Tag: Lung Cancer: Small Cell

SUMMARY: The FDA on October 2, 2025, approved Lurbinectedin (ZEPZELCA®)  in combination with Atezolizumab (TECENTRIQ®) or Atezolizumab and hyaluronidase-tqjs (TECENTRIQ HYBREZA®), for the maintenance treatment of adult patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with Atezolizumab or Atezolizumab and hyaluronidase-tqjs, Carboplatin, and Etoposide.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. While initial responses to chemotherapy are often dramatic, relapse occurs in most patients, and recurrent disease typically demonstrates resistance to previously effective regimens. Consequently, extending response durability through maintenance therapy remains a key therapeutic goal.

Lurbinectedin is a selective alkylating agent that binds to guanine residues within DNA, leading to inhibition of oncogenic transcription factors and impairment of DNA repair pathways. This disrupts the cell cycle and induces tumor cell death.
Atezolizumab is a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), blocking its interaction with PD-1 and B7.1 receptors. By inhibiting PD-L1–mediated immune evasion, Atezolizumab restores anti-tumor T-cell activity and enhances immune-mediated tumor elimination.

The IMforte Trial: Study Design

The IMforte Trial is a global, open-label, randomized Phase III study (NCT05091567) conducted to evaluate the efficacy and safety of Lurbinectedin plus Atezolizumab as first-line maintenance therapy for adults with Extensive-Stage SCLC (ES-SCLC). In this study, a total of 660 treatment-naïve patients received induction therapy with Atezolizumab, Carboplatin, and Etoposide for four 21-day cycles. Of these, 483 patients without disease progression were randomized 1:1 to receive either:

• Lurbinectedin 3.2 mg/m² IV every 3 weeks with G-CSF prophylaxis plus Atezolizumab 1200 mg IV every 3 weeks, or
• Atezolizumab alone 1200 mg IV every 3 weeks

Treatment was continued until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included baseline liver metastases, ECOG performance status, LDH levels, and receipt of prophylactic cranial irradiation. The Primary endpoints were Independent Review Facility (IRF)–assessed Progression-Free Survival (PFS) and Overall Survival (OS) from the start of maintenance therapy.

Efficacy Outcomes

After a median follow-up of 15 months, the IMforte study achieved both of its Primary endpoints:

• Median PFS: 5.4 months with Lurbinectedin plus Atezolizumab vs 2.1 months with Atezolizumab alone (HR=0.54; 95% CI: 0.43–0.67; P<0.0001)
• Median OS: 13.2 months vs 10.6 months, respectively (HR=0.73; 95% CI: 0.57–0.95; P=0.0174)

These outcomes reflect a 46% reduction in the risk of disease progression or death and a 27% reduction in the risk of death with the combination regimen. Median maintenance treatment duration was 4.1 months for the combination arm and 2.1 months for the monotherapy arm.

Safety and Tolerability

The combination of Lurbinectedin and Atezolizumab demonstrated a manageable safety profile with no new safety signals.

• Any-grade treatment-related adverse events (TRAEs):5% (combo) vs 40.0% (monotherapy)
• Grade 3–4 TRAEs: 25.6% vs 5.8%
• Grade 5 TRAEs: 0.8% vs 0.4%

The most common adverse reactions (≥30%) were lymphopenia, thrombocytopenia, anemia, leukopenia, neutropenia, nausea, and fatigue/asthenia. Discontinuations due to adverse events occurred in 6.2% and 3.3% of patients, respectively.

Clinical Interpretation

IMforte is the first global Phase III study to demonstrate significant improvement in both PFS and OS with a first-line maintenance approach in ES-SCLC. By integrating the DNA-damaging activity of Lurbinectedin with the immune reactivation potential of PD-L1 blockade, the combination offers a dual mechanism to counter both tumor proliferation and immune evasion. These results establish Lurbinectedin plus Atezolizumab as a new standard maintenance option for patients whose disease remains controlled after induction chemoimmunotherapy, an important milestone in a disease where long-term survival has historically been rare.

