Summary Basis of Decision for Imdelltra

Clinical Pharmacology

Tarlatamab, the medicinal ingredient in 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 tumour cells, and CD3 expressed on the surface of T cells. Tarlatamab triggers T-cell activation, production of inflammatory cytokines, and lysis of DLL3-expressing cells.

In non-clinical studies, tarlatamab displayed anti-tumour activity in mouse models of small cell lung cancer.

Based on a population pharmacokinetic analysis using pooled data from 420 patients, the exposure of tarlatamab increased dose proportionally every 2 weeks in the evaluated dose range of 1 mg to 100 mg (10 times the highest approved recommended dosage). Approximate steady-state exposures in serum tarlatamab were achieved by Cycle 2, Day 15. Tarlatamab pharmacokinetics can be described with a two-compartment disposition model with first-order elimination. The results of the population pharmacokinetic analysis supported the proposed dose of 1 mg on Day 1, followed by 10 mg on Day 8, Day 15, and every 2 weeks thereafter. No clinically relevant differences in exposure to tarlatamab were identified according to patient characteristics, including age, body weight, sex, race, mild or moderate renal impairment, or mild hepatic impairment. The effects of severe renal impairment and moderate or severe hepatic impairment on the pharmacokinetics of tarlatamab are unknown due to limited data.

The pharmacodynamic response after a single infusion of tarlatamab was characterized by a transient cytokine elevation. Transient elevation of the serum cytokines interleukin (IL)-2, IL-6, IL-8, IL-10, and interferon gamma (IFN-γ) were observed at doses of 0.3 mg tarlatamab and above. Peak elevation of cytokines was generally observed 24 hours following the initial dose of tarlatamab at 1 mg on Cycle 1 Day 1, and the concentrations generally returned to baseline levels prior to the next infusion on Cycle 1 Day 8.

The analyses of the exposure-response relationships for efficacy measures confirmed that the exposures associated with the proposed dosing regimen of 10 mg every 2 weeks (Q2W) maximize the efficacy of tarlatamab. The analyses of exposure-response relationships for adverse events did not identify major safety concerns for the proposed dosage. However, a positive exposure-response relationship was identified between tarlatamab exposure and neutropenia or neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS). Additionally, a higher risk was observed of any grade neutropenia or neurologic toxicity, including ICANS, at higher exposures. No clinically relevant impact was observed on the corrected QT (QTc) interval.

For further details, please refer to the Imdelltra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Imdelltra was supported by the pivotal Phase II study DeLLphi-301 (20200491). This single-arm, open-label study was conducted in adult patients with extensive-stage small cell lung cancer (ES-SCLC) who progressed after receiving platinum-based chemotherapy and at least one other prior therapy. In total, 99 patients received intravenous infusions of 1 mg Imdelltra on Day 1, followed by 10 mg on Days 8 and 15, and 10 mg every 2 weeks until disease progression or intolerable toxicity.

The study population received a median of 2 prior therapies. All patients received prior platinum-based chemotherapy and 73.7% had previously been treated with a programmed death ligand-1 (PD-L1) inhibitor. Most patients (98%) had metastatic disease at baseline. Platinum sensitivity status, defined by the time to progression after first-line platinum-based chemotherapy, was known for 69 (70%) patients. Twenty-seven (27%) patients had platinum-resistant SCLC, i.e., the disease progression occurred less than 90 days after the end of first-line platinum-based chemotherapy. Forty-two patients (42%) had platinum-sensitive disease, i.e., the disease progression occurred 90 days or longer after the end of first-line platinum-based chemotherapy.

The primary efficacy endpoint was the objective response rate (ORR), assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 guidelines. The reported ORR was 40.4% (95% confidence interval [CI]: 30.7%, 50.7%). The median duration of response was not reached (95% CI: 5.9 months, not estimable [NE]) after a median follow-up time of 8.3 months. The ORR was consistent across most patient subgroups, including an ORR of 51.9% in platinum-resistant patients, who historically have very poor response rates.

