of hypersensitivity may include, but are not limited to, rash and bronchospasm. Monitor patients for signs and symptoms of hypersensitivity during treatment with IMDELLTRATM and manage as clinically indicated. Withhold or consider permanent discontinuation of IMDELLTRATM based on severity.

Embryo-Fetal Toxicity: Based on its mechanism of action, IMDELLTRATM may cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMDELLTRATM and for 2 months after the last dose.
ADVERSE REACTIONS

The most common (> 20%) adverse reactions were CRS (55%), fatigue (51%), pyrexia (36%), dysgeusia (36%), decreased appetite (34%), musculoskeletal pain (30%), constipation (30%), anemia (27%) and nausea (22%). The most common (≥ 2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes (57%), decreased sodium (16%), increased uric acid (10%), decreased total neutrophils (6%), decreased hemoglobin (5%), increased activated partial thromboplastin time (5%), decreased potassium (5%), increased aspartate aminotransferase (3.2%), decreased white blood cells (3.8%), decreased platelets (3.2%), and increased alanine aminotransferase (2.1%).
Serious adverse reactions occurred in 58% of patients. Serious adverse reactions in > 3% of patients included CRS (24%), pneumonia (6%), pyrexia (3.7%), and hyponatremia (3.6%). Fatal adverse reactions occurred in 2.7% of patients including pneumonia (0.5%), aspiration (0.5%), pulmonary embolism (0.5%), respiratory acidosis (0.5%), and respiratory failure (0.5%).
DOSAGE AND ADMINISTRATION: Important Dosing Information

Administer IMDELLTRATM as an intravenous infusion over one hour.
Administer IMDELLTRATM according to the step-up dosing schedule in the IMDELLTRATM PI (Table 1) to reduce the incidence and severity of CRS.
For Cycle 1, administer recommended concomitant medications before and after Cycle 1 IMDELLTRATM infusions to reduce the risk of CRS reactions as described in the PI (Table 3).
IMDELLTRATM should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity including ICANS.
Due to the risk of CRS and neurologic toxicity, including ICANS, monitor patients from the start of the IMDELLTRATM infusion for 22 to 24 hours on Cycle 1 Day 1 and Cycle 1 Day 8 in an appropriate healthcare setting.
Recommend that patients remain within 1 hour of an appropriate healthcare setting for a total of 48 hours from start of the infusion with IMDELLTRATM following Cycle 1 Day 1 and Cycle 1 Day 8 doses, accompanied by a caregiver.
Prior to administration of IMDELLTRATM evaluate complete blood count, liver enzymes, and bilirubin before each dose, and as clinically indicated.
Ensure patients are well hydrated prior to administration of IMDELLTRATM.
Please see IMDELLTRA full Prescribing Information, including BOXED WARNINGS

About Small Cell Lung Cancer
SCLC is one of the most aggressive and devastating solid tumor malignancies, with a median survival of approximately 12 months following initial therapy and a 3% five-year relative survival rate for ES-SCLC.6,7,8 Current second-line treatments impart a short duration of response (median DoR: 3.3–5.3 months) and limited survival (median OS: 5.8-9.3 months), while current third-line treatments for SCLC, which consist primarily of chemotherapy, yield a short median DoR of 2.6 months and a median OS of 4.4-5.3 months.9,10,11,12,13 SCLC comprises ~15% of the 2.4 million plus patients diagnosed with lung cancer worldwide each year.14,15,16 Despite initial high response rates to first-line platinum-based chemotherapy, most patients quickly relapse within months and require subsequent treatment options.14

About IMDELLTRA (taralatamab-dlle) Clinical Trials
Amgen’s robust IMDELLTRA development program includes the DeLLphi clinical trials, which evaluate IMDELLTRA as both a monotherapy and in combination regimens in earlier lines of SCLC, and DeLLpro clinical trials, which evaluate the efficacy and safety of tarlatamab in neuroendocrine prostate cancer.

In the Phase 1 DeLLphi-300 study, IMDELLTRA showed responses in 23.4% of patients with encouraging durability in heavily pre-treated patients with SCLC.17 In the Phase 2 DeLLphi-301 study, IMDELLTRA administered as 10 mg dose every two weeks demonstrated an ORR of 40% in patients with advanced SCLC who had failed two or more prior lines of treatment. In the DeLLphi-301 Phase 2 trial, the most frequent treatment-related adverse events seen with 10 mg Q2W dosing regimen were CRS (51%), pyrexia (32%), and decreased appetite (23%). CRS events were predominantly grade 1 or 2 and occurred most often after the first or second dose.2 Treatment discontinuation for adverse events occurred in 4-7% of patients in the two trials.4,17

Tarlatamab is being investigated in multiple studies including DeLLphi-303, a Phase 1b study investigating tarlatamab in combination with standard-of-care therapies in first-line ES-SCLC; DeLLphi-304, a randomized Phase 3 trial comparing tarlatamab monotherapy with standard-of-care chemotherapy in second-line treatment of SCLC; DeLLphi-305, a randomized Phase 3 trial comparing tarlatamab in combination with durvalumab versus durvalumab alone as first-line maintenance treatment in ES-SCLC; DeLLphi-306, a randomized placebo-controlled Phase 3 trial of tarlatamab following concurrent chemoradiotherapy in limited-stage SCLC; and DeLLpro-300, a Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer.18

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About Bispecific T-Cell Engager (BiTE) Technology
BiTE technology is a targeted immuno-oncology platform that is designed to engage a patient’s own T cells to any tumor-specific antigen, activating the cytotoxic potential of T cells to eliminate detectable cancer. The BiTE immuno-oncology platform has the potential to treat different cancer types through tumor-specific antigens. The BiTE platform has a goal of leading to off-the-shelf solutions, which have the potential to make innovative T-cell treatment available to all providers when their patients need it. For more than a decade, Amgen has been advancing this innovative technology, which has demonstrated strong efficacy in hematological malignancies and now a solid tumor with the approval of IMDELLTRA. Amgen remains committed to progressing multiple BiTE molecules across a broad range of hematologic and solid tumor malignancies, paving the way for additional applications in more tumor types. Amgen is further investigating BiTE technology with the goal of enhancing patient experience and therapeutic potential. To learn more about BiTE technology, visit BiTE Technology 101.