IMDELLTRA® Plus IMFINZI® Shows Landmark Overall Survival Benefit in First-Line Extensive-Stage Small Cell Lung Cancer
Amgen (NASDAQ: AMGN) announced landmark results from the Phase 3 DeLLphi-305 study, reporting that the trial met its primary endpoint at a pre-specified interim analysis and demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) for IMDELLTRA® (tarlatamab-dlle) combined with AstraZeneca’s Imfinzi® (durvalumab), compared with durvalumab alone.
The findings could represent an important development in the treatment of extensive-stage small cell lung cancer (ES-SCLC), one of the most aggressive forms of lung cancer and a disease in which long-term survival remains challenging despite advances in first-line treatment.
DeLLphi-305 evaluated IMDELLTRA as a first-line maintenance treatment in adults with ES-SCLC whose disease had not progressed following initial therapy with durvalumab, platinum-based chemotherapy and etoposide. In addition to demonstrating a significant overall survival benefit, the study showed statistically significant and clinically meaningful improvements in progression-free survival (PFS) and objective response rate (ORR) among patients receiving the combination of IMDELLTRA and durvalumab.
Amgen said the safety profile of IMDELLTRA combined with durvalumab was consistent with the known safety profiles of the individual medicines, with no new or unexpected safety signals identified in the study.
DeLLphi-305 Meets Primary Endpoint
The primary endpoint of DeLLphi-305 was overall survival, an important measure in ES-SCLC given the aggressive nature of the disease and the limited durability of existing treatment approaches.
At a pre-specified interim analysis, the study demonstrated that patients treated with IMDELLTRA in combination with durvalumab experienced a statistically significant and clinically meaningful improvement in overall survival compared with those receiving durvalumab alone.
The study also met key secondary efficacy measures, showing statistically significant and clinically meaningful improvements in progression-free survival and objective response rate.
These results suggest that the addition of IMDELLTRA to maintenance durvalumab may provide benefits across multiple measures of disease control, rather than affecting only one aspect of treatment outcome.
Amgen described the findings as landmark results, particularly because DeLLphi-305 represents the first Phase 3 study involving a Bispecific T-cell Engager (BiTE®) therapy to demonstrate an overall survival benefit in the first-line maintenance setting for ES-SCLC.
The company plans to present detailed DeLLphi-305 data at an upcoming international medical congress and share the findings with regulatory authorities.
Potential Shift in First-Line Maintenance Treatment
Jay Bradner, M.D., executive vice president, Research and Development, Artificial Intelligence and Data at Amgen, said the results could extend the role of IMDELLTRA beyond its current treatment setting.
“IMDELLTRA has already revolutionized the standard of survival for patients with extensive stage small cell lung cancer whose disease progressed on or after prior treatment,” Bradner said.
He added that the DeLLphi-305 findings suggest IMDELLTRA could potentially further change the survival standard by moving treatment earlier in the disease journey.
Bradner also emphasized the aggressive nature of ES-SCLC and the difficulty of achieving substantial improvements in survival in this patient population.
“Despite clinical advances, extensive stage small cell lung cancer remains one of the most aggressive and difficult-to-treat cancers, and substantial improvements in survival are rare,” he said, underscoring the significance of the DeLLphi-305 results.
Importance of Earlier Intervention in ES-SCLC
The timing of the DeLLphi-305 study is particularly important because many patients with ES-SCLC experience disease progression relatively quickly following initial treatment.
Although first-line treatment can provide disease control, the aggressive biology of SCLC means that many patients eventually relapse. A substantial proportion of patients may also never receive second-line treatment because their disease progresses rapidly or their health deteriorates before another treatment can be initiated.
Jacob Sands, MD, associate chief of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, highlighted this challenge.
“Given the aggressive nature of small cell lung cancer, many patients quickly relapse on current therapy and never reach second-line treatment,” Sands said. “These patients do not have time to wait, making substantial progress in the first-line setting critically important.”
He described the DeLLphi-305 survival findings as among the most compelling results he has seen during his career treating people with ES-SCLC.
According to Sands, the results could potentially reshape the natural history of the disease and represent an important milestone for patients and physicians.
IMDELLTRA and Imfinzi Combination
The DeLLphi-305 regimen combines two different therapeutic approaches.
IMDELLTRA, or tarlatamab-dlle, is a BiTE immunotherapy designed to engage T cells and direct them toward cancer cells. Imfinzi, or durvalumab, is an immune checkpoint inhibitor targeting PD-L1.