Indication

In response to Health Canada’s request, the sponsor revised the proposed indication to more accurately reflect the patient population studied in the pivotal trial. Both the sponsor’s proposed indication and the indication approved by Health Canada are stated below.

Sponsor's proposed indication	Health Canada-approved indication
Imdelltra is indicated for the treatment of adult patients with advanced small cell lung cancer (SCLC) with disease progression on or after at least two prior lines of therapy.	Imdelltra is indicated for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after at least two prior lines of therapy including platinum-based chemotherapy.

For more information, refer to the Imdelltra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Imdelltra was evaluated in 187 patients with relapsed or refractory ES-SCLC from the pivotal study DeLLphi-301 and the first-in-human supportive study DeLLphi-300. These patients were treated with Imdelltra according to the recommended dosage regimen.

Nearly all patients reported treatment-emergent adverse events (TEAEs). The most common adverse events (reported in 20% of patients or more) were cytokine release syndrome (CRS), fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea. Serious adverse events were reported in 55.6% of patients, and severe (Grade 3 or 4) adverse events were reported in 63.1% of patients. Dose interruption due to adverse events was reported for 30.5% of patients, and 6.8% of patients permanently discontinued treatment due to adverse events. Fatal adverse events, including pneumonia, aspiration, respiratory failure, myocardial infarction, pulmonary embolism, and respiratory acidosis, occurred in 3.7% of patients.

The most important safety concerns observed with Imdelltra were CRS and ICANS. Cytokine release syndrome was reported in 55.1% of patients and ICANS was reported in 3.7% of patients. Most events were of low-grade severity. No fatal events of CRS or ICANS occurred. Two patients discontinued treatment with Imdelltra due to CRS and no patients discontinued treatment due to ICANS.

The risks of CRS and ICANS are highlighted in a Serious Warnings and Precautions box in the Imdelltra Product Monograph. Due to these risks, patients should be hospitalized and monitored for 24 hours and should remain within close proximity to a hospital for 48 hours from the start of the first two doses of Imdelltra. Additional risk mitigation and management strategies are provided in the Product Monograph, including step-up dosing, concomitant medication, dose interruption, dose discontinuation, and recommendations for supportive care.

Additional safety concerns with Imdelltra treatment include hepatoxicity, infections, tumour lysis syndrome and cytopenia.

For more information, refer to the Imdelltra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Data from various non-clinical studies were included in the submission, which assessed the mechanism of action, pharmacodynamics, pharmacology, and toxicology of tarlatamab in numerous model systems.

The cynomolgus monkey was chosen as a species for toxicological analysis. Cluster of differentiation 3 (CD3) and delta-like ligand 3 (DLL3) in monkeys are similar to their human counterparts; therefore, tarlatamab binds to both human and monkey CD3 and DLL3. However, as DLL3 is expressed intracellularly in normal cells and tissues, the pharmacological relevance of this species to cancer patients is unknown.

The toxicology studies in cynomolgus monkeys evaluated the safety of intravenous administration (the intended route of administration) of tarlatamab. Reductions in lymphocyte populations observed at doses greater than or equal to 1,000 mcg/kg were reversible during the recovery period. The repeat-dose toxicity studies included a 10-day study in which doses of 100 mcg/kg and higher were administered, a one-month study and a three-month study in which doses of up to 4,500 mcg/kg were administered. Changes in lymphocyte populations were observed, which correlated with decreases in the total levels of CD3, CD4, and CD8 T cells. Decreases in neutrophil numbers were observed at the highest dose (4,500 mcg/kg) in the one-month study. Reductions were detected in red blood cells, hemoglobin, and hematocrit in the 10-day study (at doses of 100 mcg/kg and higher) which were not reported in longer-term studies. This observation was considered by the sponsor as procedure-related. There were no unscheduled deaths at the maximum dose used in these studies (4,500 mcg/kg), which is approximately 9-fold higher than the clinical dose administered to patients.