Key Takeaways for Oncology Practice

• Unmet Need: SCLC remains an aggressive malignancy with limited long-term treatment options.
• Clinical Significance: IMforte is the first Phase III trial to demonstrate both OS and PFS gains with a first-line maintenance regimen in ES-SCLC.
• Mechanistic Synergy: Combines DNA-targeted cytotoxic activity (Lurbinectedin) with PD-L1 blockade (Atezolizumab) for enhanced and durable tumor control.
• Practice Impact: Establishes Lurbinectedin plus Atezolizumab as an FDA-approved maintenance option for patients with ES-SCLC who respond to induction chemoimmunotherapy.
• Safety: Manageable toxicity profile; regular hematologic and clinical monitoring recommended.

Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Paz-Ares L, Borghaei H, Liu SV, et al. The Lancet 2025;405:2129-2143.

SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Nearly all patients with SCLC experience disease recurrence during or after standard platinum-based chemotherapy, underscoring the need for novel treatment strategies Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-Like Protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab (IMDELLTRA®) is a first-in-class bispecific T-cell engager immunotherapy that directs the patients T cells to cancer cells expressing Delta-Like Ligand 3 (DLL3), independent of Major Histocompatibility Complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

In May 2024, the U.S. FDA granted accelerated approval to Tarlatamab for adult patients with extensive-stage SCLC whose disease progressed after platinum-based chemotherapy. This decision was based largely on early clinical benefit observed in the Phase 2 DeLLphi-301 trial, where Tarlatamab demonstrated a 40% Overall Response Rate (ORR) in previously treated patients. Now, confirmatory results from the Phase 3 DeLLphi-304 trial further support the role of Tarlatamab in the treatment landscape, and mark a potential new standard of care for recurrent SCLC.

Phase 3 DeLLphi-304: Study Design and Population
DeLLphi-304 was a global, randomized, open-label trial comparing Tarlatamab, with standard-of-care chemotherapy which included Topotecan, Lurbinectedin, or Amrubicin, in patients with extensive-stage SCLC, whose disease progressed after platinum-based chemotherapy. A total of 509 patients were randomized 1:1 to receive either Tarlatamab (N=254) or chemotherapy (N=255). The median patient age was 65 yrs, Approximately 45% of randomized patients had current or previous brain metastases, 35% had liver metastases, 71% had received previous therapy with checkpoint inhibitors and 44% had platinum-resistant disease. Stratification factors included prior PD-L1 inhibitor treatment, chemotherapy-free interval, presence of brain metastases, and intended chemotherapy regimen. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Patient-Reported Outcomes (PROs), and Safety.

Tarlatamab Demonstrates Significant Survival Benefit
At a median follow-up of approximately 11 months, Tarlatamab demonstrated a statistically and clinically significant improvement in OS:

• Median OS: 13.6 vs 8.3 months (HR 0.60; 95% CI: 0.47–0.77; P<0.001)
• Median PFS: 4.2 vs 3.2 months (HR 0.72; 95% CI: 0.59–0.88; P<0.001)

This translated to a 40% reduction in the risk of death for patients receiving Tarlatamab. The survival benefit extended across all prespecified subgroups, including age, gender, race, and prior anti–PD-L1 therapy. The ORR was 35% in the Tarlatamab group and 20% in the chemotherapy group.

Improved Symptom Control and Quality of Life
Beyond survival, Tarlatamab provided clinically meaningful improvements in Patient-Reported Outcomes, including relief from hallmark symptoms of SCLC:

• Dyspnea score improved at 18 weeks: –1.94 with Tarlatamab vs +7.20 with CTx (mean difference –9.14; P< 0.001)
• Cough improvement: 16% vs 9% (Odds Ratio 2.04; P = 0.012)
• Chest pain improvement: 9% vs 4% (Odds Ratio 1.84; P = 0.100) – not significant

These findings reflect an overall better patient experience and potential Quality-of-Life benefit with Tarlatamab therapy.

Safety Profile and Tolerability
Tarlatamab was associated with a more favorable safety profile compared to chemotherapy:

• Grade 3 or more Treatment-Related Adverse Events (TRAEs): 27% (Tarlatamab) vs 62% (Chemotherapy)
• Discontinuations due to TRAEs: 3% vs 6%
• Most common Grade 3 or more TRAEs with Tarlatamab were neutropenia (4%) and lymphopenia (4%)
• Cytokine Release Syndrome (CRS) occurred in 56% of patients (mostly grade 1-2) and was manageable in clinical settings

These safety results support Tarlatamab as a more tolerable alternative to conventional chemotherapy.

