Tarlatamab Shows Promise in SCLC

A novel compound targeting a tumor-specific surface protein may offer hope to patients with small cell lung cancer (SCLC) whose disease has advanced despite receiving prior therapies (N Engl J Med 2023 Oct 20 [Epub ahead of print]).

That's encouraging news, said Luis Paz-Ares, MD, PhD, of Hospital Universitario 12 de Octubre in Madrid, Spain, because SCLC is an “aggressive disease with poor survival outcomes,” with no treatments approved for use if two standard regimens don't work. He presented the study's results at the 2023 ESMO Congress, held October 20–24 in Madrid.

Tarlatamab (Amgen) is an investigational bispecific T-cell engager (BiTE) that targets delta-like ligand 3 (DLL3), which is expressed on the surface of up to 94% of SCLC cells—with minimal expression on normal cells. Typical overall survival (OS) for patients is rarely longer than 8 months after receiving a second therapy, but in a phase I trial, tarlatamab showed promising activity, with a median duration of response of 12.3 months. This prompted the launch of DeLLphi-301.

This trial involved 196 patients with extensive-stage SCLC who had already received a median of two therapies, including platinum-based chemotherapy. They were randomly assigned to receive either 10 mg or 100 mg of tarlatamab every 2 weeks until the disease progressed. Twelve additional patients were subsequently enrolled in the trial's dose-expansion phase at the 10-mg dose.

The overall objective response rate was 40% with the 10-mg dose and 32% with the 100-mg dose, with the median duration of response not reached in either arm. At data cutoff, 56% of responses were ongoing.

Median progression-free survival was 4.9 months in patients who received 10 mg of tarlatamab and 3.9 months in those who received 100 mg. Median OS was 14.3 months with the lower dose and not estimable with 100 mg. Paz-Ares cautioned the OS data are “not yet mature.”

Overall, 29% of patients who received the lower dose experienced a grade 3 or higher treatment-related adverse event, leading to dose interruption or reduction in 14%. Rates with the higher dose were 33% and 29%, respectively.

Cytokine release syndrome (CRS) was common, generally occurring with the first or second dose of the BiTE. It affected 49% of patients in the 10-mg arm, but all cases were grade 1 or 2 and were manageable. However, with the higher dose, grade 3 or higher CRS was seen in 6% of patients, and grade 1 or 2 CRS affected 55% of patients.

Ten milligrams of tarlatamab showed “durable anticancer activity and manageable safety,” concluded Paz-Ares, who noted that the efficacy and safety of the dose will be compared with standard-of-care chemotherapy in the DeLLphi-304 trial. DeLLphi-301 did not have a control arm.

Discussant Pilar Garrido, MD, PhD, of Ramón y Cajal University Hospital in Madrid, agreed, saying that the low dose of tarlatamab showed “encouraging results in a highly selected population,” with “manageable safety in a setting of huge clinical need.”

However, she questioned whether the study represented the real-world population: The median age of patients in the study was low—64 years—but overall, nearly half of patients with SCLC are at least 70 years old.

Garrido also noted that patients needed to stay in the hospital for 48 hours for monitoring when receiving tarlatamab infusions, but a subsequent 34-patient substudy did find that the hospital stay can be shortened to 24 hours without compromising safety. Still, “this is challenging for us because of the organizational impact but also thinking about the inconvenience for our patients,” Garrido said, “so it's important to find another way” to deliver the drug.

Another potentially significant stumbling block is the generally limited experience of clinicians in managing CRS.

Other limitations were the short follow-up period and the lack of predictive biomarkers, Garrido said, as well as a lack of data on the drug's activity in the brain. –Liam Davenport

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