Bispecific Antibody Active in Relapsed/Refractory Small Cell Lung Cancer

A first-in-class bispecific antibody achieved durable responses in a fourth of patients with advanced small cell lung cancer (SCLC) and disease control in more than half, a preliminary clinical trial showed.

Tarlatamab, targeting delta-like ligand 3 (DLL3) and CD3, resulted in an objective response rate of 23.4% and a disease control rate (DCR) of 51.4% in 107 patients with relapsed/refractory SCLC, half of whom had already received a PD-1/L1 inhibitor. Median duration of response was 12.3 months.

Grade ≥3 treatment-related adverse events (TRAEs) occurred in almost a third of patients, and a majority had cytokine release syndrome (CRS), which was grade 1/2 in all but one case, reported Luis Paz-Ares, MD, of Hospital Universitario 12 de Octubre in Madrid, and co-authors, in the Journal of Clinical Oncology.

“With over 100 patients treated in the phase I study, tarlatamab has shown tolerability and remarkable antitumor activity over a wide range of target doses in patients with heavily pretreated small-cell lung cancer,” the authors wrote of their findings. “A promising response rate, high median duration of response, and encouraging median overall survival, along with a reasonable safety profile, observed in this study form the basis for planned and ongoing later-stage studies.”

Emphasizing the preliminary nature of the findings and the focus on safety and tolerability, co-author Hossein Borghaei, DO, of Fox Chase Cancer Center in Philadelphia, agreed that the results are encouraging.

“I think the findings are interesting and offer some hope that this drug can in fact be active in patients with small cell lung cancer,” Borghaei told MedPage Today via email. “I am clearly biased since I have been involved in the trial from the beginning and we have treated many patients on this protocol at our institution.”

“The drug does have some serious side effects that need to be considered and discussed with patients carefully,” he said. “From an activity point of view, the responses and durability of responses have been promising and encouraging. Additional studies are needed to establish the activity of this drug in different patient populations with advanced, metastatic small cell lung cancer.”

Biomarker analysis data are too preliminary to know whether the drug’s activity might be limited to DLL3-expressing tumors or to the broader population of patients with SCLC, he added. Similarly, more work is needed to determine whether targeting DLL3 has applicability to other types of cancer.

Advanced SCLC has few treatment options, particularly in the relapsed/refractory setting. Topotecan is used most often in second line but has an unfavorable safety profile, Paz-Ares and co-authors noted. Lurbinectedin (Zepzelca) received conditional approval for second-line treatment of SCLC on the basis of response data, but a randomized trial subsequently showed no survival benefit. Currently, no therapy has an approved third-line indication for these patients.

The Notch signaling pathway regulates neuroendocrine differentiation in SCLC. Inhibitory DLL3 is aberrantly expressed on the surface of as many as 85% of SCLC cells but not normal cells, making it an attractive therapeutic target, the authors continued. Laboratory studies suggest that DLL3 plays a role in tumor growth, migration, and invasion.

The DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine demonstrated preliminary activity against SCLC in a phase I trial. A bispecific T-cell engager, tarlatamab binds DLL3 on cancer cells and CD3 on T cells to induce T cell-mediated tumor lysis. The drug promoted tumor regression in preclinical models of SCLC, leading to a first-in-human clinical trial.

Investigators in the multinational, open-label, dose-escalation phase I DeLLphi-300 trial enrolled patients with SCLC that had progressed or recurred after at least one previous platinum-containing regimen and, if standard of care, a PD-1/L1 inhibitor in addition to chemotherapy. Dose escalation ranged from 0.003 to 100 mg Q2W. Treatment continued until disease progression or unacceptable toxicity.

The primary endpoint was a composite of safety-related outcomes. Antitumor activity, including response, progression-free survival (PFS), and overall survival (OS), was a secondary objective.

The patient population had a median treatment history of two prior lines of therapy, and 49.5% of the patients had received a PD-1/L1 inhibitor. The safety analysis showed that 97 patients (90.7%) had at least one TRAE, and 33 (30.8%) had grade ≥3 TRAEs, including one fatal case of pneumonitis. CRS occurred in 56 patients (52%) and was grade 3 severity in one patient. The maximum tolerated dose was not reached.

Antitumor activity included two complete responses and 23 partial responses, and an additional 30 patients had stable disease. The data showed that 39 patients had tumor shrinkage of at least 30%. The longest response duration was 14.9 months. Median PFS was 3.7 months and median OS was 13.2 months.