Looking Ahead: Optimizing Treatment Sequencing
While the DeLLphi-304 trial has established Tarlatamab as an effective option post-platinum therapy, questions remain regarding its integration into the broader SCLC treatment paradigm. PD-L1 inhibitors already form part of standard first-line and maintenance therapy. Early-phase studies have shown that Tarlatamab can be safely combined with anti–PD-L1 agents, and this is being further evaluated in the ongoing DeLLphi-305 trial, a Phase 3 study assessing Tarlatamab plus PD-L1 inhibition as first-line maintenance following chemotherapy. Additionally, biomarker-driven analyses from DeLLphi-304 are underway to help identify patients most likely to benefit from Tarlatamab and those who may achieve durable responses.

Conclusion
The DeLLphi-304 trial positions Tarlatamab as a practice-changing therapy for patients with SCLC that has progressed after platinum-based chemotherapy. With significant improvements in Overall and Progression-Free Survival, better symptom control, and a favorable safety profile, Tarlatamab redefines second-line treatment for a historically underserved patient population. These results not only represent a meaningful advance in SCLC therapy but also signal a broader shift toward targeted immunotherapy strategies in aggressive thoracic malignancies.

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. Mountzios G, Sun L, Cho BC, et al. for the DeLLphi-304 Investigators. N Engl J Med 2025;393:349-361

 

SUMMARY: The FDA on May 16, 2024, granted accelerated approval to IMDELLTRA® (Tarlatamab-dlle) for Extensive Stage-Small Cell Lung Cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 13-15% of all lung cancers. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis. Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab is a first-in-class bispecific T-cell engager immunotherapy that directs the patient’s T cells to cancer cells expressing delta-like ligand 3 (DLL3), independent of major histocompatibility complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

The present FDA approval was based on the efficacy of Tarlatamab in the open-label, global, multicenter, multi-cohort, Phase 2 DeLLphi-301 trial, which included patients with Relapsed/Refractory Extensive Stage Small Cell Lung Cancer with disease progression after platinum-based chemotherapy. In this Phase 2 study, patients received a step dose of Tarlatamab 1 mg IV on day 1 of cycle 1, after which they received the target dose of either 10 mg or 100 mg on day 8 and day 15 of cycle 1 and every 2 weeks thereafter in 28-day cycles (two doses per cycle) until disease progression or unacceptable toxicity. Overall 134 patients received Tarlatamab 10 mg IV, the median age in this group was 64 years and the median duration of treatment in this group was 5.1 months. Positivity for DLL3 expression on tumor cells was not required for trial entry and patients with symptomatic brain metastases, interstitial lung disease or non-infectious pneumonitis, and active immunodeficiency were excluded.

The Primary end point was Objective Response Rate (Complete or Partial Response), as assessed by Blinded Independent Central Review. Secondary end points included Duration of Response, Progression-Free Survival and Overall Survival. Efficacy was evaluated in 99 patients with disease progression enrolled in this study, who received Tarlatamab 10 mg IV, following platinum-based chemotherapy.

The Objective Response Rate was 40% and median Duration of Response was 9.7 months. The researchers noted that this Objective Response Rate far exceeded the historical control benchmark of 15% for the Primary end point. Of the 69 patients with available data regarding platinum sensitivity status, the ORR was 52% in 27 patients with platinum-resistant Small Cell Lung Cancer (defined as progression less than 90 days after last dose of platinum therapy) and 31% in 42 patients with platinum-sensitive Small Cell Lung Cancer (defined as progression 90 or more days after last dose of platinum therapy). The median Overall Survival was 14.3 months, with final and complete survival data still not mature. The most common adverse reactions were Cytokine Release Syndrome (CRS), fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, and constipation, anemia and nausea.

It was concluded that Tarlatamab represents a new immunotherapeutic approach for Small Cell Lung Cancer. It is the first and only DLL3-targeting Bispecific T-cell Engager therapy, establishing itself as an effective and innovative treatment option for patients with previously treated Small Cell Lung Cancer.

Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. Ahn M-J, Cho BC, Felip E, et al. for the DeLLphi-301 Investigators. N Engl J Med 2023;389:2063-2075