Overall survival (OS) in extensive-stage small-cell lung cancer (ES-SCLC) approached 2 years with tarlatamab (Imdelltra) combination maintenance therapy after first-line chemoimmunotherapy, a large randomized trial showed.
Median OS increased from 12.7 months with single-agent durvalumab (Imfinzi) maintenance to 21 months with the addition of the bispecific T-cell engager tarlatamab. Median PFS improved from 1.9 months with durvalumab alone to 7.4 months with the combination. The OS and PFS benefits were consistent across all prespecified subgroups. Half of all patients who had objective responses with the combination remained in response for a year or longer.
Treatment-related adverse events (TRAEs), including grade ≥3 TRAEs, occurred more often with the combination maintenance therapy, but a similar proportion of patients discontinued treatment because of TRAEs, reported Jacob Sands, MD, of Dana-Farber Cancer Institute in Boston, at the European Society for Medical Oncology (ESMO) congress in Madrid.
“The DeLLphi-305 trial has demonstrated unprecedented outcomes in both median overall survival and median progression-free survival, along with durability for a substantial subset of patients, all with a toxicity profile that appears manageable,” said Sands. “With all of this together, this highlights DeLLphi-305 with tarlatamab and durvalumab in the maintenance setting as a new standard of care in the treatment of extensive-stage small-cell lung cancer.”
At the conclusion of the talk, the ESMO audience responded with a standing ovation and cheering that lasted almost a minute. The study was reported simultaneously in the New England Journal of Medicine.
ESMO invited discussant Stephen Liu, MD, of the Georgetown Lombardi Comprehensive Cancer Center in Washington, followed with a superlative-infused assessment of the findings and their implications.
“What we’ve just seen represents a remarkable improvement in survival for patients with small-cell lung cancer,” said Liu. “Small cell has been an exceptionally lethal subtype of lung cancer, characterized by robust initial responses to chemotherapy, followed by rapid, predictable relapse.”
“What DeLLphi-305 teaches us is that maintenance tarlatamab fundamentally changes the outcome for small-cell lung cancer,” he added. “That earlier delivery of tarlatamab profoundly improves survival in a setting where tarlatamab delivery is safer and requires less intense monitoring…These data do more than show us a better way to treat patients with small-cell lung cancer. They provide our patients with real, credible hope in a disease where hope has been in short supply.”
Results of the phase III DeLLphi-305 trial essentially replicated those of the phase I DeLLphi-303 trial reported barely a month ago at the World Lung Cancer Conference. Involving 88 patients with ES-SCLC, the DeLLphi-303 trial showed a median OS of 25 months, 12-month OS of 82%, and 18-month OS of 75% in patients who received tarlatamab and atezolizumab (Tecentriq), following first-line chemoimmunotherapy. Those results compared with a historical OS of 12-13 months in ES-SCLC treated with first-line chemoimmunotherapy, said Sands.
The multinational DeLLphi-305 trial involved 563 patients with newly diagnosed ES-SCLC. All patients received induction therapy consisting of platinum-etoposide chemotherapy plus the PD-L1 inhibitor durvalumab. Investigators then randomized patients to maintenance treatment with durvalumab alone or in combination with tarlatamab. The primary endpoint was OS.
The study population had a median age of 65, and men accounted for about 70% of all the patients. A majority of the patients identified as white, and 90% were current or former smokers.
After a median follow-up of about 16 months, the tarlatamab group had a 58% lower OS hazard (95% CI 0.32-0.54, P<0.001). The 12-month OS was 79% in the combination arm and 53% in the single-agent durvalumab group. With a 14-month median follow-up for PFS, the combination arm had a 66% lower hazard (95% CI 0.28-0.42, P<0.001). The OS and PFS advantages for the tarlatamab arm persisted across all prespecified subgroups.
Objective response rates were 26.4% with the combination and 4.1% with single-agent durvalumab (P<0.001), and median duration of response was 12.7 months with tarlatamab-durvalumab and 5.6 months with single-agent durvalumab.
Liu said identification and clinical application of biomarkers for patient selection will be a key issue moving forward.
“As of today, there should be no selection criteria for tarlatamab, and I struggle to find a group where this regimen would not be the preferred regimen,” he said. “However, I believe it is very important that we have a deep mechanistic understanding of the drugs we develop. It is not enough to know if the drugs work or how well they work. We need to know why they work, so that we can make better decisions for the patients in front of us, but also so we can apply these data as the disease changes. And small-cell lung cancer is changing.”