The combination is being investigated as a strategy to enhance immune-mediated control of ES-SCLC following initial treatment.
In DeLLphi-305, patients first received treatment with durvalumab, platinum-based chemotherapy and etoposide. Those whose disease had not progressed then entered the maintenance setting, where IMDELLTRA was evaluated in combination with durvalumab.
This approach is designed to intervene at an earlier stage of the treatment journey rather than waiting until the cancer has already progressed.
Amgen said the results build on earlier findings from the DeLLphi clinical development program, including the Phase 2 DeLLphi-303 trial.
Building on DeLLphi-303 Findings
The DeLLphi-305 study builds on the results of DeLLphi-303, which generated encouraging efficacy and tolerability findings for IMDELLTRA in combination with anti-PD-L1 checkpoint inhibitors in first-line ES-SCLC.
The earlier findings provided a rationale for evaluating the combination in a larger Phase 3 study and potentially moving IMDELLTRA into an earlier stage of treatment.
DeLLphi-305 was specifically designed to investigate whether introducing IMDELLTRA during first-line maintenance could improve outcomes for a broader group of patients with ES-SCLC.
This strategy is important because the number of patients who remain well enough to receive second-line therapy can be limited. Moving an effective treatment into first-line maintenance could therefore potentially allow more patients to receive it.
The positive DeLLphi-305 results provide clinical evidence supporting that development strategy.
Safety Profile Remains Consistent
Alongside the efficacy findings, Amgen reported that the safety profile of IMDELLTRA in combination with durvalumab was consistent with the known safety profiles of the individual medicines.
No new or unexpected safety signals were identified in DeLLphi-305.
The study included specific monitoring requirements following administration of IMDELLTRA. Patients were monitored in a healthcare setting for one to two hours following IMDELLTRA infusion on Cycle 1 Day 1 and Cycle 1 Day 8. In certain regions, including Europe, monitoring lasted six to eight hours.
The monitoring approach reflects the clinical considerations associated with administering IMDELLTRA and is an important component of the treatment program as the medicine is investigated across different lines of therapy.
Additional safety details are expected to be provided when the complete DeLLphi-305 findings are presented at a future international medical congress.
Significant Unmet Need in Small Cell Lung Cancer
Small cell lung cancer accounts for approximately 13% to 15% of more than 2.6 million lung cancer cases diagnosed globally each year.
Despite representing a smaller proportion of overall lung cancer cases than non-small cell lung cancer, SCLC is characterized by rapid growth and early spread. These characteristics make disease control and durable survival particularly difficult to achieve.
ES-SCLC represents an advanced form of the disease in which the cancer has spread extensively and is generally not considered amenable to localized treatment approaches.
While treatment advances have improved outcomes for some patients, the prognosis remains poor. Amgen cited a median survival of approximately one year from the beginning of first-line maintenance treatment and reported that only around 40% of patients receive second-line therapy.
These figures highlight the importance of improving treatment outcomes before disease progression occurs.
First Phase 3 BiTE Study to Show Overall Survival Benefit in First-Line Maintenance
One of the most notable aspects of the DeLLphi-305 findings is the significance of the result for the BiTE therapy class.
According to Amgen, DeLLphi-305 is the first Phase 3 study involving a BiTE therapy to demonstrate an overall survival benefit in the first-line maintenance setting for ES-SCLC.
The achievement could have broader implications for the development of T-cell-engaging therapies in aggressive cancers.
By demonstrating improvements in overall survival, progression-free survival and objective response rate, the study provides evidence across multiple efficacy measures and strengthens the rationale for continued investigation of IMDELLTRA earlier in the ES-SCLC treatment pathway.
Expanding the DeLLphi Clinical Development Program
The DeLLphi program represents Amgen’s broader effort to evaluate IMDELLTRA across different stages and lines of treatment in small cell lung cancer.
Following FDA approval of IMDELLTRA for adults with ES-SCLC whose disease has progressed on or after platinum-based chemotherapy, the company has continued investigating the therapy in earlier disease settings and combination regimens.
The program includes evaluations of IMDELLTRA as a monotherapy as well as in combination with other treatments.
DeLLphi-305 represents an important step in this strategy by moving the therapy into first-line maintenance after patients have completed initial chemoimmunotherapy without disease progression.
The positive results could support future regulatory discussions regarding this earlier treatment setting.
Next Steps for IMDELLTRA
Amgen will now prepare to present detailed DeLLphi-305 findings at an upcoming international medical congress. The company also plans to share the data with regulatory authorities.