Minimal to mild mononuclear cell infiltrates were observed in the pituitary glands of monkeys at doses of 50 mcg/kg and higher, and similar infiltrates or mixed cell infiltrates were observed in multiple tissues. In the 10-day study, increases in C-reactive protein, monocyte chemoattractant protein-1 (MCP-1), and interferon gamma (IFN-γ) were reported at doses of 100 mcg/kg and higher, suggesting an inflammatory response to tarlatamab. In the one-month study, increases in heart rate were noted at some time points. No such observations were noted in the three-month study.

A one-month toxicology study was also conducted in mice, using a murine surrogate of tarlatamab that differed only in the CD3-binding domain. Decreases in neutrophils and lymphocytes were noted at doses of 500 mcg/kg and higher.

Although tarlatamab demonstrates cross-reactivity with murine DLL3, it does not recognize murine CD3. The activity of tarlatamab was therefore evaluated in orthotopic xenograft models and patient-derived xenograft models of small cell lung cancer (SCLC) in immunocompromised mice, supplemented with human immune cells (either peripheral blood mononuclear cells [PBMCs] or T cells) prior to the administration of tarlatamab. Orthotopic models of SCLC were used to evaluate weekly intraperitoneal injections of tarlatamab (at doses of 0.1 mg/kg or higher), and results indicated that tumour growth was prevented. Additionally, ablation of tumour growth was demonstrated in SCLC models treated with tarlatamab, relative to those treated with an isotype control bispecific antibody. These results suggest that tarlatamab engages T cells by ligating DLL3-expressing cells, resulting in the lysis of DLL3-expressing cells.

An embryo-fetal developmental study was conducted in mice using the murine surrogate of tarlatamab during the period of organogenesis, in which the surrogate antibody was administered to pregnant mice on gestational days 6 and 13. No maternal toxicities and no fetal abnormalities were observed. However, the murine surrogate of tarlatamab was detected in fetal serum at concentrations 30-fold higher than those measured in maternal serum, suggesting that tarlatamab can cross the placenta. Considering that DLL3 is normally expressed intracellularly and that multiple murine genetic studies (knockout and loss-of-function) in the literature have reported developmental disruptions, the lack of abnormal observations is not surprising.

As the mechanism of action of tarlatamab involves T-cell activation, release of cytokines, and induction of inflammation, there is a potential for tarlatamab to adversely affect pregnancy. The potential for fetal harm is included in the Imdelltra Product Monograph. Additionally, a warning is included for females of reproductive potential to use contraception during treatment and for 2 months subsequent to the last dose of Imdelltra. The risk of exposure to tarlatamab through breast milk is unknown. However, since maternal immunoglobulin G antibodies are found in breast milk, patients treated with Imdelltra are also advised not to breastfeed their infant during treatment and for 2 months after the last dose.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Imdelltra Product Monograph. Considering the intended use of Imdelltra, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Imdelltra Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

The drug substance, tarlatamab, is a bispecific T-cell engager molecule. It consists of two single-chain variable fragment (scFv) binding domains: one specific for delta-like ligand 3 (DLL3), and the other specific for the T-cell coreceptor cluster of differentiation 3 (CD3). These are fused to a single-chain fragment crystallizable half-life extension (scFc HLE) moiety. The scFc can bind to the neonatal Fc receptor (FcRn), thereby prolonging the serum half-life of tarlatamab. The bispecific binding of tarlatamab to T cells and DLL3-positive tumour cells induces T cell-mediated cytotoxicity of the DLL3-expressing cancer cells.

The biochemical, biophysical, and biological features of tarlatamab were evaluated in detailed studies that provided a comprehensive characterization of its structural and functional properties and allowed for an assessment of critical quality attributes.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Tarlatamab, the drug substance, is manufactured using recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. A culture of cells expressing tarlatamab is initiated from a single working cell bank vial and transferred to progressively larger vessels as it expands to reach commercial scale. Tarlatamab is harvested from the cell culture fluid and purified through a downstream process including multiple chromatography steps interspersed with viral inactivation and filtration steps. The drug substance is filled into ethylene-vinyl acetate (EVA) bags, frozen, and stored at -30 °C ± 10 °C.

