A New Era in Small Cell Lung Cancer Treatment with Ifinatamab Deruxtecan

Small cell lung cancer (SCLC) is an aggressive, treatment-resistant lung cancer subtype. It tends to progress rapidly and, despite responding well to initial treatment, often develops resistance, recurs, and progresses. Over the past 10 years, although various targeted drugs and immunotherapies have entered use for many lung cancer subtypes, only a few new treatments have been approved for small cell lung cancer: adding immunotherapy to first-line systemic chemotherapy. This difficult situation demands research into more effective treatments. Antibody-drug conjugates are emerging in this context.

A New Player on the Scene

The antibody-drug conjugate ifinatamab deruxtecan has shown “strong and durable efficacy” in small cell lung cancer patients who have received multiple prior treatments. Developed by Japan's Daiichi Sankyo biotechnology company, it has not yet received FDA (Food and Drug Administration in the United States) approval for any cancer. However, it is being tested in human clinical trials for various cancers, particularly SCLC.

A Distinctive Feature of Cancer Cells as a Target

B7 homolog 3 (B7-H3) is an immune-regulatory protein on the cell membrane that is overexpressed in many tumor types, including SCLC. Approximately two-thirds of SCLC patients show moderate to high B7-H3 expression, which is associated with disease progression and shorter survival. Ifinatamab deruxtecan (I-DXd) is a new B7-H3-targeting antibody-drug conjugate using clinically validated deruxtecan technology. It combines a B7-H3-binding antibody with a potent topoisomerase I inhibitor chemotherapy payload, potentially increasing selective tumor-cell death while reducing systemic exposure to the payload.

A Study Presented at the 2023 World Conference on Lung Cancer

Dr. Melissa L. Johnson presented these findings at the 2023 World Conference on Lung Cancer as a subgroup analysis of the DS7300-A-J101 trial.

Dr. Johnson and colleagues conducted the phase I/II DS7300-A-J101 trial of I-DXd in 205 patients with advanced solid tumors (arising in tissues and organs) who had received multiple prior lines of treatment.

At the conference, Dr. Johnson presented results for the SCLC subgroup from part 1 of the study. The analysis included 22 patients, not selected for B7-H3 expression, treated with I-DXd at doses ranging from 4.8 to 16 mg/kg. The efficacy analysis included 21 patients receiving ≥ 6.4 mg/kg, with a median follow-up of 11.7 months. The 22 patients had received a median of two prior treatment lines, mainly platinum-based chemotherapy and immunotherapy.

Key Findings

• Confirmed objective responses occurred in 52.4% of patients, including complete responses in 4.8%.
• Median progression-free survival was 5.8 months, and median overall survival was 12.2 months.

Two patients were reported to remain on treatment.

All 17 patients evaluable for B7-H3 expression showed moderate to high expression. Researchers reported no trend between B7-H3 levels and best overall response, progression-free survival, or overall survival.

I-DXd had tolerable, manageable toxicity. Grade 3 or higher treatment-related side effects occurred in 36.4% of patients, and one death was attributed to treatment. Five patients discontinued because of treatment-related side effects, with one case each of interstitial lung disease, pneumonia, cardiac failure, embolism, and COVID-19 pneumonia. Nausea was the most common treatment-related side effect... Preventive treatment for nausea and vomiting was not permitted early in the trial, but antiemetic prophylaxis is now used in all I-DXd studies.

A phase II trial of I-DXd as second- or third-line treatment for advanced SCLC is currently ongoing.

Commentary

Other antibody-drug conjugate targets (DLL3, CD56, and TROP-2) have previously been tested in SCLC, but did not show efficacy as meaningful as B7-H3-targeting I-DXd and caused more side effects.

In this study, however, we saw preliminary subgroup findings with ifinatamab deruxtecan (I-DXd), an antibody-drug conjugate against B7-H3, an interesting new target overexpressed in SCLC and several other solid tumors. Despite the small numbers and preliminary data, objective responses occurred in more than half of patients and, importantly, responses were durable.

It is important to note that these patients had heavily pretreated, resistant SCLC. Median progression-free survival of 5.6 months and median overall survival exceeding one year are therefore very promising.