Additional information from the full dataset will be important for understanding the magnitude of the overall survival benefit, progression-free survival results, response rates and detailed safety findings.
The results announced by Amgen establish that the Phase 3 study achieved its primary endpoint at the pre-specified interim analysis, while also demonstrating meaningful improvements in key secondary efficacy outcomes.
For patients with ES-SCLC, the findings could represent an important advance because improving outcomes in the first-line maintenance setting may give more patients an opportunity to benefit before their disease progresses.
With ES-SCLC remaining one of the most aggressive and difficult-to-treat cancers, the DeLLphi-305 results add potentially significant evidence to the evolving treatment landscape. Amgen’s planned presentation of the complete findings and discussions with regulatory authorities will determine the next steps for IMDELLTRA in this earlier stage of disease.
If the findings are confirmed through regulatory review and subsequent clinical development, the combination of IMDELLTRA and durvalumab could potentially establish a new approach to first-line maintenance treatment for people living with extensive-stage small cell lung cancer.
About the Phase 3 DeLLphi-305 Study
The DeLLphi-305 trial is sponsored by Amgen, with partial funding and durvalumab provided by AstraZeneca. It is a global Phase 3, randomized, open-label clinical trial evaluating the efficacy and safety of IMDELLTRA in combination with durvalumab compared to durvalumab alone as first-line maintenance treatment for patients with ES-SCLC who had not progressed following treatment with durvalumab, platinum-based chemotherapy and etoposide.
Five hundred and sixty-three patients who completed initial treatment with durvalumab, platinum-based chemotherapy and etoposide were randomized 1:1 to receive either IMDELLTRA in combination with durvalumab or durvalumab alone until progression or unacceptable toxicity. Following IMDELLTRA infusion on Cycle 1 Day 1 and Cycle 1 Day 8, patients were monitored in a healthcare setting for 1 to 2 hours (6 to 8 hours in certain regions including Europe).
The trial included patients with both treated and untreated asymptomatic brain metastases at baseline. The primary outcome measure of the trial is OS. Secondary endpoints include progression-free survival (PFS) and objective response rate (ORR).8
About Tarlatamab Clinical Trials
Tarlatamab is being investigated in multiple studies including DeLLphi-303, a Phase 1b study investigating tarlatamab in combination with standard-of-care (SOC) therapies in first-line ES-SCLC; DeLLphi-304, a randomized Phase 3 study comparing tarlatamab monotherapy with SOC chemotherapy in second-line treatment of SCLC; DeLLphi-305, a randomized Phase 3 study comparing tarlatamab in combination with durvalumab vs.
durvalumab alone as first-line maintenance treatment in ES-SCLC; DeLLphi-306, a randomized placebo-controlled Phase 3 study of tarlatamab following concurrent chemoradiotherapy in limited-stage SCLC; DeLLphi-308, a Phase 1b study evaluating subcutaneous tarlatamab in second-line or later ES-SCLC; DeLLphi-309, a Phase 2 study evaluating alternative intravenous dosing regimens with tarlatamab in second-line ES-SCLC; DeLLphi-310, a Phase 1b study of tarlatamab in combination with YL201 with or without durvalumab in patients with ES-SCLC; DeLLphi-311,
a Phase 1b study of tarlatamab in combination with etakafusp alfa (AB248), a novel CD8+ T-cell selective interleukin-2 (IL-2), in patients with ES-SCLC; DeLLphi-312, a randomized Phase 3 study evaluating tarlatamab in combination with durvalumab, carboplatin and etoposide as an induction and maintenance therapy in first-line treatment of ES-SCLC; DeLLphi-313, a Phase 1b study of tarlatamab in combination with zocilurtatug pelitecan, a DLL3 targeting antibody drug conjugate, with and without durvalumab in patients with ES-SCLC, and DeLLphi-315, a Phase 3 study of subcutaneous tarlatamab in patients with second-line ES-SCLC.9
For more information, please visit www.tarlatamabclinicaltrials.com.
About IMDELLTRA® (tarlatamab-dlle)
IMDELLTRA is a first-in-class targeted immunotherapy engineered by Amgen researchers to bind to both DLL3 on tumor cells and CD3 on T cells, thereby activating T cells to kill DLL3-expressing SCLC cells. This results in the formation of a cytolytic synapse with lysis of the cancer cell.10,11 DLL3 is a protein that is expressed on the surface of SCLC cells in ~85-96% of patients with SCLC, but is minimally expressed on healthy cells, making it an exciting target.