The drug product manufacturing process and process parameters for the 1 mg/vial and 10 mg/vial presentations are essentially the same, except for differences in the formulation step, fill weight targets, and lyophilization cycles. During the manufacturing of the 1 mg/vial presentation, the drug substance is diluted to a target concentration after thawing. The manufacturing process for the 10 mg/vial presentation does not include a drug substance dilution step. Both resultant solutions then undergo formulation, bioburden reduction filtration, an in-process hold step for the filtered formulated drug product, sterile filtration, aseptic filling, partial stoppering, lyophilization, capping, inspection, and storage at 2 °C to 8 °C.

The manufacturing processes were validated using consecutively manufactured batches of the drug substance and the drug product. Each batch of the drug substance was initiated from a different working cell bank vial. The process parameters, in-process controls, and release and stability specifications were evaluated, and the results indicated that the manufacturing processes consistently yield drug substance and drug product with the required quality attributes. Results from additional validation studies for both the drug substance and drug product manufacturing processes also provided evidence that these processes can maintain the quality of the drug substance and drug product during manufacturing and transport.

An intravenous solution stabilizer (IVSS) is supplied with Imdelltra to coat the intravenous bag prior to the addition of reconstituted Imdelltra, in order to prevent the adsorption of Imdelltra to the intravenous bags and tubing. The IVSS manufacturing process includes the following steps: formulation, bioburden reduction filtration, in-process hold of filtered formulated IVSS, sterile filtration, filling, stoppering, capping, inspection, and storage at 2 °C to 8 °C. Multiple validation studies were conducted which showed that the established processes maintain the quality of the IVSS during manufacturing.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of tarlatamab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Imdelltra is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

An appropriate control strategy, including in-process controls and process parameters, control of raw materials, adventitious agents and microbial contamination control, and specifications, has been established to assure the consistent production of high-quality Imdelltra drug substance and drug product.

The analytical procedures used in release and stability testing were validated according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Compendial methods were verified under conditions of use and the outcome was satisfactory.

Release and stability specifications complied with ICH guidelines, and were established based on product and process knowledge and statistical analyses of release and stability data. The established specifications are considered adequate to ensure the identity, purity, potency, and product safety of Imdelltra.

A two-tiered reference standard system is in place. Reference standards have been well characterised, and an appropriate program was established to qualify future primary and working reference material.

A risk assessment of elemental impurities was conducted. The risk of elemental impurities in the Imdelltra drug product is low, and in line with the threshold outlined in ICH guidelines. No additional controls are required.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. Imdelltra and the IVSS vials should be stored in the original package at 2 °C to 8 °C and protected from light until time of use. They must not be frozen. The prepared Imdelltra infusion bag is stable for 8 hours from the time of reconstitution at 20 °C to 25 °C, or for 7 days from the time of reconstitution at 2 °C to 8 °C.

Facilities and Equipment

No on-site evaluations were recommended or performed, based on successful results from prior inspections of the drug substance and drug product manufacturing sites conducted by the United States Food and Drug Administration. Overall, the facilities are considered suitable for the manufacturing of Imdelltra drug substance and the drug product.

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing processes of the drug substance and drug product to prevent contamination and maintain microbial control.

The materials used in the manufacturing processes meet compendial requirements and/or in-house specifications.

The master and working cell banks were established according to ICH guidelines. The results of qualification studies indicate that the starting materials were free from microbial and viral adventitious agents and meet all acceptance criteria for identity, culture purity, and genetic stability. The cell banks are suitable for use in the production of the drug substance. In-process testing is performed to monitor for bioburden, mycoplasma, and viruses. Purification process steps designed to inactivate and remove any potential viral contaminants from the cell culture process are adequately validated.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.