Imdelltra Approved for Treatment of Extensive-Stage Small Cell Lung Cancer on or Following Disease Progression While on Platinum-Based Chemotherapies

Lung cancer represents the most common cancer in the world to date, with the National Cancer Institute estimating 234,580 new cases in the United States in 2024.¹ Lung cancer can be classified 2 ways histologically: non–small cell lung cancer (NSCLC) (approximately 85% of cases) and small cell lung cancer (SCLC) (approximately 15% of cases).² SCLC is the more aggressive form and characterized by its rapid proliferation and high metastases rate.³ Although less common than NSCLC, SCLC is associated with a significantly lower 5-year survival rate in localized and distant disease.⁴

Globally, approximately 250,000 people are diagnosed with SCLC each year, with approximately 200,000 deaths.⁵ SCLC is primarily diagnosed in the later stages of life in patients aged >65 years.⁶ Although there are many modifiable and nonmodifiable risk factors associated with SCLC incidence, smoking history remains the largest predictor for risk of contracting SCLC. Smoking history is present in 95% of all SCLC cases, and smoking cessation is the most effective method of reducing risk.⁵ Other factors that increase risk include exposures to known carcinogens (asbestos), secondhand smoke, environmental pollution, and certain genetic dispositions.³

As time passes and the effect of changes in smoking habits start to take effect, there is a markedly noticeable decrease in the incidence of lung cancer overall.⁵ However, SCLC continues to pose a significant clinical challenge due to its aggressive nature. The overall 5-year survival rate differs heavily by stage, with localized tumors having a significantly higher survival rate (30%) than distant (3%).⁴ Overall, as a large portion of patients do display advanced disease at the time of diagnosis, the 5-year survival rate is approximately 7% across all stages of disease.⁴

Treatment modalities for SCLC are largely dependent on stage. For patients with limited-stage disease, based on disease progression and other patient factors, patients may receive some combination of surgery, radiation, and chemotherapy.⁷ Extensive-stage disease is predominantly managed with systemic chemotherapies and immunotherapies.⁷ Immunotherapies may include atezolizumab and durvalumab, which are both PD-L1 immune checkpoint inhibitors that are approved in the treatment of extensive-stage SCLC.⁷ Chemotherapy options are often combinations with a variety of agents, but standard treatment includes both etoposide and a platinum-based agent such as cisplatin.⁷

The unmet need in SCLC is high, particularly for efficacious treatment options with novel targets. Innovation in SCLC has been minimal until recently. Although there are newer agents such as single-agent nivolumab and atezolizumab currently being marketed, there was a lack of clear benefit in the use of these agents in SCLC.⁸ Ipilimumab showed promising efficacy, but at the cost of high toxicities, illustrating the need for continued research and development for novel SCLC treatments.⁸

FDA Approval of Tarlatamab for Treating Extensive-Stage-SCLC

On May 16, 2024, the FDA granted accelerated approval to tarlatamab-dlle (Imdelltra; Amgen Inc) for the treatment of extensive-stage SCLC with disease progression on or after platinum-based chemotherapy.⁸ Tarlatamab-dlle was granted priority review, breakthrough designation, orphan drug designation, and is currently approved under accelerated approval based on overall response rate (ORR, 40%; 97.5% confidence interval [CI], 29-52) and duration of response (DOR; median months until first progression, 9.7).^9-11

Mechanism of Action

Tarlatamab-dlle is a bispecific T-cell engager that binds to DLL3 expressed on the surface of tumor cells and CD3 expressed on the surface of T cells. Tarlatamab-dlle causes T-cell activation that results in lysis of DLL3-expressing tumor cells.¹¹

Dosing and Administration

Tarlatamab-dlle is prepared as an intravenous infusion and utilizes a step-up procedure to reduce the risk of adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).¹¹ Bispecific agents including tarlatamab-dlle are prone to adverse events such as CRS that may cause treatment delays. The step-up process is utilized in combination with pre- and post-medications, including steroids and hydration.¹¹

The manufacturer recommends monitoring during the step-up process be performed in an appropriate healthcare setting.¹¹ Initial infusions for cycle 1 require monitoring for 22 to 24 hours, and the patient remains within 1 hour of an appropriate healthcare setting for a total of 48 hours from the start of the first infusion. Subsequent cycles require less monitoring and do not have to be in a healthcare setting unless the patient experiences grade ≥2 CRS, ICANS, or neurological toxicity.

Pivotal Clinical Trial

The FDA approval of tarlatamab-dlle for the treatment of extensive-stage-SCLC with disease progression on or after platinum-based chemotherapy is based on findings from the DeLLphi-301 (NCT05060016) study.¹⁰ This trial was an open-label, multicenter, multicohort clinical trial utilizing patients with confirmed relapsed or refractory extensive-stage SCLC.¹⁰ To be included in the study, patients were required to have relapsed or refractory extensive-stage SCLC with disease progression after receiving previous treatment with platinum-based chemotherapy, an ECOG Performance Status of 0 or 1, and at least 1 measurable lesion as defined by RECIST v1.1.¹⁰ Patients could not have symptomatic brain metastases, evidence of interstitial lung disease or noninfectious pneumonitis, or active immunodeficiency.¹⁰

Ninety-nine patients enrolled into the trial received tarlatamab-dlle intravenously at an initial dose of 1 mg on cycle 1 day 1 followed by 10 mg on days 8 and 15, and every 2 weeks until disease progression or unacceptable toxicity.¹⁰ The primary efficacy endpoints were ORR and DOR as evaluated by Blinded Independent Central Review according to RECIST v1.1 criteria.¹⁰ Assessments of the tumor were done every 6 weeks for the first 48 weeks and every 12 weeks afterwards.¹⁰

Of the 99 patients enrolled into the trial, the ORR was 40% (97.5% CI, 29-52), with a complete response rate of 1% and a partial response rate of 39%.¹⁰ In terms of DOR, participants had a Kaplan-Meier estimated median of 9.7 months until first sign of disease progression, with 68% and 40% of patients having a DOR of 6 months and 12 months, respectively.¹¹

Adverse Events

The most commonly reported adverse events (>20%) in the trial patients were CRS (51%), fatigue (51%), pyrexia (35%), and decreased appetite (29%).¹⁰ The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes (57%), decreased sodium (16%), and increased uric acid (10%).¹¹

Use in Specific Populations

There are no data that indicate safe use of tarlatamab-dlle in pregnant patients.¹¹ However, based on the mechanism of action, tarlatamab-dlle may affect a woman’s ability to maintain a pregnancy.¹¹ The background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20%, respectively. Due to the potential risk of tarlatamab-dlle, female patients are recommended to verify their pregnancy status and utilize effective contraception during and for 2 months after receiving tarlatamab-dlle.¹¹

Tarlatamab-dlle also has no current data to support its presence in human milk, milk production, or its effects on a breastfed child.¹¹ However, because of the potential for serious adverse events in the breastfed child, patients are advised not to breastfeed during treatment with tarlatamab-dlle and for 2 months after the last dose is administered.¹¹

There were no overall differences in pharmacokinetics or safety that were observed between older (≥65 years) and younger (≤65 years) patients, and there are no current recommendations for use of this agent in pediatric patients.¹¹

Warnings and Precautions

CRS is a serious life-threatening adverse event that can occur with the use of tarlatamab-dlle.¹¹ CRS is characterized by pyrexia, hypotension, hypoxia, and other nonspecific symptoms.¹¹ Utilization of the recommended step-up dosing, premedication, and hydration in an appropriate healthcare facility for cycle 1 can assist in reducing the risk of CRS.¹¹

ICANS is another serious adverse event that is associated with tarlatamab-dlle use.¹¹ The onset of ICANS can be concurrent with CRS, or appear separate from it, and is characterized by neurological symptoms including confused state, depressed level of consciousness, and disorientation. Upon the initial signs of ICANS, patients may need treatment held or discontinued as well as appropriate supportive care based on severity.¹

Other adverse events include cytopenias, serious infections, hepatotoxicity, hypersensitivity, and embryo-fetal toxicity.¹¹

Conclusion

Patients diagnosed with extensive-stage SCLC have poor prognoses, but recent advancements in the oncology field provide novel new ways to treat SCLC apart from traditional surgical, radiation, and combination chemotherapy modalities. The DeLLphi-301 study demonstrated that tarlatamab-dlle had objective tumor responses in patients with extensive-stage SCLC with disease progression, on or after platinum chemotherapy. Tarlatamab-dlle represents a new and effective treatment option for those with extensive-stage SCLC and a novel mechanism of action warranting further research that may have applications in a variety of other tumor types.

References

1. National Cancer Institute. Common cancer types. Accessed July 12, 2024. https://www.cancer.gov/types/common-cancers
2. Basumallik N, Agarwal M. Small cell lung cancer [Updated 2023 Jul 10]. Treasure Island, FL: StatPearls; 2024. Accessed November 7, 2024. https://www.ncbi.nlm.nih.gov/books/NBK482458/
3. Yale Medicine. Small cell lung cancer. Accessed July 12, 2024. https://www.yalemedicine.org/conditions/small-cell-lung-cancer#:~:text=Due%20to%20how%20quickly%20it,bones%2C%20adrenal%20glands%20and%20brain
4. American Cancer Society. Lung cancer survival rates. Accessed July 20, 2024. https://www.cancer.org/cancer/types/lung-cancer/detection-diagnosis-staging/survival-rates.html
5. Wang Q, Gümüş ZH, Colarossi C, et al. SCLC: epidemiology, risk factors, genetic susceptibility, molecular pathology, screening, and early detection. J Thoracic Oncol. 2022;18.
6. American Cancer Society. Key statistics for lung cancer. Accessed July 12, 2024. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
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8. Cancer Therapy Advisor. Treatment for relapsed SCLC remains area of high unmet need. Accessed October 11, 2024. https://www.cancertherapyadvisor.com/news/sclc-small-cell-lung-cancer-relapsed-treatment-unmet-need/
9. FDA. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. Accessed July 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer
10. Ahn M, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389(22).
11. FDA. Amgen. Imdelltra (tarlatamab) [package insert]. Accessed July 14, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761344s000lbl.pdf